Effect of Immediate and Delayed High-Strain Loading on Tendon-to-Bone Healing After Anterior Cruciate Ligament Reconstruction

PubMed Central

Packer, Jonathan D.; Bedi, Asheesh; Fox, Alice J.; Gasinu, Selom; Imhauser, Carl W.; Stasiak, Mark; Deng, Xiang-Hua; Rodeo, Scott A.

2014-01-01

Background: We previously demonstrated, in a rat anterior cruciate ligament (ACL) graft reconstruction model, that the delayed application of low-magnitude-strain loading resulted in improved tendon-to-bone healing compared with that observed after immediate loading and after prolonged immobilization. The purpose of this study was to determine the effect of higher levels of strain loading on tendon-to-bone healing. Methods: ACL reconstruction was carried out in a rat model in three randomly assigned groups: high-strain daily loading beginning on either (1) postoperative day one (immediate-loading group; n = 7) or (2) postoperative day four (delayed-loading group; n = 11) or (3) after prolonged immobilization (immobilized group; n = 8). Animals were killed two weeks after surgery and micro-computed tomography (micro-CT) and biomechanical testing of the bone-tendon-bone complex were carried out. Results: The delayed-loading group had greater tissue mineral density than either the immediate-loading or immobilized group (mean [and standard deviation], 813.0 ± 24.9 mg/mL compared with 778.4 ± 32.6 mg/mL and 784.9 ± 26.4 mg/mL, respectively; p < 0.05). There was a trend toward greater bone volume per total volume fraction in both the immobilized and the delayed-loading group compared with the immediate-loading group (0.24 ± 0.03 and 0.23 ± 0.06 compared with 0.20 ± 0.05; p = 0.06). Trabecular thickness was greater in the immobilized group compared with the immediate-loading group (106.5 ± 23.0 μm compared with 72.6 ± 10.6 μm; p < 0.01). There were no significant differences in failure load or stiffness between the immobilized group and either high-strain cyclic-loading group. Conclusions: Immediate application of high-strain loading appears to have a detrimental effect on healing in this rat model. Any beneficial effects of delayed loading on the healing tendon-bone interface (after a brief period of immobilization) may be offset by the detrimental effects of

The Effects of Platelet-Rich Plasma on Bone Marrow Stromal Cell Transplants for Tendon Healing In Vitro

PubMed Central

Morizaki, Yutaka; Zhao, Chunfeng; An, Kai-Nan; Amadio, Peter C.

2010-01-01

Purpose In this study we investigated the effect of platelet-rich plasma (PRP) and bone-marrow derived stromal cell (BMSC)-seeded interposition in an in vitro canine tendon repair model. Methods Bone marrow, peripheral blood, and tendons were harvested from mixed breed dogs. BMSC were cultured and passaged from adherent cells of bone marrow suspension. PRP was purified from peripheral blood using a commercial kit. 192 flexor digitorum profundus tendons were used for the study. Tendons repaired with a simple suture were used as a control group. In treatment groups, a collagen gel patch was interposed at the tendon repair site prior to suture. There were three treatment groups according to the type of collagen patch; a patch with PRP, a patch with BMSC, and a patch with PRP and BMSC. The repaired tendons were evaluated by biomechanical testing and by histological survey after 2 and 4 weeks in tissue culture. To evaluate viability, cells were labeled with PKH26 and surveyed under confocal microscopy after culture. Results The maximum breaking strength and stiffness of the healing tendons with the BMSC-seeded PRP patch was significantly higher than the healing tendons without a patch or with a cell-seeded patch (p<0.02). Viable BMSC were present at both 2 and 4 weeks. Conclusions PRP enhanced the effect of BMSC-seeded collagen gel interposition in this in vitro model. Based on these results we now plan to investigate this effect in vivo. PMID:20951509

Tissue Engineering Strategies for the Tendon/ligament-to-bone insertion

PubMed Central

Smith, Lester; Xia, Younan; Galatz, Leesa M.; Genin, Guy M.; Thomopoulos, Stavros

2012-01-01

Injuries to connective tissues are painful and disabling and result in costly medical expenses. These injuries often require re-attachment of an unmineralized connective tissue to bone. The uninjured tendon/ligament-to-bone insertion (enthesis) is a functionally graded material that exhibits a gradual transition from soft tissue (i.e., tendon or ligament) to hard tissue (i.e., mineralized bone) through a fibrocartilaginous transition region. This transition is believed to facilitate force transmission between the two dissimilar tissues by ameliorating potentially damaging interfacial stress concentrations. The transition region is impaired or lost upon tendon/ligament injury and is not regenerated following surgical repair or natural healing, exposing the tissue to risk of re-injury. The need to regenerate a robust tendon-to-bone insertion has led a number of tissue engineering repair strategies. This review treats the tendon-to-bone insertion site as a tissue structure whose primary role is mechanical and discusses current and emerging strategies for engineering the tendon/ligament-to-bone insertion in this context. The focus lies on strategies for producing mechanical structures that can guide and subsequently sustain a graded tissue structure and the associated cell populations. PMID:22185608

Tissue-engineering strategies for the tendon/ligament-to-bone insertion.

PubMed

Smith, Lester; Xia, Younan; Galatz, Leesa M; Genin, Guy M; Thomopoulos, Stavros

2012-01-01

Injuries to connective tissues are painful and disabling and result in costly medical expenses. These injuries often require reattachment of an unmineralized connective tissue to bone. The uninjured tendon/ligament-to-bone insertion (enthesis) is a functionally graded material that exhibits a gradual transition from soft tissue (i.e., tendon or ligament) to hard tissue (i.e., mineralized bone) through a fibrocartilaginous transition region. This transition is believed to facilitate force transmission between the two dissimilar tissues by ameliorating potentially damaging interfacial stress concentrations. The transition region is impaired or lost upon tendon/ligament injury and is not regenerated following surgical repair or natural healing, exposing the tissue to risk of reinjury. The need to regenerate a robust tendon-to-bone insertion has led a number of tissue engineering repair strategies. This review treats the tendon-to-bone insertion site as a tissue structure whose primary role is mechanical and discusses current and emerging strategies for engineering the tendon/ligament-to-bone insertion in this context. The focus lies on strategies for producing mechanical structures that can guide and subsequently sustain a graded tissue structure and the associated cell populations.

Effect of platelet-rich plasma on tendon-to-bone healing after rotator cuff repair in rats: an in vivo experimental study.

PubMed

Hapa, Onur; Cakıcı, Hüsamettin; Kükner, Aysel; Aygün, Hayati; Sarkalan, Nazlı; Baysal, Gökhan

2012-01-01

The purpose of this experimental study was to analyze the effects of local autologous platelet-rich plasma (PRP) injection on tendon-to-bone healing in a rotator cuff repair model in rats. Rotator cuff injury was created in 68 left shoulders of rats. PRP was obtained from the blood of an additional 15 rats. The 68 rats were divided into 4 groups with 17 rats in each group; PRP group (Week 2), control group (Week 2), PRP group (Week 4), and control group (Week 4). Platelet-rich plasma or saline was injected to the repair area intraoperatively. Rats were sacrificed 2 and 4 weeks after the surgery. Histological analysis using a semiquantitative scoring was performed on 7 rats per group. Tendon integrity and increases in vascularity and inflammatory cells and the degree of new bone formation were evaluated and compared between the groups. The remaining tendons (n=10) were mechanically tested. Degree of inflammation and vascularity were less in the study group at both time intervals (p<0.05). Tendon continuity was better in the study group at 2 weeks (p<0.05). Obvious new bone formation was detected in the control group at 4 weeks (p<0.05). Biomechanically, platelet-rich plasma-treated specimens were stronger at 2 weeks (p<0.05). Local autologous PRP injection may have beneficial effects on initial rotator cuff tendon-to-bone healing and enhance initial tendon-to-bone healing remodeling. This may represent a clinically important improvement in rotator cuff repair.

The development and morphogenesis of the tendon-to-bone insertion What development can teach us about healing

PubMed Central

Thomopoulos, Stavros; Genin, Guy M.; Galatz, Leesa M.

2013-01-01

The attachment of dissimilar materials is a major challenge because of the high levels of stress that develop at such interfaces. An effective solution to this problem develops at the attachment of tendon (a compliant “soft tissue”) to bone (a stiff “hard tissue”). This tissue, the “enthesis”, transitions from tendon to bone through gradations in structure, composition, and mechanical properties. These gradations are not regenerated during tendon-to-bone healing, leading to a high incidence of failure after surgical repair. Understanding the development of the enthesis may allow scientists to develop treatments that regenerate the natural tendon-to-bone insertion. Recent work has demonstrated that both biologic and mechanical factors drive the development and morphogenesis of the enthesis. A cascade of biologic signals similar to those seen in the growth plate promotes mineralization of cartilage on the bony end of the enthesis and the formation of fibrocartilage on the tendon end of the enthesis. Mechanical loading is also necessary for the development of the enthesis. Removal of muscle load impairs the formation of bone, fibrocartilage, and tendon at the developing enthesis. This paper reviews recent work on the development of the enthesis, with an emphasis on the roles of biologic and mechanical factors. PMID:20190378

Tendon healing in a bone tunnel. Part II: Histologic analysis after biodegradable interference fit fixation in a model of anterior cruciate ligament reconstruction in sheep.

PubMed

Weiler, Andreas; Hoffmann, Reinhard F G; Bail, Hermann J; Rehm, Oliver; Südkamp, Norbert P

2002-02-01

Tendon-to-bone healing of soft-tissue grafts has been described to progress by the development of a fibrous interzone that undergoes a maturation process leading to the development of an indirect type of ligament insertion. Previous studies used extra-articular models or fixation far away from the joint line; thus, no data are available investigating tendon-to-bone healing of a soft-tissue graft fixed anatomically. Therefore, we studied the tendon-to-bone healing of the anatomic soft-tissue graft interference fit fixation in a model of anterior cruciate ligament (ACL) reconstruction in sheep. Animal study. Thirty-five mature sheep underwent ACL reconstruction with an autologous Achilles tendon split graft. Grafts were directly fixed with biodegradable poly-(D,L-lactide) interference screws. Animals were euthanized after 6, 9, 12, 24, and 52 weeks and histologic evaluations were performed. Undecalcified specimens were evaluated under normal and polarized light. Additionally, animals received a polychrome sequential labeling (tetracycline, xylenol orange, and calcein green) to determine bone growth per time under fluorescent light. Intratunnel histologic findings at 6 weeks showed a tendon-bone junction with only a partial fibrous interzone between the graft tissue and the surrounding bone. A mature intratunnel tendon-bone junction with a zone of fibrocartilage was found at 9 to 12 weeks. At the tunnel entrance site a wide regular ligamentous insertion site was seen in all specimens after 24 weeks. This insertion showed regular patterns such as the direct type of insertion of a normal ligament with a dense basophilic transition zone consisting of mineralized cartilage. A fibrous interzone between the graft tissue and the bone tunnel was only partially developed, which is in contrast to all previous studies in which nonanatomic fixation was used. Thus, it is reasonable to assume that the tendon-to-bone healing in the present study may progress partially by direct

Flexible bipolar nanofibrous membranes for improving gradient microstructure in tendon-to-bone healing.

PubMed

Li, Xiaoxi; Cheng, Ruoyu; Sun, Zhiyong; Su, Wei; Pan, Guoqing; Zhao, Song; Zhao, Jinzhong; Cui, Wenguo

2017-10-01

Enthesis is a specialized tissue interface between the tendon and bone. Enthesis structure is very complex because of gradient changes in its composition and structure. There is currently no strategy to create a suitable environment and to regenerate the gradual-changing enthesis because of the modular complexities between two tissue types. Herein, a dual-layer organic/inorganic flexible bipolar fibrous membrane (BFM) was successfully fabricated by electrospinning to generate biomimetic non-mineralized fibrocartilage and mineralized fibrocartilage in tendon-to-bone integration of enthesis. The growth of the in situ apatite nanoparticle layer was induced on the nano hydroxyapatite-poly-l-lactic acid (nHA-PLLA) fibrous layer in simulated body solution, and the poly-l-lactic acid (PLLA) fibrous layer retained its original properties to induce tendon regeneration. The in vivo results showed that BFM significantly increased the area of glycosaminoglycan staining at the tendon-bone interface and improved collagen organization when compared to the simplex fibrous membrane (SFM) of PLLA. Implanting the bipolar membrane also induced bone formation and fibrillogenesis as assessed by micro-CT and histological analysis. Biomechanical testing showed that the BFM group had a greater ultimate load-to-failure and stiffness than the SFM group at 12weeks after surgery. Therefore, this flexible bipolar nanofibrous membrane improves the healing and regeneration process of the enthesis in rotator cuff repair. In this study, we generated a biomimetic dual-layer organic/inorganic flexible bipolar fibrous membrane by sequential electrospinning and in situ biomineralization, producing integrated bipolar fibrous membranes of PLLA fibrous membrane as the upper layer and nHA-PLLA fibrous membrane as the lower layer to mimic non-mineralized fibrocartilage and mineralized fibrocartilage in tendon-to-bone integration of enthesis. Flexible bipolar nanofibrous membranes could be easily fabricated

The effect of platelet-rich fibrin matrix on rotator cuff tendon healing: a prospective, randomized clinical study.

PubMed

Rodeo, Scott A; Delos, Demetris; Williams, Riley J; Adler, Ronald S; Pearle, Andrew; Warren, Russell F

2012-06-01

There is a strong need for methods to improve the biological potential of rotator cuff tendon healing. Platelet-rich fibrin matrix (PRFM) allows delivery of autologous cytokines to healing tissue, and limited evidence suggests a positive effect of platelet-rich plasma on tendon biology. To evaluate the effect of platelet-rich fibrin matrix on rotator cuff tendon healing. Randomized controlled trial; Level of evidence, 2. Seventy-nine patients undergoing arthroscopic rotator cuff tendon repair were randomized intraoperatively to either receive PRFM at the tendon-bone interface (n = 40) or standard repair with no PRFM (n = 39). Standardized repair techniques were used for all patients. The postoperative rehabilitation protocol was the same in both groups. The primary outcome was tendon healing evaluated by ultrasound (intact vs defect at repair site) at 6 and 12 weeks. Power Doppler ultrasound was also used to evaluate vascularity in the peribursal, peritendinous, and musculotendinous and insertion site areas of the tendon and bone anchor site. Secondary outcomes included standardized shoulder outcome scales (American Shoulder and Elbow Surgeons [ASES] and L'Insalata) and strength measurements using a handheld dynamometer. Patients and the evaluator were blinded to treatment group. All patients were evaluated at minimum 1-year follow-up. A logistic regression model was used to predict outcome (healed vs defect) based on tear severity, repair type, treatment type (PRFM or control), and platelet count. Overall, there were no differences in tendon-to-bone healing between the PRFM and control groups. Complete tendon-to-bone healing (intact repair) was found in 24 of 36 (67%) in the PRFM group and 25 of 31 (81%) in the control group (P = .20). There were no significant differences in healing by ultrasound between 6 and 12 weeks. There were gradual increases in ASES and L'Insalata scores over time in both groups, but there were no differences in scores between the groups

The effects of chronic unloading and gap formation on tendon-to-bone healing in a rat model of massive rotator cuff tears

PubMed Central

Killian, Megan L.; Cavinatto, Leonardo; Shah, Shivam A.; Sato, Eugene J.; Ward, Samuel R.; Havlioglu, Necat; Galatz, Leesa M.; Thomopoulos, Stavros

2014-01-01

The objective of this study was to understand the effect of pre-repair rotator cuff chronicity on post-repair healing outcomes using a chronic and acute multi-tendon rat rotator cuff injury model. Full-thickness dual tendon injuries (supra- and infraspinatus) were created unilaterally in adult male Sprague Dawley rats, and left chronically detached for 8 or 16 weeks. After chronic detachment, tears were repaired and acute dual tendon injuries were created and immediately repaired on contralateral shoulders. Tissue level outcomes for bone, tendon, and muscle were assessed 4 or 8 weeks after repair using histology, microcomputed tomography, biomechanical testing, and biochemical assays. Substantial gap formation was seen in 35% of acute repairs and 44% of chronic repairs. Gap formation negatively correlated with mechanical and structural outcomes for both healing time points regardless of injury duration. Bone and histomorphometry, as well as biomechanics, were similar between acute and chronic injury and repair regardless of chronicity and duration of healing. This study was the first to implement a multi-tendon rotator cuff injury with surgical repair following both chronic and acute injuries. Massive tear in a rodent model resulted in gap formation regardless of injury duration which had detrimental effects on repair outcomes. PMID:24243733

The effects of chronic unloading and gap formation on tendon-to-bone healing in a rat model of massive rotator cuff tears.

PubMed

Killian, Megan L; Cavinatto, Leonardo; Shah, Shivam A; Sato, Eugene J; Ward, Samuel R; Havlioglu, Necat; Galatz, Leesa M; Thomopoulos, Stavros

2014-03-01

The objective of this study was to understand the effect of pre-repair rotator cuff chronicity on post-repair healing outcomes using a chronic and acute multi-tendon rat rotator cuff injury model. Full-thickness dual tendon injuries (supra- and infraspinatus) were created unilaterally in adult male Sprague Dawley rats, and left chronically detached for 8 or 16 weeks. After chronic detachment, tears were repaired and acute dual tendon injuries were created and immediately repaired on contralateral shoulders. Tissue level outcomes for bone, tendon, and muscle were assessed 4 or 8 weeks after repair using histology, microcomputed tomography, biomechanical testing, and biochemical assays. Substantial gap formation was seen in 35% of acute repairs and 44% of chronic repairs. Gap formation negatively correlated with mechanical and structural outcomes for both healing time points regardless of injury duration. Bone and histomorphometry, as well as biomechanics, were similar between acute and chronic injury and repair regardless of chronicity and duration of healing. This study was the first to implement a multi-tendon rotator cuff injury with surgical repair following both chronic and acute injuries. Massive tear in a rodent model resulted in gap formation regardless of injury duration which had detrimental effects on repair outcomes. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Atelocollagen Enhances the Healing of Rotator Cuff Tendon in Rabbit Model.

PubMed

Suh, Dong-Sam; Lee, Jun-Keun; Yoo, Ji-Chul; Woo, Sang-Hun; Kim, Ga-Ram; Kim, Ju-Won; Choi, Nam-Yong; Kim, Yongdeok; Song, Hyun-Seok

2017-07-01

Failure of rotator cuff healing is a common complication despite the rapid development of surgical repair techniques for the torn rotator cuff. To verify the effect of atelocollagen on tendon-to-bone healing in the rabbit supraspinatus tendon compared with conventional cuff repair. Controlled laboratory study. A tear of the supraspinatus tendon was created and repaired in 46 New Zealand White rabbits. They were then randomly allocated into 2 groups (23 rabbits per group; 15 for histological and 8 for biomechanical test). In the experimental group, patch-type atelocollagen was implanted between bone and tendon during repair; in the control group, the torn tendon was repaired without atelocollagen. Each opposite shoulder served as a sham (tendon was exposed only). Histological evaluation was performed at 4, 8, and 12 weeks. Biomechanical tensile strength was tested 12 weeks after surgery. Histological evaluation scores of the experimental group (4.0 ± 1.0) were significantly superior to those of the control group (7.7 ± 2.7) at 12 weeks ( P = .005). The load to failure was significantly higher in the experimental group (51.4 ± 3.9 N) than in the control group (36.4 ± 5.9 N) ( P = .001). Histological and biomechanical studies demonstrated better results in the experimental group using atelocollagen in a rabbit model of the supraspinatus tendon tear. Atelocollagen patch could be used in the cuff repair site to enhance healing.

Rotator Cuff Repair with a Tendon-Fibrocartilage-Bone Composite Bridging Patch

PubMed Central

Ji, Xiaoxi; Chen, Qingshan; Thoreson, Andrew R.; Qu, Jin; An, Kai-Nan; Amadio, Peter C.; Steinmann, Scott P.; Zhao, Chunfeng

2015-01-01

Background To compare the mechanical performance of a rotator cuff repaired with a novel tendon-fibrocartilage-bone composite bridging patch vs the traditional Mason-Allen repair in an in vitro canine model. Methods Twenty shoulders and 10 bridging patches from patellar tendon were harvested. The patches were trimmed and sliced into 2 layers. An infraspinatus tendon tear was created in each shoulder. Modified Mason-Allen sutures were used to repair the infraspinatus tendon to the greater tuberosity, with or without the bridging patch (bridging patch group and controls, respectively). Shoulders were loaded to failure under displacement control at a rate of 0.5mm/sec. Findings The ultimate tensile load was significantly higher in the bridging patch group than control (mean [SD], 365.46 [36.45] vs 272.79 [48.88] N; P<.001). Stiffness at the greater tuberosity repair site and the patch-infraspinatus tendon repair site was significantly higher than the control repair site (93.96 [27.72] vs 42.62 [17.48] N/mm P<.001; 65.94 [24.51] vs 42.62 [17.48] N/mm P=.02, respectively). Interpretation The tendon-fibrocartilage-bone composite bridging patch achieved higher ultimate tensile load and stiffness at the patch–greater tuberosity repair site compared with traditional repair in a canine model. This composite tissue transforms the traditional tendon-to-bone healing interface (with dissimilar tissues) into a pair of bone-to-bone and tendon-to-tendon interfaces, which may improve healing quality and reduce retear rate. PMID:26190097

Rotator cuff repair with a tendon-fibrocartilage-bone composite bridging patch.

PubMed

Ji, Xiaoxi; Chen, Qingshan; Thoreson, Andrew R; Qu, Jin; An, Kai-Nan; Amadio, Peter C; Steinmann, Scott P; Zhao, Chunfeng

2015-11-01

To compare the mechanical performance of a rotator cuff repaired with a novel tendon-fibrocartilage-bone composite bridging patch vs the traditional Mason-Allen repair in an in vitro canine model. Twenty shoulders and 10 bridging patches from patellar tendon were harvested. The patches were trimmed and sliced into 2 layers. An infraspinatus tendon tear was created in each shoulder. Modified Mason-Allen sutures were used to repair the infraspinatus tendon to the greater tuberosity, with or without the bridging patch (bridging patch group and controls, respectively). Shoulders were loaded to failure under displacement control at a rate of 0.5mm/s. The ultimate tensile load was significantly higher in the bridging patch group than control (mean [SD], 365.46 [36.45] vs 272.79 [48.88] N; P<.001). Stiffness at the greater tuberosity repair site and the patch-infraspinatus tendon repair site was significantly higher than the control repair site (93.96 [27.72] vs 42.62 [17.48] N/mm P<.001; 65.94 [24.51] vs 42.62 [17.48] N/mm P=.02, respectively). The tendon-fibrocartilage-bone composite bridging patch achieved higher ultimate tensile load and stiffness at the patch-greater tuberosity repair site compared with traditional repair in a canine model. This composite tissue transforms the traditional tendon-to-bone healing interface (with dissimilar tissues) into a pair of bone-to-bone and tendon-to-tendon interfaces, which may improve healing quality and reduce retear rate. Copyright © 2015 Elsevier Ltd. All rights reserved.

THE ROLE OF MECHANOBIOLOGY IN TENDON HEALING

PubMed Central

Killian, Megan L.; Cavinatto, Leonardo; Galatz, Leesa M.; Thomopoulos, Stavros

2011-01-01

Mechanical cues affect tendon healing, homeostasis, and development in a variety of settings. Alterations in the mechanical environment are known to result in changes in the expression of extracellular matrix proteins, growth factors, transcription factors, and cytokines that can alter tendon structure and cell viability. Loss of muscle force in utero or in the immediate postnatal period delays tendon and enthesis development. The response of healing tendons to mechanical load varies depending on anatomic location. Flexor tendons require motion to prevent adhesion formation, yet excessive force results in gap formation and subsequent weakening of the repair. Excessive motion in the setting of anterior cruciate ligament reconstruction causes accumulation of macrophages, which are detrimental to tendon graft healing. Complete removal of load is detrimental to rotator cuff healing, yet large forces are also harmful. Controlled loading can enhance healing in most settings; however, a fine balance must be reached between loads that are too low (leading to a catabolic state) and too high (leading to micro-damage). This review will summarize existing knowledge of the mechanobiology of tendon development, homeostasis, and healing. PMID:22244066

Modulation of early functional recovery of Achilles tendon to bone unit after transection by BPC 157 and methylprednisolone.

PubMed

Krivic, A; Majerovic, M; Jelic, I; Seiwerth, S; Sikiric, P

2008-05-01

In the presented study we compared the effect of stable peptide BPC 157 and methylprednisolone on early functional recovery after Achilles tendon to bone transection in a rat model before collagen healing started. Surgical transection of the right Achilles tendon to bone area was performed in seventy two Wistar Albino male rats. Healing Achilles tendon edges were harvested at days 1-4 following the transection. Using Achilles functional index (AFI), myeloperoxidase activity, histological inflammatory cell influx and vascular index early functional recovery was evaluated. Agents (stable peptide BPC 157 10 microg methylprednisolone 5 mg, normal saline 5 ml) were given alone (/kg b.w., intraperitoneally, once daily, first 30 min after surgery, last 24 h before analysis). Control group received normal saline 5 ml/kg. BPC 157 improved functional recovery (AFI values increased at all time points, p <0.05) by anti-inflammatory (decreased myeloperoxidase (MPO) activity and histological inflammatory cell influx, p <0.05) and increased new blood vessel formation (increased vascular index, p <0.05). Methyprednisolone decreased MPO activity and histological inflammatory cell influx, (p <0.05) but also decreased new blood vessel formation and did not affect early functional recovery. Stable peptide BPC 157 with combined anti-inflammatory action and induction of early new blood vessel formation facilitates early functional recovery in Achilles tendon to bone healing.

Icariin Promotes Tendon-Bone Healing during Repair of Rotator Cuff Tears: A Biomechanical and Histological Study.

PubMed

Ye, Chenyi; Zhang, Wei; Wang, Shengdong; Jiang, Shuai; Yu, Yuanbin; Chen, Erman; Xue, Deting; Chen, Jianzhong; He, Rongxin

2016-10-25

To investigate whether the systematic administration of icariin (ICA) promotes tendon-bone healing after rotator cuff reconstruction in vivo, a total of 64 male Sprague Dawley rats were used in a rotator cuff injury model and underwent rotator cuff reconstruction (bone tunnel suture fixation). Rats from the ICA group ( n = 32) were gavage-fed daily with ICA at 0.125 mg/g, while rats in the control group ( n = 32) received saline only. Micro-computed tomography, biomechanical tests, serum ELISA (calcium; Ca, alkaline phosphatase; AP, osteocalcin; OCN) and histological examinations (Safranin O and Fast Green staining, type I, II and III collagen (Col1, Col2, and Col3), CD31, and vascular endothelial growth factor (VEGF)) were analyzed two and four weeks after surgery. In the ICA group, the serum levels of AP and OCN were higher than in the control group. More Col1-, Col2-, CD31-, and VEGF-positive cells, together with a greater degree of osteogenesis, were detected in the ICA group compared with the control group. During mechanical testing, the ICA group showed a significantly higher ultimate failure load than the control group at both two and four weeks. Our results indicate that the systematic administration of ICA could promote angiogenesis and tendon-bone healing after rotator cuff reconstruction, with superior mechanical strength compared with the controls. Treatment for rotator cuff injury using systematically-administered ICA could be a promising strategy.

Phenytoin accelerates tendon healing in a rat model of Achilles tendon rupture.

PubMed

Hajipour, B; Navali, A M; Mohammad, S Ali; Mousavi, G; Akbari, M Gahvechi; Miyandoab, T Maleki; Roshangar, L; Saleh, B Mohammadi; Kermani, T Asvadi; Laleh, F Moutab; Ghabili, M

2016-01-01

Tendons are vulnerable to various types of acute or chronic injures. Different methods have been investigated to achieve better healing. Phenytoin is a drug which could stimulate fibroblasts to produce collagen. This experimental study was performed to assess the effect of phenytoin on tendon healing in a rat model of tendon rupture. Thirty healthy rats were divided into 3 groups, 1) Sham group; 2) Tendon rupture; 3) Tendon rupture+phenytoin (100 mg/kg intraperitoneally) for 21 days. On 21st day after tendon injury, the rats were anesthetized and tendon tissue was sampled for studying by light and electron microscopy. Qualitative and quantitative microscopic comparisons of the repair tissues of both groups were made on the 21st day. The results obtained from light and electron microscopy studies showed that tendon tissue healing was significantly better in phenytoin group compared to the control group (p < 0.05). Systemic administration of phenytoin may have a positive effect on tendon healing by increasing fibroblast quantity, fibrillar collagen synthesis, vascularity, and suppressing inflammation (Tab. 2, Ref. 25).

P2 porous titanium implants improve tendon healing in an acute rat supraspinatus repair model.

PubMed

Tucker, Jennica J; Gordon, Joshua A; Zanes, Robert C; Zuskov, Andrey; Vinciguerra, John D; Bloebaum, Roy D; Soslowsky, Louis J

2017-03-01

Current techniques in rotator cuff repair often lack structural integrity. P 2 porous titanium-coated constructs (DJO Surgical, Austin, TX, USA) promote osseointegration and soft tissue ingrowth. This study examined the ability of this material to improve the structural integrity of supraspinatus tendon repair in a rat model. We hypothesized that P 2 implants placed at the tendon-to-bone interface would improve mechanical and histologic measures of supraspinatus healing. Forty rats underwent supraspinatus repairs with P 2 implants in 1 shoulder and standard repair in the other. Rats were humanely killed at time 0 (n = 3), 2 weeks (n = 8), 4 weeks (n = 15), and 12 weeks (n = 14). Tendon-to-bone composite specimens were harvested and evaluated mechanically and histologically. Tendon cross-sectional area was decreased in the P 2 implant group at 4 weeks, percentage of relaxation was increased at 2 weeks, elastic modulus was increased at 4 weeks, and maximum load and maximum stress were both increased at 2 and 4 weeks. Histologic analysis revealed no foreign body reactions within or around the P 2 implant, and healthy viable bone was visible within the P 2 implant. The results support our hypothesis, specifically in early healing, in this randomized controlled animal study. These data support the use of P 2 porous titanium implants to improve tendon-to-bone healing. Copyright © 2017 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.

Pulsed electromagnetic field therapy improves tendon-to-bone healing in a rat rotator cuff repair model.

PubMed

Tucker, Jennica J; Cirone, James M; Morris, Tyler R; Nuss, Courtney A; Huegel, Julianne; Waldorff, Erik I; Zhang, Nianli; Ryaby, James T; Soslowsky, Louis J

2017-04-01

Rotator cuff tears are common musculoskeletal injuries often requiring surgical intervention with high failure rates. Currently, pulsed electromagnetic fields (PEMFs) are used for treatment of long-bone fracture and lumbar and cervical spine fusion surgery. Clinical studies examining the effects of PEMF on soft tissue healing show promising results. Therefore, we investigated the role of PEMF on rotator cuff healing using a rat rotator cuff repair model. We hypothesized that PEMF exposure following rotator cuff repair would improve tendon mechanical properties, tissue morphology, and alter in vivo joint function. Seventy adult male Sprague-Dawley rats were assigned to three groups: bilateral repair with PEMF (n = 30), bilateral repair followed by cage activity (n = 30), and uninjured control with cage activity (n = 10). Rats in the surgical groups were sacrificed at 4, 8, and 16 weeks. Control group was sacrificed at 8 weeks. Passive joint mechanics and gait analysis were assessed over time. Biomechanical analysis and μCT was performed on left shoulders; histological analysis on right shoulders. Results indicate no differences in passive joint mechanics and ambulation. At 4 weeks the PEMF group had decreased cross-sectional area and increased modulus and maximum stress. At 8 weeks the PEMF group had increased modulus and more rounded cells in the midsubstance. At 16 weeks the PEMF group had improved bone quality. Therefore, results indicate that PEMF improves early tendon healing and does not alter joint function in a rat rotator cuff repair model. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:902-909, 2017. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Bone marrow mesenchymal stem cells do not enhance intra-synovial tendon healing despite engraftment and homing to niches within the synovium.

PubMed

Khan, Mohammad R; Dudhia, Jayesh; David, Frederic H; De Godoy, Roberta; Mehra, Vedika; Hughes, Gillian; Dakin, Stephanie G; Carr, Andrew J; Goodship, Allen E; Smith, Roger K W

2018-06-19

Intra-synovial tendon injuries display poor healing, which often results in reduced functionality and pain. A lack of effective therapeutic options has led to experimental approaches to augment natural tendon repair with autologous mesenchymal stem cells (MSCs) although the effects of the intra-synovial environment on the distribution, engraftment and functionality of implanted MSCs is not known. This study utilised a novel sheep model which, although in an anatomically different location, more accurately mimics the mechanical and synovial environment of the human rotator cuff, to determine the effects of intra-synovial implantation of MSCs. A lesion was made in the lateral border of the lateral branch of the ovine deep digital flexor tendon within the digital sheath and 2 weeks later 5 million autologous bone marrow MSCs were injected under ultrasound guidance into the digital sheath. Tendons were recovered post mortem at 1 day, and 1-2, 4, 12 and 24 weeks after MSC injection. For the 1-day and 1-2-week groups, MSCs labelled with fluorescent-conjugated magnetic iron-oxide nanoparticles (MIONs) were tracked with MRI, histology and flow cytometry. The 4, 12 and 24-week groups were implanted with non-labelled cells and compared with saline-injected controls for healing. The MSCs displayed no reduced viability in vitro to an uptake of 20.0 ± 4.6 pg MIONs per cell, which was detectable by MRI at minimal density of ~ 3 × 10 4 cells. Treated limbs indicated cellular distribution throughout the tendon synovial sheath but restricted to the synovial tissues, with no MSCs detected in the tendon or surgical lesion. The lesion was associated with negligible morbidity with minimal inflammation post surgery. Evaluation of both treated and control lesions showed no evidence of healing of the lesion at 4, 12 and 24 weeks on gross and histological examination. Unlike other laboratory animal models of tendon injury, this novel model mimics the failed tendon healing

Enhanced tendon-to-bone repair through adhesive films.

PubMed

Linderman, Stephen W; Golman, Mikhail; Gardner, Thomas R; Birman, Victor; Levine, William N; Genin, Guy M; Thomopoulos, Stavros

2018-04-01

Tendon-to-bone surgical repairs have unacceptably high failure rates, possibly due to their inability to recreate the load transfer mechanisms of the native enthesis. Instead of distributing load across a wide attachment footprint area, surgical repairs concentrate shear stress on a small number of suture anchor points. This motivates development of technologies that distribute shear stresses away from suture anchors and across the enthesis footprint. Here, we present predictions and proof-of-concept experiments showing that mechanically-optimized adhesive films can mimic the natural load transfer mechanisms of the healthy attachment and increase the load tolerance of a repair. Mechanical optimization, based upon a shear lag model corroborated by a finite element analysis, revealed that adhesives with relatively high strength and low stiffness can, theoretically, strengthen tendon-to-bone repairs by over 10-fold. Lap shear testing using tendon and bone planks validated the mechanical models for a range of adhesive stiffnesses and strengths. Ex vivo human supraspinatus repairs of cadaveric tissues using multipartite adhesives showed substantial increase in strength. Results suggest that adhesive-enhanced repair can improve repair strength, and motivate a search for optimal adhesives. Current surgical techniques for tendon-to-bone repair have unacceptably high failure rates, indicating that the initial repair strength is insufficient to prevent gapping or rupture. In the rotator cuff, repair techniques apply compression over the repair interface to achieve contact healing between tendon and bone, but transfer almost all force in shear across only a few points where sutures puncture the tendon. Therefore, we evaluated the ability of an adhesive film, implanted between tendon and bone, to enhance repair strength and minimize the likelihood of rupture. Mechanical models demonstrated that optimally designed adhesives would improve repair strength by over 10-fold

Therapeutics for tendon regeneration: a multidisciplinary review of tendon research for improved healing.

PubMed

Paredes, J J; Andarawis-Puri, Nelly

2016-11-01

Tendon injuries, known as tendinopathies, are common musculoskeletal injuries that affect a wide range of the population. Canonical tendon healing is characterized by fibrosis, scar formation, and the loss of tissue mechanical and structural properties. Understanding the regenerative tendon environment is an area of increasing interest in the field of musculoskeletal research. Previous studies have focused on utilizing individual elements from the fields of biomechanics, developmental biology, cell and growth factor therapy, and tissue engineering in an attempt to develop regenerative tendon therapeutics. Still, the specific mechanism for regenerative healing remains unknown. In this review, we highlight some of the current approaches of tendon therapeutics and elucidate the differences along the tendon midsubstance and enthesis, exhibiting the necessity of location-specific tendon therapeutics. Furthermore, we emphasize the necessity of further interdisciplinary research in order to reach the desired goal of fully understanding the mechanisms underlying regenerative healing. © 2016 New York Academy of Sciences.

The Achilles tendon: fundamental properties and mechanisms governing healing

PubMed Central

Freedman, Benjamin R.; Gordon, Joshua A.; Soslowsky, Louis J.

2014-01-01

Summary This review highlights recent research on Achilles tendon healing, and comments on the current clinical controversy surrounding the diagnosis and treatment of injury. The processes of Achilles tendon healing, as demonstrated through changes in its structure, composition, and biomechanics, are reviewed. Finally, a review of tendon developmental biology and mechano transductive pathways is completed to recognize recent efforts to augment injured Achilles tendons, and to suggest potential future strategies for therapeutic intervention and functional tissue engineering. Despite an abundance of clinical evidence suggesting that current treatments and rehabilitation strategies for Achilles tendon ruptures are equivocal, significant questions remain to fully elucidate the basic science mechanisms governing Achilles tendon injury, healing, treatment, and rehabilitation. PMID:25332943

Kartogenin with PRP promotes the formation of fibrocartilage zone in the tendon-bone interface.

PubMed

Zhou, Yiqin; Zhang, Jianying; Yang, Jinsong; Narava, Manoj; Zhao, Guangyi; Yuan, Ting; Wu, Haishan; Zheng, Nigel; Hogan, MaCalus V; Wang, James H-C

2017-12-01

Treatment of tendon-bone junction injuries is a challenge because tendon-bone interface often heals poorly and the fibrocartilage zone, which reduces stress concentration, at the interface is not formed. In this study, we used a compound called kartogenin (KGN) with platelet-rich plasma (PRP) to induce the formation of fibrocartilage zone in a rat tendon graft-bone tunnel model. The experimental rats received KGN-PRP or PRP injections in the tendon graft-bone tunnel interface. The control group received saline. After 4, 8 and 12 weeks, Safranin O staining of the tendon graft-bone tunnels revealed abundant proteoglycans in the KGN-PRP group indicating the formation of cartilage-like transition zone. Immunohistochemical and immuno-fluorescence staining revealed collagen types I (Col-I) and II (Col-II) in the newly formed fibrocartilage zone. Both fibrocartilage zone formation and maturation were healing time dependent. In contrast, the PRP and saline control groups had no cartilage-like tissues and minimal Col-I and Col-II staining. Some gaps were also present in the saline control group. Finally, pull-out strength in the KGN-PRP-treated group at 8 weeks was 1.4-fold higher than the PRP-treated group and 1.6-fold higher than the saline control group. These findings indicate that KGN, with PRP as a carrier, promotes the formation of fibrocartilage zone between the tendon graft and bone interface. Thus, KGN-PRP may be used as a convenient cell-free therapy in clinics to promote fibrocartilage zone formation in rotator calf repair and anterior cruciate ligament reconstruction, thereby enhancing the mechanical strength of the tendon-bone interface and hence the clinical outcome of these procedures. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Healing of donor site in bone-tendon-bone ACL reconstruction accelerated with plasma rich in growth factors: a randomized clinical trial.

PubMed

Seijas, Roberto; Rius, Marta; Ares, Oscar; García-Balletbó, Montserrat; Serra, Iván; Cugat, Ramón

2015-04-01

To determine whether the use of plasma rich in growth factors accelerates healing of the donor site in bone-tendon-bone anterior cruciate ligament (ACL) reconstruction (patellar graft). The use of the patellar graft presents post-operative problems such as anterior knee pain, which limits its use and leads to preference being taken for alternative grafts. A double-blind, randomized, clinical trial was performed comparing two groups of patients who underwent ACL reconstruction using patellar tendon graft and comparing the use of plasma rich in growth factors at the donor site after graft harvest in terms of local regeneration by ultrasound assessment. The plasma rich in growth factors group shows earlier donor site regeneration in comparison with the control group (2 months earlier), with significant differences in the first 4 months of the follow-up. The application of plasma rich in growth factors shows accelerated tissue regeneration processes with respect to the control group. This fact, together with the previously published with similar conclusions, can create a knowledge basis in order to set out new recovery guidelines following ACL reconstruction. Therapeutic study, Level I.

Low-Magnitude, High-Frequency Vibration Fails to Accelerate Ligament Healing but Stimulates Collagen Synthesis in the Achilles Tendon.

PubMed

Thompson, William R; Keller, Benjamin V; Davis, Matthew L; Dahners, Laurence E; Weinhold, Paul S

2015-05-01

Low-magnitude, high-frequency vibration accelerates fracture and wound healing and prevents disuse atrophy in musculoskeletal tissues. To investigate the role of low-magnitude, high-frequency vibration as a treatment to accelerate healing of an acute ligament injury and to examine gene expression in the intact Achilles tendon of the injured limb after low-magnitude, high-frequency vibration. Controlled laboratory study. Complete surgical transection of the medial collateral ligament (MCL) was performed in 32 Sprague-Dawley rats, divided into control and low-magnitude, high-frequency vibration groups. Low-magnitude, high-frequency vibration started on postoperative day 2, and rats received vibration for 30 minutes a day for 12 days. All rats were sacrificed 2 weeks after the operation, and their intact and injured MCLs were biomechanically tested or used for histological analysis. Intact Achilles tendons from the injured limb were evaluated for differences in gene expression. Mechanical testing revealed no differences in the ultimate tensile load or the structural stiffness between the control and vibration groups for either the injured or intact MCL. Vibration exposure increased gene expression of collagen 1 alpha (3-fold), interleukin 6 (7-fold), cyclooxygenase 2 (5-fold), and bone morphogenetic protein 12 (4-fold) in the intact Achilles tendon when compared with control tendons ( P < .05). While no differences were observed in the mechanical or histological properties of the fully transected MCL after low-magnitude, high-frequency vibration treatment, significant enhancements in gene expression were observed in the intact Achilles tendon. These included collagen, several inflammatory cytokines, and growth factors critical for tendons. As low-magnitude, high-frequency vibration had no negative effects on ligament healing, vibration therapy may be a useful tool to accelerate healing of other tissues (bone) in multitrauma injuries without inhibiting ligament healing

Angiogenesis in healing autogenous flexor-tendon grafts.

PubMed

Gelberman, R H; Chu, C R; Williams, C S; Seiler, J G; Amiel, D

1992-09-01

On the basis of recent evidence that flexor tendon grafts may heal without the ingrowth of vascular adhesions, eighteen autogenous donor tendons of intrasynovial and extrasynovial origin were transferred to the synovial sheaths in the forepaws of nine dogs, and controlled passive mobilization was instituted early in the postoperative period. The angiogenic responses of the tendon grafts were determined with perfusion studies with India ink followed by cleaing of the tissues with the Spalteholz technique at two, four, and six weeks. A consistent pattern of neovascularization was noted in the donor tendons of extrasynovial origin. Vascular adhesions arising from the flexor digitorum superficialis and the tendon sheath enveloped the tendon grafts by two weeks. By six weeks, the vascularity of the tendon grafts of extrasynovial origin appeared completely integrated with that of the surrounding tissues. Examination of cross sections revealed that the segments of tendon had been completely vascularized by obliquely oriented intratendinous vessels. In contrast, the flexor tendon grafts of intrasynovial origin healed without ingrowth of vascular adhesions. Primary intrinsic neovascularization took place from the proximal and, to a lesser extent, distal sites of the sutures. Examination of cross sections revealed vessels extending through the surface layer of the tendon graft, with small vessels penetrating the interior of the tendons at regular intervals.

Tendon-to-bone attachment: from development to maturity.

PubMed

Zelzer, Elazar; Blitz, Einat; Killian, Megan L; Thomopoulos, Stavros

2014-03-01

The attachment between tendon and bone occurs across a complex transitional tissue that minimizes stress concentrations and allows for load transfer between muscles and skeleton. This unique tissue cannot be reconstructed following injury, leading to high incidence of recurrent failure and stressing the need for new clinical approaches. This review describes the current understanding of the development and function of the attachment site between tendon and bone. The embryonic attachment unit, namely, the tip of the tendon and the bone eminence into which it is inserted, was recently shown to develop modularly from a unique population of Sox9- and Scx-positive cells, which are distinct from tendon fibroblasts and chondrocytes. The fate and differentiation of these cells is regulated by transforming growth factor beta and bone morphogenetic protein signaling, respectively. Muscle loads are then necessary for the tissue to mature and mineralize. Mineralization of the attachment unit, which occurs postnatally at most sites, is largely controlled by an Indian hedgehog/parathyroid hormone-related protein feedback loop. A number of fundamental questions regarding the development of this remarkable attachment system require further study. These relate to the signaling mechanism that facilitates the formation of an interface with a gradient of cellular and extracellular phenotypes, as well as to the interactions between tendon and bone at the point of attachment. Copyright © 2014 Wiley Periodicals, Inc.

Tendon basic science: Development, repair, regeneration, and healing.

PubMed

Andarawis-Puri, Nelly; Flatow, Evan L; Soslowsky, Louis J

2015-06-01

Tendinopathy and tendon rupture are common and disabling musculoskeletal conditions. Despite the prevalence of these injuries, a limited number of investigators are conducting fundamental, basic science studies focused on understanding processes governing tendinopathies and tendon healing. Development of effective therapeutics is hindered by the lack of fundamental guiding data on the biology of tendon development, signal transduction, mechanotransduction, and basic mechanisms underlying tendon pathogenesis and healing. To propel much needed progress, the New Frontiers in Tendon Research Conference, co-sponsored by NIAMS/NIH, the Orthopaedic Research Society, and the Icahn School of Medicine at Mount Sinai, was held to promote exchange of ideas between tendon researchers and basic science experts from outside the tendon field. Discussed research areas that are underdeveloped and represent major hurdles to the progress of the field will be presented in this review. To address some of these outstanding questions, conference discussions and breakout sessions focused on six topic areas (Cell Biology and Mechanics, Functional Extracellular Matrix, Development, Mechano-biology, Scarless Healing, and Mechanisms of Injury and Repair), which are reviewed in this special issue and briefly presented in this review. Review articles in this special issue summarize the progress in the field and identify essential new research directions. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Transcription factor scleraxis vitally contributes to progenitor lineage direction in wound healing of adult tendon in mice.

PubMed

Sakabe, Tomoya; Sakai, Keiko; Maeda, Toru; Sunaga, Ataru; Furuta, Nao; Schweitzer, Ronen; Sasaki, Takako; Sakai, Takao

2018-04-20

Tendon is a dense connective tissue that transmits high mechanical forces from skeletal muscle to bone. The transcription factor scleraxis (Scx) is a highly specific marker of both precursor and mature tendon cells (tenocytes). Mice lacking scx exhibit a specific and virtually complete loss of tendons during development. However, the functional contribution of Scx to wound healing in adult tendon has not yet been fully characterized. Here, using ScxGFP -tracking and loss-of-function systems, we show in an adult mouse model of Achilles tendon injury that paratenon cells, representing a stem cell antigen-1 (Sca-1)-positive and Scx-negative progenitor subpopulation, display Scx induction, migrate to the wound site, and produce extracellular matrix (ECM) to bridge the defect, whereas resident tenocytes exhibit a delayed response. Scx induction in the progenitors is initiated by transforming growth factor β (TGF-β) signaling. scx -deficient mice had migration of Sca-1-positive progenitor cell to the lesion site but impaired ECM assembly to bridge the defect. Mechanistically, scx -null progenitors displayed higher chondrogenic potential with up-regulation of SRY-box 9 (Sox9) coactivator PPAR-γ coactivator-1α (PGC-1α) in vitro , and knock-in analysis revealed that forced expression of full-length scx significantly inhibited Sox9 expression. Accordingly, scx -null wounds formed cartilage-like tissues that developed ectopic ossification. Our findings indicate a critical role of Scx in a progenitor-cell lineage in wound healing of adult mouse tendon. These progenitor cells could represent targets in strategies to facilitate tendon repair. We propose that this lineage-regulatory mechanism in tissue progenitors could apply to a broader set of tissues or biological systems in the body. © 2018 Sakabe et al.

Do postoperative platelet-rich plasma injections accelerate early tendon healing and functional recovery after arthroscopic supraspinatus repair? A randomized controlled trial.

PubMed

Wang, Allan; McCann, Philip; Colliver, Jess; Koh, Eamon; Ackland, Timothy; Joss, Brendan; Zheng, Minghao; Breidahl, Bill

2015-06-01

Tendon-bone healing after rotator cuff repair directly correlates with a successful outcome. Biological therapies that elevate local growth-factor concentrations may potentiate healing after surgery. To ascertain whether postoperative and repeated application of platelet-rich plasma (PRP) to the tendon repair site improves early tendon healing and enhances early functional recovery after double-row arthroscopic supraspinatus repair. Randomized controlled trial; Level of evidence, 1. A total of 60 patients underwent arthroscopic double-row supraspinatus tendon repair. After randomization, half the patients received 2 ultrasound-guided injections of PRP to the repair site at postoperative days 7 and 14. Early structural healing was assessed with MRI at 16 weeks, and cuff appearances were graded according to the Sugaya classification. Functional scores were recorded with the Oxford Shoulder Score; Quick Disability of the Arm, Shoulder and Hand; visual analog scale for pain; and Short Form-12 quality-of-life score both preoperatively and at postoperative weeks 6, 12, and 16; isokinetic strength and active range of motion were measured at 16 weeks. PRP treatment did not improve early functional recovery, range of motion, or strength or influence pain scores at any time point after arthroscopic supraspinatus repair. There was no difference in structural integrity of the supraspinatus repair on MRI between the PRP group (0% full-thickness retear; 23% partial tear; 77% intact) and the control group (7% full-thickness retear; 23% partial tear; 70% intact) at 16 weeks postoperatively (P = .35). After arthroscopic supraspinatus tendon repair, image-guided PRP treatment on 2 occasions does not improve early tendon-bone healing or functional recovery. © 2015 The Author(s).

Obesity/Type II diabetes alters macrophage polarization resulting in a fibrotic tendon healing response

PubMed Central

Ackerman, Jessica E.; Geary, Michael B.; Orner, Caitlin A.; Bawany, Fatima

2017-01-01

Type II Diabetes (T2DM) dramatically impairs the tendon healing response, resulting in decreased collagen organization and mechanics relative to non-diabetic tendons. Despite this burden, there remains a paucity of information regarding the mechanisms that govern impaired healing of diabetic tendons. Mice were placed on either a high fat diet (T2DM) or low fat diet (lean) and underwent flexor tendon transection and repair surgery. Healing was assessed via mechanical testing, histology and changes in gene expression associated with collagen synthesis, matrix remodeling, and macrophage polarization. Obese/diabetic tendons healed with increased scar formation and impaired mechanical properties. Consistent with this, prolonged and excess expression of extracellular matrix (ECM) components were observed in obese/T2DM tendons. Macrophages are involved in both inflammatory and matrix deposition processes during healing. Obese/T2DM tendons healed with increased expression of markers of pro-inflammatory M1 macrophages, and elevated and prolonged expression of M2 macrophages markers that are involved in ECM deposition. Here we demonstrate that tendons from obese/diabetic mice heal with increased scar formation and increased M2 polarization, identifying excess M2 macrophage activity and matrix synthesis as a potential mechanism of the fibrotic healing phenotype observed in T2DM tendons, and as such a potential target to improve tendon healing in T2DM. PMID:28686669

Enhancement of Tendon–Bone Healing for Anterior Cruciate Ligament (ACL) Reconstruction Using Bone Marrow-Derived Mesenchymal Stem Cells Infected with BMP-2

PubMed Central

Dong, Yu; Zhang, Qingguo; Li, Yunxia; Jiang, Jia; Chen, Shiyi

2012-01-01

At present, due to the growing attention focused on the issue of tendon–bone healing, we carried out an animal study of the use of genetic intervention combined with cell transplantation for the promotion of this process. Here, the efficacy of bone marrow stromal cells infected with bone morphogenetic protein-2 (BMP-2) on tendon–bone healing was determined. A eukaryotic expression vector containing the BMP-2 gene was constructed and bone marrow-derived mesenchymal stem cells (bMSCs) were infected with a lentivirus. Next, we examined the viability of the infected cells and the mRNA and protein levels of BMP-2-infected bMSCs. Gastrocnemius tendons, gastrocnemius tendons wrapped by bMSCs infected with the control virus (bMSCs+Lv-Control), and gastrocnemius tendons wrapped by bMSCs infected with the recombinant BMP-2 virus (bMSCs+Lv-BMP-2) were used to reconstruct the anterior cruciate ligament (ACL) in New Zealand white rabbits. Specimens from each group were harvested four and eight weeks postoperatively and evaluated using biomechanical and histological methods. The bMSCs were infected with the lentivirus at an efficiency close to 100%. The BMP-2 mRNA and protein levels in bMSCs were significantly increased after lentiviral infection. The bMSCs and BMP-2-infected bMSCs on the gastrocnemius tendon improved the biomechanical properties of the graft in the bone tunnel; specifically, bMSCs infected with BMP-2 had a positive effect on tendon–bone healing. In the four-week and eight-week groups, bMSCs+Lv-BMP-2 group exhibited significantly higher maximum loads of 29.3 ± 7.4 N and 45.5 ± 11.9 N, respectively, compared with the control group (19.9 ± 6.4 N and 21.9 ± 4.9 N) (P = 0.041 and P = 0.001, respectively). In the eight-week groups, the stiffness of the bMSCs+Lv-BMP-2 group (32.5 ± 7.3) was significantly higher than that of the bMSCs+Lv-Control group (22.8 ± 7.4) or control groups (12.4 ± 6.0) (p = 0.036 and 0.001, respectively). Based on the histological

Extracorporeal shockwave enhanced regeneration of fibrocartilage in a delayed tendon-bone insertion repair model.

PubMed

Chow, Dick Ho Kiu; Suen, Pui Kit; Huang, Le; Cheung, Wing-Hoi; Leung, Kwok-Sui; Ng, Chun; Shi, San Qiang; Wong, Margaret Wan Nar; Qin, Ling

2014-04-01

Fibrous tissue is often formed in delayed healing of tendon bone insertion (TBI) instead of fibrocartilage. Extracorporeal shockwave (ESW) provides mechanical cues and upregulates expression of fibrocartilage-related makers and cytokines. We hypothesized that ESW would accelerate fibrocartilage regeneration at the healing interface in a delayed TBI healing model. Partial patellectomy with shielding at the TBI interface was performed on 32 female New Zealand White Rabbits for establishing this delayed TBI healing model. The rabbits were separated into the control and ESW group for evaluations at postoperative week 8 and 12. Shielding was removed at week 4 and a single ESW treatment was applied at week 6. Fibrocartilage regeneration was evaluated histomorphologically and immunohistochemically. Vickers hardness of the TBI matrix was measured by micro-indentation. ESW group showed higher fibrocartilage area, thickness, and proteoglycan deposition than the control in week 8 and 12. ESW increased expression of SOX9 and collagen II significantly in week 8 and 12, respectively. ESW group showed a gradual transition of hardness from bone to fibrocartilage to tendon, and had a higher Vickers hardness than the control group at week 12. In conclusion, ESW enhanced fibrocartilage regeneration at the healing interface in a delayed TBI healing model. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Anatomic ACL reconstruction: does the platelet-rich plasma accelerate tendon healing?

PubMed

Silva, Alcindo; Sampaio, Ricardo

2009-06-01

Recently, the use of hamstring tendons in anterior cruciate ligament repair has been increasing. However, tendon-to-bone healing occurs slowly, which can be a problem to an early return to sport activities. The use of growth factors from platelets seems to improve tissue healing. We enrolled 40 patients in a prospective study that were submitted to an anatomic reconstruction of the anterior cruciate ligament. Patients were sequentially enrolled into four groups: group A without platelet-rich plasma (PRP); group B with PRP in femoral tunnels at the end of surgery; group C with PRP in femoral tunnels at the end of surgery and intra-articular at 2- and 4 weeks after surgery; group D with PRP activated with thrombin in the femoral tunnels. All patients underwent magnetic resonance imaging of the knee 3 months after surgery to evaluate the signal intensity of the fibrous interzone (FIZ) in the femoral tunnels. We did not find any difference among the groups when comparing the signal intensity of the FIZ on magnetic resonance imaging.

The effect of seprafilm on adhesion formation and tendon healing after flexor tendon repair in chicken.

PubMed

Yilmaz, Erhan; Avci, Mustafa; Bulut, Mehmet; Kelestimur, Halidun; Karakurt, Lokman; Ozercan, Ibrahim

2010-03-01

Adhesion of the tendon, which can occur during healing of tendon repair, is negatively affected by the outcome of surgery. In this experimental study, we sought to prevent adhesion of the tendon, and determined the mechanical stiffness of repair tissue by wrapping sodium hyaluronate and carboxymethylcellulose (Seprafilm; Genzyme, Cambridge, Massachusetts) around the repaired tendon segments. The study group comprised 2 groups of 20 chickens. In group I, the right gastrocnemius tendons of the chickens were cut smoothly, and after tendon and sheath repair, the skin was sutured. In group II, the right gastrocnemius tendons of the chickens were cut, the tendons were repaired, and before skin closure, Seprafilm was wrapped around the repaired tendon segments. Plastic splints were used for holding the chickens' ankles in a neutral position, and they were allowed weight bearing for 8 weeks. In group II, anatomic space between the tendon-sheath and tendon was clear and the tendon-sheath complex was sliding easily around the repaired tendon segment, and this complex was more functional both biomechanically and histologically. Also, the Seprafilm-applied tendons (group II) were observed to be biomechanically more resistant to the tensile forces in group I. Seprafilm is an easily applied interpositional material that can be used safely to prevent adhesion during the tendon healing process. Copyright 2010, SLACK Incorporated.

Patellar tendon healing with platelet-rich plasma: a prospective randomized controlled trial.

PubMed

de Almeida, Adriano Marques; Demange, Marco Kawamura; Sobrado, Marcel Faraco; Rodrigues, Marcelo Bordalo; Pedrinelli, André; Hernandez, Arnaldo José

2012-06-01

The patellar tendon has limited ability to heal after harvesting its central third. Platelet-rich plasma (PRP) could improve patellar tendon healing. Adding PRP to the patellar tendon harvest site would improve donor site healing and improve clinical outcome at 6 months after anterior cruciate ligament (ACL) reconstruction with a patellar tendon graft. Randomized controlled trial; Level of evidence, 1. Twenty-seven patients were randomly divided to receive (n = 12) or not receive (n = 15) PRP in the patellar tendon harvest site during ACL reconstruction. The primary outcome was magnetic resonance imaging (MRI) assessment of patellar tendon healing (gap area) after 6 months. Secondary outcomes were questionnaires and isokinetic testing of ACL reconstruction with a patellar tendon graft comparing both groups. Patellar tendon gap area was significantly smaller in the PRP group (4.9 ± 5.3 mm(2); 95% confidence interval [CI], 1.1-8.8) than in the control group (9.4 ± 4.4 mm(2); 95% CI, 6.6-12.2; P = .046). Visual analog scale score for pain was lower in the PRP group immediately postoperatively (3.8 ± 1.0; 95% CI, 3.18-4.49) than in the control group (5.1 ± 1.4; 95% CI, 4.24-5.90; P = .02). There were no differences after 6 months in questionnaire and isokinetic testing results comparing both groups. We showed that PRP had a positive effect on patellar tendon harvest site healing on MRI after 6 months and also reduced pain in the immediate postoperative period. Questionnaire and isokinetic testing results were not different between the groups at 6 months.

Fluoroquinolones impair tendon healing in a rat rotator cuff repair model: a preliminary study.

PubMed

Fox, Alice J S; Schär, Michael O; Wanivenhaus, Florian; Chen, Tony; Attia, Erik; Binder, Nikolaus B; Otero, Miguel; Gilbert, Susannah L; Nguyen, Joseph T; Chaudhury, Salma; Warren, Russell F; Rodeo, Scott A

2014-12-01

Recent studies suggest that fluoroquinolone antibiotics predispose tendons to tendinopathy and/or rupture. However, no investigations on the reparative capacity of tendons exposed to fluoroquinolones have been conducted. Fluoroquinolone-treated animals will have inferior biochemical, histological, and biomechanical properties at the healing tendon-bone enthesis compared with controls. Controlled laboratory study. Ninety-two rats underwent rotator cuff repair and were randomly assigned to 1 of 4 groups: (1) preoperative (Preop), whereby animals received fleroxacin for 1 week preoperatively; (2) pre- and postoperative (Pre/Postop), whereby animals received fleroxacin for 1 week preoperatively and for 2 weeks postoperatively; (3) postoperative (Postop), whereby animals received fleroxacin for 2 weeks postoperatively; and (4) control, whereby animals received vehicle for 1 week preoperatively and for 2 weeks postoperatively. Rats were euthanized at 2 weeks postoperatively for biochemical, histological, and biomechanical analysis. All data were expressed as mean ± standard error of the mean (SEM). Statistical comparisons were performed using either 1-way or 2-way ANOVA, with P < .05 considered significant. Reverse transcriptase quantitative polymerase chain reaction (RTqPCR) analysis revealed a 30-fold increase in expression of matrix metalloproteinase (MMP)-3, a 7-fold increase in MMP-13, and a 4-fold increase in tissue inhibitor of metalloproteinases (TIMP)-1 in the Pre/Postop group compared with the other groups. The appearance of the healing enthesis in all treated animals was qualitatively different than that in controls. The tendons were friable and atrophic. All 3 treated groups showed significantly less fibrocartilage and poorly organized collagen at the healing enthesis compared with control animals. There was a significant difference in the mode of failure, with treated animals demonstrating an intrasubstance failure of the supraspinatus tendon during testing

Evaluation of the histological and mechanical features of tendon healing in a rabbit model with the use of second-harmonic-generation imaging and tensile testing.

PubMed

Hase, E; Sato, K; Yonekura, D; Minamikawa, T; Takahashi, M; Yasui, T

2016-11-01

This study aimed to evaluate the histological and mechanical features of tendon healing in a rabbit model with second-harmonic-generation (SHG) imaging and tensile testing. A total of eight male Japanese white rabbits were used for this study. The flexor digitorum tendons in their right leg were sharply transected, and then were repaired by intratendinous stitching. At four weeks post-operatively, the rabbits were killed and the flexor digitorum tendons in both right and left legs were excised and used as specimens for tendon healing (n = 8) and control (n = 8), respectively. Each specimen was examined by SHG imaging, followed by tensile testing, and the results of the two testing modalities were assessed for correlation. While the SHG light intensity of the healing tendon samples was significantly lower than that of the uninjured tendon samples, 2D Fourier transform SHG images showed a clear difference in collagen fibre structure between the uninjured and the healing samples, and among the healing samples. The mean intensity of the SHG image showed a moderate correlation (R 2 = 0.37) with Young's modulus obtained from the tensile testing. Our results indicate that SHG microscopy may be a potential indicator of tendon healing.Cite this article: E. Hase, K. Sato, D. Yonekura, T. Minamikawa, M. Takahashi, T. Yasui. Evaluation of the histological and mechanical features of tendon healing in a rabbit model with the use of second-harmonic-generation imaging and tensile testing. Bone Joint Res 2016;5:577-585. DOI: 10.1302/2046-3758.511.BJR-2016-0162.R1. © 2016 Yasui et al.

Effect of Hypercholesterolemia on Fatty Infiltration and Quality of Tendon-to-Bone Healing in a Rabbit Model of a Chronic Rotator Cuff Tear: Electrophysiological, Biomechanical, and Histological Analyses.

PubMed

Chung, Seok Won; Park, HaeBong; Kwon, Jieun; Choe, Ghee Young; Kim, Sae Hoon; Oh, Joo Han

2016-05-01

The incidence of healing failure after rotator cuff repair is high, and fatty infiltration is a crucial factor in healing failure. To verify the effect of hypercholesterolemia on fatty infiltration and the quality of tendon-to-bone healing and its reversibility by lowering the cholesterol level in a chronic tear model using the rabbit supraspinatus. Controlled laboratory study. Forty-eight rabbits were randomly allocated into 4 groups (n = 12 each). After 4 weeks of a high-cholesterol diet (groups A and B) and a regular diet (groups C and D), the supraspinatus tendon was detached and left alone for 6 weeks and then was repaired in a transosseous manner (groups A, B, and C). Group D served as a control. Group A continued to receive the high-cholesterol diet until the final evaluation (6 weeks after repair); however, at the time of repair, group B was changed to a general diet with administration of a cholesterol-lowering agent (simvastatin). Histological evaluation of the fat-to-muscle proportion was performed twice, at the time of repair and the final evaluation, and an electromyographic (EMG) test, mechanical test, and histological test of tendon-to-bone healing were performed at the final evaluation. For the EMG test, group A showed a significantly smaller area of compound muscle action potential compared with groups C and D (all P <.01), and group B showed a larger area than group A, almost up to the level of group C (P = .312). Similarly, group A showed significantly lower mechanical properties both in load-to-failure and stiffness compared with groups C and D (all P <.05). In addition, although not significantly different, the mechanical properties of group B were higher than those of group A (mean load-to-failure: group A = 42.01 N, group B = 58.23 N [P = .103]; mean stiffness: group A = 36.32 N/mm, group B = 47.22 N/mm [P = .153]). For the histological test, groups A and B showed a significantly higher fat-to-muscle proportion than did groups C and D at 6

Moderate treadmill running exercise prior to tendon injury enhances wound healing in aging rats

PubMed Central

Zhang, Jianying; Yuan, Ting; Wang, James H-C.

2016-01-01

The effect of exercise on wound healing in aging tendon was tested using a rat moderate treadmill running (MTR) model. The rats were divided into an MTR group that ran on a treadmill for 4 weeks and a control group that remained in cages. After MTR, a window defect was created in the patellar tendons of all rats and wound healing was analyzed. We found that MTR accelerated wound healing by promoting quicker closure of wounds, improving the organization of collagen fibers, and decreasing senescent cells in the wounded tendons when compared to the cage control. MTR also lowered vascularization, increased the numbers of tendon stem/progenitor cells (TSCs) and TSC proliferation than the control. Besides, MTR significantly increased the expression of stem cell markers, OCT-4 and Nanog, and tenocyte genes, Collagen I, Collagen III and tenomodulin, and down-regulated PPAR-γ, Collagen II and Runx-2 (non-tenocyte genes). These findings indicated that moderate exercise enhances healing of injuries in aging tendons through TSC based mechanisms, through which exercise regulates beneficial effects in tendons. This study reveals that appropriate exercise may be used in clinics to enhance tendon healing in aging patients. PMID:26885754

Moderate treadmill running exercise prior to tendon injury enhances wound healing in aging rats.

PubMed

Zhang, Jianying; Yuan, Ting; Wang, James H-C

2016-02-23

The effect of exercise on wound healing in aging tendon was tested using a rat moderate treadmill running (MTR) model. The rats were divided into an MTR group that ran on a treadmill for 4 weeks and a control group that remained in cages. After MTR, a window defect was created in the patellar tendons of all rats and wound healing was analyzed. We found that MTR accelerated wound healing by promoting quicker closure of wounds, improving the organization of collagen fibers, and decreasing senescent cells in the wounded tendons when compared to the cage control. MTR also lowered vascularization, increased the numbers of tendon stem/progenitor cells (TSCs) and TSC proliferation than the control. Besides, MTR significantly increased the expression of stem cell markers, OCT-4 and Nanog, and tenocyte genes, Collagen I, Collagen III and tenomodulin, and down-regulated PPAR-γ, Collagen II and Runx-2 (non-tenocyte genes). These findings indicated that moderate exercise enhances healing of injuries in aging tendons through TSC based mechanisms, through which exercise regulates beneficial effects in tendons. This study reveals that appropriate exercise may be used in clinics to enhance tendon healing in aging patients.

Role of tissue-engineered artificial tendon in healing of a large Achilles tendon defect model in rabbits.

PubMed

Moshiri, Ali; Oryan, Ahmad; Meimandi-Parizi, Abdolhamid

2013-09-01

Treatment of large Achilles tendon defects is technically demanding. Tissue engineering is an option. We constructed a collagen-based artificial tendon, covered it with a polydioxanon (PDS) sheath, and studied the role of this bioimplant on experimental tendon healing in vivo. A 2-cm tendon gap was created in the left Achilles tendon of rabbits (n = 120). The animals were randomly divided into 3 groups: control (no implant), treated with tridimensional-collagen, and treated with tridimensional-collagen-bidimensional-PDS implants. Each group was divided into 2 subgroups of 60 and 120 days postinjury (DPI). Another 50 pilot animals were used to study the host-implant interaction. Physical activity of the animals was scored and ultrasonographic and bioelectrical characteristics of the injured tendons were investigated weekly. After euthanasia, macro, micro, and nano morphologies and biophysical and biomechanical characteristics of the healing tendons were studied. Treatment improved function of the animals, time dependently. At 60 and 120 DPI, the treated tendons showed significantly higher maximum load, yield, stiffness, stress, and modulus of elasticity compared with controls. The collagen implant induced inflammation and absorbed the migrating fibroblasts in the defect area. By its unique architecture, it aligned the fibroblasts and guided their proliferation and collagen deposition along the stress line of the tendon and resulted in improved collagen density, micro-amp, micro-ohm, water uptake, and delivery of the regenerated tissue. The PDS-sheath covering amplified these characteristics. The implants were gradually absorbed and replaced by a new tendon. Minimum amounts of peritendinous adhesion, muscle atrophy, and fibrosis were observed in the treated groups. Some remnants of the implants were preserved and accepted as a part of the new tendon. The implants were cytocompatible, biocompatible, biodegradable, and effective in tendon healing and regeneration. This

Enhancement of rotator cuff tendon-bone healing with fibroblast growth factor 2 impregnated in gelatin hydrogel sheets in a rabbit model.

PubMed

Tokunaga, Takuya; Karasugi, Tatsuki; Arimura, Hitoshi; Yonemitsu, Ryuji; Sakamoto, Hidetoshi; Ide, Junji; Mizuta, Hiroshi

2017-10-01

Application of fibroblast growth factor 2 (FGF-2) may improve the healing response after rotator cuff (RC) surgical repair. This study aimed to determine whether FGF-2-impregnated gelatin hydrogel sheet (GHS) incorporation into the bony trough on the greater tuberosity facilitates healing after RC surgical repair in rabbits. We assigned 120 adult male Japanese white rabbits treated with unilateral surgery for supraspinatus tendon repair into the following groups: suture-only group (suture); suture and GHS with phosphate-buffered saline (carrier); suture and GHS with 3 µg of FGF-2 (F3); and suture and GHS with 30 µg of FGF-2 (F30). The effect of FGF-2 was assessed using histologic, biomechanical, and microcomputed tomography evaluations at 2, 6, and 12 weeks. At 12 weeks, loose fibrovascular tissues emerged at the repair site in the suture and carrier groups and dense tendon-like tissues in the F3 and F30 groups, which demonstrated significantly higher ultimate load-to-failure and stress-to-failure at 12 weeks than that in the suture and carrier groups. Microcomputed tomography imaging showed ectopic calcification formation in some specimens from each group. Appearances or frequencies were similar among groups. The histologic and biomechanical effects of FGF-2 on RC healing were obvious at ≥6 weeks postoperatively. FGF-2-impregnated GHS incorporation into the bony trough on the greater tuberosity before RC surgical repair is feasible and results in histologic and biomechanical improvements during RC healing in rabbits. No detrimental effect on ectopic calcification was observed. Copyright © 2017 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.

Direct Lentiviral-Cyclooxygenase 2 Application to the Tendon-Bone Interface Promotes Osteointegration and Enhances Return of the Pull-Out Tensile Strength of the Tendon Graft in a Rat Model of Biceps Tenodesis

PubMed Central

Wergedal, Jon E.; Stiffel, Virginia; Lau, Kin-Hing William

2014-01-01

promote tendon-to-bone healing after tenodesis or related surgeries. PMID:24848992

Effect of Tendon Stem Cells in Chitosan/β-Glycerophosphate/Collagen Hydrogel on Achilles Tendon Healing in a Rat Model.

PubMed

Yang, Zhijin; Cao, Honghui; Gao, Shang; Yang, Mingyu; Lyu, Jingtong; Tang, Kanglai

2017-09-27

BACKGROUND The aim of this study was to determine whether the local application of tendon stem cells (TSCs) with chitosan/β-glycerophosphate/collagen(C/GP/Co) hydrogel promotes healing after an acute Achilles tendon injury in a rat model. MATERIAL AND METHODS Ninety-six Sprague-Dawley (SD) rats were used to make an Achilles tendon defect model, then the animals were randomly divided into 4 groups consisting of 8 rats each: control group, hydrogel group, TSCs group, and TSCs with hydrogel group. At 2, 4, and 6 weeks after treatment, tendon samples were harvested, and the quality of tendon repair was evaluated based on histology, immunohistochemistry, and biomechanical properties. RESULTS Combining TSCs with C/GP/Co hydrogel significantly enhances tendon healing compared with the control, hydrogel, and TSCs groups. The improved healing was indicated by the improvement in histological and immunohistochemistry outcomes and the increase in the biomechanical properties of the regenerated tissue at both 4 and 6 weeks post-injury. CONCLUSIONS This study demonstrates that the transplantation of TSCs combined with C/GP/Co hydrogel significantly improved the histological, immunohistochemistry, and biomechanical outcomes of the regenerated tissue at 4 and 6 weeks after implantation. TSCs with C/GP/Co hydrogel is a potentially effective treatment for tendon injury.

Tendon healing in a bone tunnel. Part I: Biomechanical results after biodegradable interference fit fixation in a model of anterior cruciate ligament reconstruction in sheep.

PubMed

Weiler, Andreas; Peine, Ricarda; Pashmineh-Azar, Alireza; Abel, Clemens; Südkamp, Norbert P; Hoffmann, Reinhard F G

2002-02-01

Interference fit fixation of soft-tissue grafts has recently raised strong interest because it allows for anatomic graft fixation that may increase knee stability and graft isometry. Although clinical data show promising results, no data exist on how tendon healing progresses using this fixation. The purpose of the present study was to investigate anterior cruciate ligament (ACL) reconstruction biomechanically using direct tendon-to-bone interference fit fixation with biodegradable interference screws in a sheep model. Animal study. Thirty-five mature sheep underwent ACL reconstruction with an autologous Achilles tendon split graft. Grafts were directly fixed with poly-(D,L-lactide) interference screws. Animals were euthanized after 6, 9, 12, 24, and 52 weeks and standard biomechanical evaluations were performed. All grafts at time zero failed by pullout from the bone tunnel, whereas grafts at 6 and 9 weeks failed intraligamentously at the screw insertion site. At 24 and 52 weeks, grafts failed by osteocartilaginous avulsion. At 24 weeks, interference screws were macroscopically degraded. At 6 and 9 weeks tensile stress was only 6.8% and 9.6%, respectively, of the graft tissue at time zero. At 52 weeks, tensile stress of the reconstruction equaled 63.8% and 47.3% of the Achilles tendon graft at time zero and the native ACL, respectively. A complete restitution of anterior-posterior drawer displacement was found at 52 weeks compared with the time-zero reconstruction. It was found that over the whole healing period the graft fixation proved not to be the weak link of the reconstruction and that direct interference fit fixation withstands loads without motion restriction in the present animal model. The weak link during the early healing stage was the graft at its tunnel entrance site, leading to a critical decrease in mechanical properties. This finding indicates that interference fit fixation of a soft-tissue graft may additionally alter the mechanical properties of

Aging Does Not Alter Tendon Mechanical Properties During Homeostasis, but does Impair Flexor Tendon Healing

PubMed Central

Ackerman, Jessica E.; Bah, Ibrahima; Jonason, Jennifer H.; Buckley, Mark R.; Loiselle, Alayna E.

2017-01-01

Aging is an important factor in disrupted homeostasis of many tissues. While an increased incidence of tendinopathy and tendon rupture are observed with aging, it is unclear whether this is due to progressive changes in tendon cell function and mechanics over time, or an impaired repair reaction from aged tendons in response to insult or injury. In the present study we examined changes in the mechanical properties of Flexor Digitorum Longus (FDL), Flexor Carpi Ulnaris (FCU), and tail fascicles in both male and female C57Bl/6 mice between 3-27 months of age to better understand the effects of sex and age on tendon homeostasis. No change in max load at failure was observed in any group over the course of aging, although there were significant decreases in toe and linear stiffness in female mice from 3-months to 15, and to 22-27-months. No changes in cell proliferation were observed with aging, although an observable decrease in cellularity occurred in 31-month old tendons. Given that aging did not dramatically alter tendon mechanical homeostasis we hypothesized that a disruption in tendon homeostasis, via acute injury would result in an impaired healing response. Significant decreases in max load, stiffness, and yield load were observed in repairs of 22-month old mice, relative to 4-month old mice. No changes in cell proliferation were observed between young and aged, however a dramatic loss of bridging collagen extracellular matrix was observed in aged repairs suggest that matrix production, but not cell proliferation leads to impaired tendon healing with aging. PMID:28419543

Rescue plan for Achilles: Therapeutics steering the fate and functions of stem cells in tendon wound healing.

PubMed

Schneider, Magdalena; Angele, Peter; Järvinen, Tero A H; Docheva, Denitsa

2017-12-24

Due to the increasing age of our society and a rise in engagement of young people in extreme and/or competitive sports, both tendinopathies and tendon ruptures present a clinical and financial challenge. Tendon has limited natural healing capacity and often responds poorly to treatments, hence it requires prolonged rehabilitation in most cases. Till today, none of the therapeutic options has provided successful long-term solutions, meaning that repaired tendons do not recover their complete strength and functionality. Our understanding of tendon biology and healing increases only slowly and the development of new treatment options is insufficient. In this review, following discussion on tendon structure, healing and the clinical relevance of tendon injury, we aim to elucidate the role of stem cells in tendon healing and discuss new possibilities to enhance stem cell treatment of injured tendon. To date, studies mainly apply stem cells, often in combination with scaffolds or growth factors, to surgically created tendon defects. Deeper understanding of how stem cells and vasculature in the healing tendon react to growth factors, common drugs used to treat injured tendons and promising cellular boosters could help to develop new and more efficient ways to manage tendon injuries. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

Bone healing in children.

PubMed

Lindaman, L M

2001-01-01

Just as pediatric fractures and bones are basically similar to adult fractures and bones, pediatric bone healing is basically similar to adult bone healing. They both go through the three same phases of inflammation, reparation, and remodeling. It is those differences between pediatric and adult bone, however, that affect the differences in the healing of pediatric bone. Because pediatric bone can fail in compression, less initial stability and less callus formation is required to achieve a clinically stable or healed fracture. The greater subperiosteal hematoma and the stronger periosteum all contribute to a more rapid formation of callous strong enough to render the fracture healed more rapidly than the adult. Genes and hormones that are necessary for the initial formation of the skeleton are the same as, or at least similar in most instances, to those necessary for the healing of fractures. This osteogenic environment of the pediatric bone means that these fracture healing processes are already ongoing in the child at the time of the fracture. In the adult, these factors must be reawakened, leading to the slower healing time in the adult. Once the fracture is healed, the still-growing pediatric bone can correct any "sins" of fracture alignment or angulation leaving the bone with no signs of having ever been broken. The final result is bone that is, in the child's words, "as good as new."

Basic FGF or VEGF gene therapy corrects insufficiency in the intrinsic healing capacity of tendons

PubMed Central

Tang, Jin Bo; Wu, Ya Fang; Cao, Yi; Chen, Chuan Hao; Zhou, You Lang; Avanessian, Bella; Shimada, Masaru; Wang, Xiao Tian; Liu, Paul Y.

2016-01-01

Tendon injury during limb motion is common. Damaged tendons heal poorly and frequently undergo unpredictable ruptures or impaired motion due to insufficient innate healing capacity. By basic fibroblast growth factor (bFGF) or vascular endothelial growth factor (VEGF) gene therapy via adeno-associated viral type-2 (AAV2) vector to produce supernormal amount of bFGF or VEGF intrinsically in the tendon, we effectively corrected the insufficiency of the tendon healing capacity. This therapeutic approach (1) resulted in substantial amelioration of the low growth factor activity with significant increases in bFGF or VEGF from weeks 4 to 6 in the treated tendons (p < 0.05 or p < 0.01), (2) significantly promoted production of type I collagen and other extracellular molecules (p < 0.01) and accelerated cellular proliferation, and (3) significantly increased tendon strength by 68–91% from week 2 after AAV2-bFGF treatment and by 82–210% from week 3 after AAV2-VEGF compared with that of the controls (p < 0.05 or p < 0.01). Moreover, the transgene expression dissipated after healing was complete. These findings show that the gene transfers provide an optimistic solution to the insufficiencies of the intrinsic healing capacity of the tendon and offers an effective therapeutic possibility for patients with tendon disunion. PMID:26865366

Use of quantitative analysis of sonographic brightness for detection of early healing of tendon injury in horses.

PubMed

Micklethwaite, L; Wood, A K; Sehgal, C M; Polansky, M; Dowling, B A; Dart, A J; Rose, R J; Hodgson, D R

2001-08-01

To determine whether quantitative analysis of sonographic brightness could be used to detect healing of an induced injury of the superficial digital flexor tendon in horses and whether rate of healing was influenced by equine recombinant growth hormone. 8 clinically normal Standardbreds. A localized injury was created in the left and right superficial digital flexor tendons of each horse by injection of 2,000 units of collagenase. After injury, 4 horses received equine recombinant growth hormone, a possible promoter of tendon healing. Sonographic images (7.5 MHz) of the flexor tendons and ligaments of the metacarpal region were recorded on videotape prior to injury and weekly for 7 weeks after injury. Images were digitized, and sonographic brightness of tendons and ligaments was calculated. Collagenase-induced injury was sonographically similar to naturally occurring injury. After injury, sonographic brightness of the tendon decreased; after 3 weeks, brightness progressively increased, although by 7 weeks brightness had not returned to preinjury value. Equine recombinant growth hormone had no significant effect on the rate of tendon healing, as evaluated sonographically or at necropsy. As healing developed, alterations in sonographic brightness of injured tendons coincided with real changes in tendon structure. Quantitative sonographic brightness could be used to accurately monitor healing of equine tendon and ligament injuries and investigate the efficacy of various treatment regimens.

Rotator cuff repair augmentation in a rat model that combines a multilayer xenograft tendon scaffold with bone marrow stromal cells

PubMed Central

Omi, Rei; Gingery, Anne; Steinmann, Scott P.; Amadio, Peter C.; An, Kai-Nan; Zhao, Chunfeng

2016-01-01

Hypothesis A composite of multilayer tendon slices (COMTS) seeded with bone marrow stromal cells (BMSCs) may impart mechanical and biologic augmentation effects on supraspinatus tendon repair under tension, thereby improving the healing process after surgery in rats. Methods Adult female Lewis rats (n = 39) underwent transection of the supraspinatus tendon and a 2-mm tendon resection at the distal end, followed by immediate repair to its bony insertion site under tension. Animals received 1 of 3 treatments at the repair site: (1) no augmentation, (2) COMTS augmentation alone, or (3) BMSC-seeded COMTS augmentation. BMSCs were labeled with a fluorescent cell marker. Animals were euthanized 6 weeks after surgery, and the extent of healing of the repaired supraspinatus tendon was evaluated with biomechanical testing and histologic analysis. Results Histologic analysis showed gap formation between the repaired tendon and bone in all specimens, regardless of treatment. Robust fibrous tissue was observed in rats with BMSC-seeded COMTS augmentation; however, fibrous tissue was scarce within the gap in rats with no augmentation or COMTS-only augmentation. Labeled transplanted BMSCs were observed throughout the repair site. Biomechanical analysis showed that the repairs augmented with BMSC-seeded COMTS had significantly greater ultimate load to failure and stiffness compared with other treatments. However, baseline (time 0) data showed that COMTS-only augmentation did not increase mechanical strength of the repair site. Conclusion Although the COMTS scaffold did not increase the initial repair strength, the BMSC-seeded scaffold increased healing strength and stiffness 6 weeks after rotator cuff repair in a rat model. Level of evidence Basic Science Study, Animal Model. PMID:26387915

Tendon-bone graft for tendinous mallet fingers following failed splinting.

PubMed

Wang, Le; Zhang, Xu; Liu, Ze; Huang, Xiuge; Zhu, Hongwei; Yu, Yadong

2013-12-01

To describe and assess a surgical technique for the treatment of tendinous mallet fingers after failed conservative treatment. From January 2010 to March 2012, 28 tendinous mallet fingers in 28 patients were treated. All patients had greater than 25° extensor lags after 6 to 8 weeks of splinting. Four patients had a second trial of splinting, which also failed. A tendon-bone graft, taken from the extensor carpi radialis brevis and the third metacarpal base, was used for reconstruction. The mean time between the injury and operation was 74 days. The mean preoperative extension lag was 34°. Five patients reported pain in the distal interphalangeal joint. At the final follow-up, patients rated the level of pain on the distal interphalangeal and wrist joints using a visual analog scale. Joint motion was graded with the Crawford criteria. Hand function was assessed with the Disabilities of the Arm, Shoulder, and Hand questionnaire. Patients reported on their satisfaction based on the Michigan Hand Outcomes Questionnaire. Bone healing was achieved in all patients at a mean of 5 weeks. Position of bone graft was maintained until bone healing was evident in all cases. At the mean follow-up period of 15 months, nail deformity was not noted. No patient reported pain on the distal interphalangeal joint or wrist. The mean residual extension lag of the distal interphalangeal joints was 4°. The results showed that 24 digits were excellent and 4 were good based on the Crawford criteria. The Disabilities of the Arm, Shoulder, and Hand scores averaged 1, and 27 patients were satisfied with appearance of the hand. One patient sometimes felt uncomfortable regarding the appearance. A tendon-bone graft is a useful and reliable technique for the treatment of tendinous mallet fingers after failed splinting. Therapeutic IV. Copyright © 2013 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.

Bone morphogenetic protein 7 (BMP-7) influences tendon-bone integration in vitro.

PubMed

Schwarting, Tim; Lechler, Philipp; Struewer, Johannes; Ambrock, Marius; Frangen, Thomas Manfred; Ruchholtz, Steffen; Ziring, Ewgeni; Frink, Michael

2015-01-01

Successful graft ingrowth following reconstruction of the anterior cruciate ligament is governed by complex biological processes at the tendon-bone interface. The aim of this study was to investigate in an in vitro study the effects of bone morphogenetic protein 7 (BMP-7) on tendon-bone integration. To study the biological effects of BMP-7 on the process of tendon-bone-integration, two independent in vitro models were used. The first model involved the mono- and coculture of bovine tendon specimens and primary bovine osteoblasts with and without BMP-7 exposure. The second model comprised the mono- and coculture of primary bovine osteoblasts and fibroblasts. Alkaline phosphatase (ALP), lactate dehydrogenase (LDH), lactate and osteocalcin (OCN) were analyzed by ELISA. Histological analysis and electron microscopy of the tendon specimens were performed. In both models, positive effects of BMP-7 on ALP enzyme activity were observed (p<0.001). Additionally, similar results were noted for LDH activity and lactate concentration. BMP-7 stimulation led to a significant increase in OCN expression. Whereas the effects of BMP-7 on tendon monoculture peaked during an early phase of the experiment (p<0.001), the cocultures showed a maximal increase during the later stages (p<0.001). The histological analysis showed a stimulating effect of BMP-7 on extracellular matrix formation. Organized ossification zones and calcium carbonate-like structures were only observed in the BMP-stimulated cell cultures. This study showed the positive effects of BMP-7 on the biological process of tendon-bone integration in vitro. Histological signs of improved mineralization were paralleled by increased rates of osteoblast-specific protein levels in primary bovine osteoblasts and fibroblasts. Our findings indicated a role for BMP-7 as an adjuvant therapeutic agent in the treatment of ligamentous injuries, and they emphasized the importance of the transdifferentiation process of tendinous fibroblasts

Does footprint preparation influence tendon-to-bone healing after rotator cuff repair in an animal model?

PubMed

Ficklscherer, Andreas; Loitsch, Thomas; Serr, Michaela; Gülecyüz, Mehmet F; Niethammer, Thomas R; Müller, Hans-Helge; Milz, Stefan; Pietschmann, Matthias F; Müller, Peter E

2014-02-01

The aim of this study was to investigate the influence of footprint spongialization and radiofrequency ablation on rotator cuff repair outcomes compared with an untreated group in a rat model. We randomly assigned 189 Sprague-Dawley rats to either a spongialization, radiofrequency ablation, or untreated group. After separation of the supraspinatus tendon from the greater tubercle, the footprint was prepared by removing the cortical bone with a burr (spongialization), was prepared by ablating soft tissue with a radiofrequency ablation device, or was left unaltered (untreated). Biomechanical testing (after 7 weeks, n = 165) and histologic analysis after 1 and 7 weeks (n = 24) followed reinsertion. The mean load to failure was 17.51 ± 4.46 N/mm(2) in the spongialization group, 15.56 ± 4.85 N/mm(2) in the radiofrequency ablation group, and 19.21 ± 5.19 N/mm(2) in the untreated group. A significant difference was found between the spongialization and radiofrequency ablation groups (P = .0409), as well as between the untreated and radiofrequency ablation groups (P = .0014). There was no significant difference between the spongialization and untreated groups (P = .2456). The mean area of fibrocartilage transition, characterized by the presence of type II collagen, was larger after 1 and 7 weeks in the spongialization group (0.57 ± 0.1 mm(2) and 0.58 ± 0.1 mm(2), respectively) and untreated group (0.51 ± 0.1 mm(2) and 0.51 ± 0.2 mm(2), respectively) than in the radiofrequency ablation group (0.11 ± 0.1 mm(2) and 0.4 ± 0.1 mm(2), respectively) with P < .05 and P < .01. The results of this study show that radiofrequency ablation of the footprint results in a poor biomechanical and histologic outcome in an animal model. No preparation of the footprint has the same effect as spongialization. Different techniques of footprint preparation in rotator cuff repair may influence tendon-to-bone healing. Copyright © 2014 Arthroscopy Association of North America. Published by

Effect of Footprint Preparation on Tendon-to-Bone Healing: A Histologic and Biomechanical Study in a Rat Rotator Cuff Repair Model.

PubMed

Nakagawa, Haruhiko; Morihara, Toru; Fujiwara, Hiroyoshi; Kabuto, Yukichi; Sukenari, Tsuyoshi; Kida, Yoshikazu; Furukawa, Ryuhei; Arai, Yuji; Matsuda, Ken-Ichi; Kawata, Mitsuhiro; Tanaka, Masaki; Kubo, Toshikazu

2017-08-01

To compare the histologic and biomechanical effects of 3 different footprint preparations for repair of tendon-to-bone insertions and to assess the behavior of bone marrow-derived cells in each method of insertion repair. We randomized 81 male Sprague-Dawley rats and green fluorescent protein-bone marrow chimeric rats into 3 groups. In group A, we performed rotator cuff repair after separating the supraspinatus tendon from the greater tuberosity and removing the residual tendon tissue. In group B, we also drilled 3 holes into the footprint. The native fibrocartilage was preserved in groups A and B. In group C, we excavated the footprint until the cancellous bone was exposed. Histologic repair of the tendon-to-bone insertion, behavior of the bone marrow-derived cells, and ultimate force to failure were examined postoperatively. The areas of metachromasia in groups A, B, and C were 0.033 ± 0.019, 0.089 ± 0.022, and 0.002 ± 0.001 mm 2 /mm 2 , respectively, at 4 weeks and 0.029 ± 0.022, 0.090 ± 0.039, and 0.003 ± 0.001 mm 2 /mm 2 , respectively, at 8 weeks. At 4 and 8 weeks postoperatively, significantly higher cartilage matrix production was observed in group B than in group C (4 weeks, P = .002; 8 weeks, P < .001). In green fluorescent protein-bone marrow chimeric rats in group B, bone marrow-derived chondrogenic cells infiltrated the fibrocartilage layer. Ultimate force to failure was significantly higher in group B (19.7 ± 3.4 N) than in group C (16.7 ± 2.0 N) at 8 weeks (P = .031). Drilling into the footprint and preserving the fibrocartilage improved the quality of repair tissue and biomechanical strength at the tendon-to-bone insertion after rotator cuff repair in an animal model. Drilling into the footprint and preserving the fibrocartilage can enhance repair of tendon-to-bone insertions. This method may be clinically useful in rotator cuff repair. Copyright © 2017 Arthroscopy Association of North America. Published by Elsevier Inc. All

The role of bone sialoprotein in the tendon-bone insertion.

PubMed

Marinovich, Ryan; Soenjaya, Yohannes; Wallace, Gregory Q; Zuskov, Andre; Dunkman, Andrew; Foster, Brian L; Ao, Min; Bartman, Kevin; Lam, Vida; Rizkalla, Amin; Beier, Frank; Somerman, Martha J; Holdsworth, David W; Soslowsky, Louis J; Lagugné-Labarthet, François; Goldberg, Harvey A

2016-01-01

Tendons/ligaments insert into bone via a transitional structure, the enthesis, which is susceptible to injury and difficult to repair. Fibrocartilaginous entheses contain fibrocartilage in their transitional zone, part of which is mineralized. Mineral-associated proteins within this zone have not been adequately characterized. Members of the Small Integrin Binding Ligand N-linked Glycoprotein (SIBLING) family are acidic phosphoproteins expressed in mineralized tissues. Here we show that two SIBLING proteins, bone sialoprotein (BSP) and osteopontin (OPN), are present in the mouse enthesis. Histological analyses indicate that the calcified zone of the quadriceps tendon enthesis is longer in Bsp(-/-) mice, however no difference is apparent in the supraspinatus tendon enthesis. In an analysis of mineral content within the calcified zone, micro-CT and Raman spectroscopy reveal that the mineral content in the calcified fibrocartilage of the quadriceps tendon enthesis are similar between wild type and Bsp(-/-) mice. Mechanical testing of the patellar tendon shows that while the tendons fail under similar loads, the Bsp(-/-) patellar tendon is 7.5% larger in cross sectional area than wild type tendons, resulting in a 16.5% reduction in failure stress. However, Picrosirius Red staining shows no difference in collagen organization. Data collected here indicate that BSP is present in the calcified fibrocartilage of murine entheses and suggest that BSP plays a regulatory role in this structure, influencing the growth of the calcified fibrocartilage in addition to the weakening of the tendon mechanical properties. Based on the phenotype of the Bsp(-/-) mouse enthesis, and the known in vitro functional properties of the protein, BSP may be a useful therapeutic molecule in the reattachment of tendons and ligaments to bone. Copyright © 2016 International Society of Matrix Biology. All rights reserved.

The Role of Bone Sialoprotein in the Tendon-Bone Insertion

PubMed Central

Marinovich, Ryan; Soenjaya, Yohannes; Wallace, Gregory Q.; Zuskov, Andre; Dunkman, Andrew; Foster, Brian L.; Ao, Min; Bartman, Kevin; Lam, Vida; Rizkalla, Amin; Beier, Frank; Somerman, Martha J.; Holdsworth, David W.; Soslowsky, Louis J.; Lagugné-Labarthet, François; Goldberg, Harvey A.

2016-01-01

Tendons/ligaments insert into bone via a transitional structure, the enthesis, which is susceptible to injury and difficult to repair. Fibrocartilaginous entheses contain fibrocartilage in their transitional zone, part of which is mineralized. Mineral-associated proteins within this zone have not been adequately characterized. Members of the Small Integrin Binding Ligand N-Linked Glycoprotein (SIBLING) family are acidic phosphoproteins expressed in mineralized tissues. Here we show that two SIBLING proteins, bone sialoprotein (BSP) and osteopontin (OPN), are present in the mouse enthesis. Histological analyses indicate that the calcified zone of the quadriceps tendon enthesis is longer in Bsp−/− mice, however no difference is apparent in the supraspinatus tendon enthesis. In an analysis of mineral content within the calcified zone, micro-CT and Raman spectroscopy reveal that the mineral content in the calcified fibrocartilage of the quadriceps tendon enthesis are similar between wild type and Bsp−/− mice. Mechanical testing of the patellar tendon shows that while the tendons fail under similar loads, the Bsp−/− patellar tendon is 7.5% larger in cross sectional area than wild type tendons, resulting in a 16.5% reduction in failure stress. However, picrosirius red staining shows no difference in collagen organization. Data collected here indicate that BSP is present in the calcified fibrocartilage of murine entheses and suggest that BSP plays a regulatory role in this structure, influencing the growth of the calcified fibrocartilage in addition to the weakening of the tendon mechanical properties. Based on the phenotype of the Bsp−/− mouse enthesis, and the known in vitro functional properties of the protein, BSP may be a useful therapeutic molecule in the reattachment of tendons and ligaments to bone. PMID:26826499

Effect of Calendula officinalis cream on achilles tendon healing.

PubMed

Aro, A A; Perez, M O; Vieira, C P; Esquisatto, M A M; Rodrigues, R A F; Gomes, L; Pimentel, E R

2015-02-01

In recent years, the scientific community has undertaken research on plant extracts, searching for compounds with pharmacological activities that can be used in diverse fields of medicine. Calendula officinalis L. is known to have antioxidant, anti-inflammatory, antibacterial, and wound healing properties when used to treat skin burns. Therefore, the purpose of this study was to analyze the effects of C. officinalis on the initial phase of Achilles tendon healing. Wistar rats were separated in three groups: Calendula (Cal)-rats with a transected tendon were treated with topical applications of C. officinalis cream and then euthanized 7 days after injury; Control (C)-rats were treated with only vehicle after transection; and Normal (N)-rats without tenotomy. Higher concentrations of hydroxyproline (an indicator of total collagen) and non-collagenous proteins were observed in the Cal group in relation to the C group. Zymography showed no difference in the amount of the isoforms of metalloproteinase-2 and of metalloproteinase-9, between C and Cal groups. Polarization microscopy images analysis showed that the Cal group presented a slightly higher birefringence compared with the C group. In sections of tendons stained with toluidine blue, the transected groups presented higher metachromasy as compared with the N group. Immunocytochemistry analysis for chondroitin-6-sulfate showed no difference between the C and Cal groups. In conclusion, the topical application of C. officinalis after tendon transection increases the concentrations of collagen and non-collagenous proteins, as well as the collagen organization in the initial phase of healing. © 2014 Wiley Periodicals, Inc.

The promoting effect of pentadecapeptide BPC 157 on tendon healing involves tendon outgrowth, cell survival, and cell migration.

PubMed

Chang, Chung-Hsun; Tsai, Wen-Chung; Lin, Miao-Sui; Hsu, Ya-Hui; Pang, Jong-Hwei Su

2011-03-01

Pentadecapeptide BPC 157, composed of 15 amino acids, is a partial sequence of body protection compound (BPC) that is discovered in and isolated from human gastric juice. Experimentally it has been demonstrated to accelerate the healing of many different wounds, including transected rat Achilles tendon. This study was designed to investigate the potential mechanism of BPC 157 to enhance healing of injured tendon. The outgrowth of tendon fibroblasts from tendon explants cultured with or without BPC 157 was examined. Results showed that BPC 157 significantly accelerated the outgrowth of tendon explants. Cell proliferation of cultured tendon fibroblasts derived from rat Achilles tendon was not directly affected by BPC 157 as evaluated by MTT assay. However, the survival of BPC 157-treated cells was significantly increased under the H(2)O(2) stress. BPC 157 markedly increased the in vitro migration of tendon fibroblasts in a dose-dependent manner as revealed by transwell filter migration assay. BPC 157 also dose dependently accelerated the spreading of tendon fibroblasts on culture dishes. The F-actin formation as detected by FITC-phalloidin staining was induced in BPC 157-treated fibroblasts. The protein expression and activation of FAK and paxillin were determined by Western blot analysis, and the phosphorylation levels of both FAK and paxillin were dose dependently increased by BPC 157 while the total amounts of protein was unaltered. In conclusion, BPC 157 promotes the ex vivo outgrowth of tendon fibroblasts from tendon explants, cell survival under stress, and the in vitro migration of tendon fibroblasts, which is likely mediated by the activation of the FAK-paxillin pathway.

Effects of sodium hyaluronate on tendon healing and adhesion formation in horses.

PubMed

Gaughan, E M; Nixon, A J; Krook, L P; Yeager, A E; Mann, K A; Mohammed, H; Bartel, D L

1991-05-01

Sodium hyaluronate reduces adhesions after tendon repair in rodents and dogs, and has been used in limited clinical trials in people. To evaluate its effect on tendon healing and adhesion formation in horses and to compare these effects with those of a compound of similar visco-elastic properties, a study was performed in horses, using a model of collagenase injection in the flexor tendons within the digital sheath. Eight clinically normal horses were randomly allotted to 2 groups. Adhesion formation between the deep digital flexor tendon and the tendon sheath at the pastern region was induced in the forelimbs of all horses. Using tenoscopic control, a 20-gauge needle was inserted into the deep digital flexor tendon of horses under general anesthesia and 0.2 ml of collagenase (2.5 mg/ml) was injected. The procedure was repeated proximally at 2 other sites, spaced 1.5 cm apart. A biopsy forceps was introduced, and a 5-mm tendon defect was created at each injection site. Group-A horses had 120 mg of sodium hyaluronate (NaHA) gel injected into the tendon sheath of one limb. Group-B horses had methylcellulose gel injected at the same sites. The contralateral limbs of horses in both groups served as surgical, but noninjected, controls. Horses were euthanatized after 8 weeks of stall rest. Ultrasonographic evaluation revealed improved tendon healing after NaHa injection, but no difference in peritendinous adhesion formation. Tendon sheath fluid volume and hyaluronic acid (HA) content were greater in NaHA-treated limbs. Gross pathologic examination revealed considerably fewer and smaller adhesions when limbs were treated with NaHA. However, significant difference in pull-out strengths was not evident between NaHA-treated and control limbs. Histologically, the deep digital flexor tendon from the NaHA-treated limbs had reduced inflammatory cell infiltration, improved tendon structure, and less intratendinous hemorrhage. Treatment with methylcullulose had no significant

Functional Attachment of Soft Tissues to Bone: Development, Healing, and Tissue Engineering

PubMed Central

Lu, Helen H.; Thomopoulos, Stavros

2014-01-01

Connective tissues such as tendons or ligaments attach to bone across a multitissue interface with spatial gradients in composition, structure, and mechanical properties. These gradients minimize stress concentrations and mediate load transfer between the soft and hard tissues. Given the high incidence of tendon and ligament injuries and the lack of integrative solutions for their repair, interface regeneration remains a significant clinical challenge. This review begins with a description of the developmental processes and the resultant structure-function relationships that translate into the functional grading necessary for stress transfer between soft tissue and bone. It then discusses the interface healing response, with a focus on the influence of mechanical loading and the role of cell-cell interactions. The review continues with a description of current efforts in interface tissue engineering, highlighting key strategies for the regeneration of the soft tissue–to-bone interface, and concludes with a summary of challenges and future directions. PMID:23642244

Outcomes of acute Achilles tendon rupture repair with bone marrow aspirate concentrate augmentation.

PubMed

Stein, Benjamin E; Stroh, David Alex; Schon, Lew C

2015-05-01

Optimal treatment of acute Achilles tendon ruptures remains controversial. Positive results using stem-cell-bearing concentrates have been reported with other soft-tissue repairs, but no studies exist on outcomes of bone marrow aspirate concentrate (BMAC) augmentation in primary Achilles tendon repair. We reviewed patients with sport-related Achilles tendon ruptures treated via open repair augmented with BMAC injection from 2009 to 2011. Data on operative complications, strength, range of motion, rerupture, calf circumference and functional improvement through progressive return to sport and the Achilles tendon Total Rupture Score (ATRS) were analysed. A total of 27 patients (28 tendons) treated with open repair and BMAC injection were identified (mean age 38.3 ± 9.6 years). At mean follow-up of 29.7 ± 6.1 months, there were no reruptures. Walking without a boot was at 1.8 ± 0.7 months, participation in light activity was at 3.4 ± 1.8 months and 92% (25 of 27) of patients returned to their sport at 5.9 ± 1.8 months. Mean ATRS at final follow-up was 91 (range 72-100) points. One case of superficial wound dehiscence healed with local wound care. No soft-tissue masses, bone formation or tumors were observed in the operative extremity. Excellent results, including no re-ruptures and early mobilisation, were observed in this small cohort with open Achilles tendon repair augmented by BMAC. No adverse outcomes of biologic treatment were observed with this protocol. The efficacy of BMAC in the operative repair of acute Achilles tendon ruptures warrants further study. IV - Therapeutic.

The histology of tendon attachments to bone in man.

PubMed Central

Benjamin, M; Evans, E J; Copp, L

1986-01-01

Based on a parallel study of a wide range of human tendons from embalmed dissecting room subjects and from a study of dried bones, an explanation is offered for the well known similarity in gross appearance between the markings left by certain tendons (e.g. those of the rotator cuff) and by articular surfaces on dried bones. Epiphyseal tendons leave markings on bones that look like those left by articular surfaces. These tendons have a prominent zone of fibrocartilage at their attachment site and the deepest part of this is calcified, just as the deepest part of articular hyaline cartilage is calcified. After maceration of the soft tissues, the calcified (fibro) cartilage is left attached to the bone at articular surfaces and at the sites of tendon attachment. In all cases, the tissues separate at the basophilic tidemark between the calcified and uncalcified regions. This tidemark is smooth where there is much overlying uncalcified (fibro) cartilage and it is the smoothness that gives the typical appearance of the dried bone. Blood vessels do not generally traverse the tendon fibrocartilage plugs. Hence the areas are devoid of vascular foramina. The functional significance of tendon fibrocartilage is discussed with particular reference to supraspinatus. It is suggested that the uncalcified fibrocartilage ensures that the tendon fibres do not bend, splay out or become compressed at a hard tissue interface, and are thereby offered some protection from wear and tear. It is also suggested that the fibrocartilage plug of supraspinatus prevents the tendon from rubbing on the head of the humerus. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 PMID:3693113

Effect of Implanting a Soft Tissue Autograft in a Central-Third Patellar Tendon Defect: Biomechanical and Histological Comparisons

PubMed Central

Kinneberg, Kirsten R. C.; Galloway, Marc T.; Butler, David L.; Shearn, Jason T.

2011-01-01

Previous studies by our laboratory have demonstrated that implanting a stiffer tissue engineered construct at surgery is positively correlated with repair tissue stiffness at 12 weeks. The objective of this study was to test this correlation by implanting a construct that matches normal tissue biomechanical properties. To do this, we utilized a soft tissue patellar tendon autograft to repair a central-third patellar tendon defect. Patellar tendon auto-graft repairs were contrasted against an unfilled defect repaired by natural healing (NH). We hypothesized that after 12 weeks, patellar tendon autograft repairs would have biomechanical properties superior to NH. Bilateral defects were established in the central-third patellar tendon of skeletally mature (one year old), female New Zealand White rabbits (n = 10). In one limb, the excised tissue, the patellar tendon autograft, was sutured into the defect site. In the contralateral limb, the defect was left empty (natural healing). After 12 weeks of recovery, the animals were euthanized and their limbs were dedicated to bio-mechanical (n = 7) or histological (n = 3) evaluations. Only stiffness was improved by treatment with patellar tendon autograft relative to natural healing (p = 0.009). Additionally, neither the patellar tendon autograft nor natural healing repairs regenerated a normal zonal insertion site between the tendon and bone. Immunohistochemical staining for collagen type II demonstrated that fibrocartilage-like tissue was regenerated at the tendon-bone interface for both repairs. However, the tissue was disorganized. Insufficient tissue integration at the tendon-to-bone junction led to repair tissue failure at the insertion site during testing. It is important to re-establish the tendon-to-bone insertion site because it provides joint stability and enables force transmission from muscle to tendon and subsequent loading of the tendon. Without loading, tendon mechanical properties

The paratenon contributes to scleraxis-expressing cells during patellar tendon healing.

PubMed

Dyment, Nathaniel A; Liu, Chia-Feng; Kazemi, Namdar; Aschbacher-Smith, Lindsey E; Kenter, Keith; Breidenbach, Andrew P; Shearn, Jason T; Wylie, Christopher; Rowe, David W; Butler, David L

2013-01-01

The origin of cells that contribute to tendon healing, specifically extrinsic epitenon/paratenon cells vs. internal tendon fibroblasts, is still debated. The purpose of this study is to determine the location and phenotype of cells that contribute to healing of a central patellar tendon defect injury in the mouse. Normal adult patellar tendon consists of scleraxis-expressing (Scx) tendon fibroblasts situated among aligned collagen fibrils. The tendon body is surrounded by paratenon, which consists of a thin layer of cells that do not express Scx and collagen fibers oriented circumferentially around the tendon. At 3 days following injury, the paratenon thickens as cells within the paratenon proliferate and begin producing tenascin-C and fibromodulin. These cells migrate toward the defect site and express scleraxis and smooth muscle actin alpha by day 7. The thickened paratenon tissue eventually bridges the tendon defect by day 14. Similarly, cells within the periphery of the adjacent tendon struts express these markers and become disorganized. Cells within the defect region show increased expression of fibrillar collagens (Col1a1 and Col3a1) but decreased expression of tenogenic transcription factors (scleraxis and mohawk homeobox) and collagen assembly genes (fibromodulin and decorin). By contrast, early growth response 1 and 2 are upregulated in these tissues along with tenascin-C. These results suggest that paratenon cells, which normally do not express Scx, respond to injury by turning on Scx and assembling matrix to bridge the defect. Future studies are needed to determine the signaling pathways that drive these cells and whether they are capable of producing a functional tendon matrix. Understanding this process may guide tissue engineering strategies in the future by stimulating these cells to improve tendon repair.

Bromelain in the early phase of healing in acute crush Achilles tendon injury.

PubMed

Aiyegbusi, A I; Duru, F I O; Anunobi, C C; Noronha, C C; Okanlawon, A O

2011-01-01

Bromelain, an enzyme extracted from the stem of the pineapple plant has been proposed as a treatment for reducing pain and swelling following acute muscle injuries but studies are yet to be done on its effect on tendon healing. This study therefore investigated the effects of bromelain on tenocyte proliferation and the tendon malondialdehyde (MDA) level in the early stage of healing in a crush injury to the Achilles tendon of Sprague-Dawley rats. Twenty four male rats were divided randomly into three groups; groups 2 and 3 had induced crush injury to the left Achilles tendon. Group 1; nil injury and nil treatment, Group 2; nil treatment, Group 3; oral bromelain treatment. Bromelain was given at a dosage of 7 mg/kg body weight daily over the first 14 days post-injury. On day 15 post injury, the animals were killed and the tendons excised and processed for histological study and MDA assay. The results showed a significant increase in the tenocyte population in the bromelain group; p < 0.05. There was, however, no significant difference in the MDA level. Based on this study, 600 GDU bromelain given once daily in acute tendon injury at a dosage of 7 mg/kg promoted healing by stimulating tenocyte proliferation. Copyright © 2010 John Wiley & Sons, Ltd.

Micro-mechanical properties of the tendon-to-bone attachment.

PubMed

Deymier, Alix C; An, Yiran; Boyle, John J; Schwartz, Andrea G; Birman, Victor; Genin, Guy M; Thomopoulos, Stavros; Barber, Asa H

2017-07-01

The tendon-to-bone attachment (enthesis) is a complex hierarchical tissue that connects stiff bone to compliant tendon. The attachment site at the micrometer scale exhibits gradients in mineral content and collagen orientation, which likely act to minimize stress concentrations. The physiological micromechanics of the attachment thus define resultant performance, but difficulties in sample preparation and mechanical testing at this scale have restricted understanding of structure-mechanical function. Here, microscale beams from entheses of wild type mice and mice with mineral defects were prepared using cryo-focused ion beam milling and pulled to failure using a modified atomic force microscopy system. Micromechanical behavior of tendon-to-bone structures, including elastic modulus, strength, resilience, and toughness, were obtained. Results demonstrated considerably higher mechanical performance at the micrometer length scale compared to the millimeter tissue length scale, describing enthesis material properties without the influence of higher order structural effects such as defects. Micromechanical investigation revealed a decrease in strength in entheses with mineral defects. To further examine structure-mechanical function relationships, local deformation behavior along the tendon-to-bone attachment was determined using local image correlation. A high compliance zone near the mineralized gradient of the attachment was clearly identified and highlighted the lack of correlation between mineral distribution and strain on the low-mineral end of the attachment. This compliant region is proposed to act as an energy absorbing component, limiting catastrophic failure within the tendon-to-bone attachment through higher local deformation. This understanding of tendon-to-bone micromechanics demonstrates the critical role of micrometer scale features in the mechanics of the tissue. The tendon-to-bone attachment (enthesis) is a complex hierarchical tissue with features at

Quantitative US Elastography Can Be Used to Quantify Mechanical and Histologic Tendon Healing in a Rabbit Model of Achilles Tendon Transection.

PubMed

Yamamoto, Yohei; Yamaguchi, Satoshi; Sasho, Takahisa; Fukawa, Taisuke; Akatsu, Yorikazu; Akagi, Ryuichiro; Yamaguchi, Tadashi; Takahashi, Kenji; Nagashima, Kengo; Takahashi, Kazuhisa

2017-05-01

Purpose To determine the time-dependent change in strain ratios (SRs) at the healing site of an Achilles tendon rupture in a rabbit model of tendon transection and to assess the correlation between SRs and the mechanical and histologic properties of the healing tissue. Materials and Methods Experimental methods were approved by the institutional animal care and use committee. The Achilles tendons of 24 New Zealand white rabbits (48 limbs) were surgically transected. The SRs of Achilles tendons were calculated by using compression-based quantitative ultrasonographic elastography measurements obtained 2, 4, 8, and 12 weeks after transection. After in vivo elastography, the left Achilles tendon was harvested for mechanical testing of ultimate load, ultimate stress, elastic modulus, and linear stiffness, and the right tendons were harvested for tissue histologic analysis with the Bonar scale. Time-dependent changes in SRs, mechanical parameters, and Bonar scale scores were evaluated by using repeated-measures analysis of variance. The correlation between SRs and each measured variable was evaluated by using the Spearman rank correlation coefficient. Results Mean SRs and Bonar scale values decreased as a function of time after transection, whereas mechanical parameters increased (P < .001). SR correlated with ultimate stress (ρ = 0.68, P <.001,) elastic modulus (ρ = 0.74, P <.001), and the Bonar scale (ρ = 0.87, P <.001). Conclusion Quantitative elastography could be a useful method with which to evaluate mechanical and histologic properties of the healing tendon. © RSNA, 2017 Online supplemental material is available for this article.

The revitalisation of flexor tendon allografts with bone marrow stromal cells and mechanical stimulation: An ex vivo model revitalising flexor tendon allografts.

PubMed

Wu, J H; Thoreson, A R; Gingery, A; An, K N; Moran, S L; Amadio, P C; Zhao, C

2017-03-01

The present study describes a novel technique for revitalising allogenic intrasynovial tendons by combining cell-based therapy and mechanical stimulation in an ex vivo canine model. Specifically, canine flexor digitorum profundus tendons were used for this study and were divided into the following groups: (1) untreated, unprocessed normal tendon; (2) decellularised tendon; (3) bone marrow stromal cell (BMSC)-seeded tendon; and (4) BMSC-seeded and cyclically stretched tendon. Lateral slits were introduced on the tendon to facilitate cell seeding. Tendons from all four study groups were distracted by a servohydraulic testing machine. Tensile force and displacement data were continuously recorded at a sample rate of 20 Hz until 200 Newton of force was reached. Before testing, the cross-sectional dimensions of each tendon were measured with a digital caliper. Young's modulus was calculated from the slope of the linear region of the stress-strain curve. The BMSCs were labeled for histological and cell viability evaluation on the decellularized tendon scaffold under a confocal microscope. Gene expression levels of selected extracellular matrix tendon growth factor genes were measured. Results were reported as mean ± SD and data was analyzed with one-way ANOVAs followed by Tukey's post hoc multiple-comparison test. We observed no significant difference in cross-sectional area or in Young's modulus among the four study groups. In addition, histological sections showed that the BMSCs were aligned well and viable on the tendon slices after two-week culture in groups three and four. Expression levels of several extracellular matrix tendon growth factors, including collagen type I, collagen type III, and matrix metalloproteinase were significantly higher in group four than in group three (p < 0.05). Lateral slits introduced into de-cellularised tendon is a promising method of delivery of BMSCs without compromising cell viability and tendon mechanical properties. In addition

Effect of eccentric exercise on the healing process of injured patellar tendon in rats.

PubMed

Nakamura, Kenichi; Kitaoka, Katsuhiko; Tomita, Katsuro

2008-07-01

Earlier studies have reported positive results from eccentric training in patients with tendon disorders. The reasons for the beneficial clinical effects of eccentric training are not known. Vascularization followed by regression of the vasculature enhances the healing response of injured tendons. Eccentric exercise induces a more beneficial healing response than concentric exercise. Sixty rats with patellar tendon injuries were divided into three groups: nonexercise controls (group N; n = 20); concentric exercise group (group C; n = 20); eccentric exercise group (group E; n = 20). Each rat was taught to run uphill or downhill for 14 days. Patellar tendons were removed 1, 4, 7, 10, and 14 days following injury. Vascular endothelial growth factor (VEGF), angiopoietin-1, and angiopoietin-2 were measured by reverse transcription polymerase chain reaction. In group C, VEGF mRNA was increased 1 and 4 days following injury but was decreased on days 7, 10, and 14. In group E, VEGF mRNA was elevated only on day 1. In group N, VEGF mRNA remained at a low level throughout all 14 days. The angiopoietin-2/angiopoietin-1 ratio was higher for group C than for group E. In the presence of VEGF, angiopoietin-1 promotes vessel stability, whereas angiopoietin-2 has the opposite effect. Eccentric exercise contributes to stabilized angiogenesis during the early phase of tendon injury. Conversely, concentric exercise, which induces destabilized angiogenesis, leads to a delayed healing response. Initiation of eccentric exercise immediately after tendon injury may help improve healing by reducing vascularity.

Role of biomechanics in the understanding of normal, injured, and healing ligaments and tendons

PubMed Central

Jung, Ho-Joong; Fisher, Matthew B; Woo, Savio L-Y

2009-01-01

Ligaments and tendons are soft connective tissues which serve essential roles for biomechanical function of the musculoskeletal system by stabilizing and guiding the motion of diarthrodial joints. Nevertheless, these tissues are frequently injured due to repetition and overuse as well as quick cutting motions that involve acceleration and deceleration. These injuries often upset this balance between mobility and stability of the joint which causes damage to other soft tissues manifested as pain and other morbidity, such as osteoarthritis. The healing of ligament and tendon injuries varies from tissue to tissue. Tendinopathies are ubiquitous and can take up to 12 months for the pain to subside before one could return to normal activity. A ruptured medial collateral ligament (MCL) can generally heal spontaneously; however, its remodeling process takes years and its biomechanical properties remain inferior when compared to the normal MCL. It is also known that a midsubstance anterior cruciate ligament (ACL) tear has limited healing capability, and reconstruction by soft tissue grafts has been regularly performed to regain knee function. However, long term follow-up studies have revealed that 20–25% of patients experience unsatisfactory results. Thus, a better understanding of the function of ligaments and tendons, together with knowledge on their healing potential, may help investigators to develop novel strategies to accelerate and improve the healing process of ligaments and tendons. With thousands of new papers published in the last ten years that involve biomechanics of ligaments and tendons, there is an increasing appreciation of this subject area. Such attention has positively impacted clinical practice. On the other hand, biomechanical data are complex in nature, and there is a danger of misinterpreting them. Thus, in these review, we will provide the readers with a brief overview of ligaments and tendons and refer them to appropriate methodologies used to

Functional tissue engineering of tendon: Establishing biological success criteria for improving tendon repair.

PubMed

Breidenbach, Andrew P; Gilday, Steven D; Lalley, Andrea L; Dyment, Nathaniel A; Gooch, Cynthia; Shearn, Jason T; Butler, David L

2014-06-27

Improving tendon repair using Functional Tissue Engineering (FTE) principles has been the focus of our laboratory over the last decade. Although our primary goals were initially focused only on mechanical outcomes, we are now carefully assessing the biological properties of our tissue-engineered tendon repairs so as to link biological influences with mechanics. However, given the complexities of tendon development and healing, it remains challenging to determine which aspects of tendon biology are the most important to focus on in the context of tissue engineering. To address this problem, we have formalized a strategy to identify, prioritize, and evaluate potential biological success criteria for tendon repair. We have defined numerous biological properties of normal tendon relative to cellular phenotype, extracellular matrix and tissue ultra-structure that we would like to reproduce in our tissue-engineered repairs and prioritized these biological criteria by examining their relative importance during both normal development and natural tendon healing. Here, we propose three specific biological criteria which we believe are essential for normal tendon function: (1) scleraxis-expressing cells; (2) well-organized and axially-aligned collagen fibrils having bimodal diameter distribution; and (3) a specialized tendon-to-bone insertion site. Moving forward, these biological success criteria will be used in conjunction with our already established mechanical success criteria to evaluate the effectiveness of our tissue-engineered tendon repairs. © 2013 Published by Elsevier Ltd.

Local Application of Gelatin Hydrogel Sheets Impregnated With Platelet-Derived Growth Factor BB Promotes Tendon-to-Bone Healing After Rotator Cuff Repair in Rats.

PubMed

Tokunaga, Takuya; Ide, Junji; Arimura, Hitoshi; Nakamura, Takayuki; Uehara, Yusuke; Sakamoto, Hidetoshi; Mizuta, Hiroshi

2015-08-01

To determine whether the local application of platelet-derived growth factor BB (PDGF-BB) in hydrogel sheets would promote healing and improve histologic characteristics and biomechanical strength after rotator cuff (RC) repair in rats. To assess the effect of PDGF-BB on tendon-to-bone healing we divided 36 adult male Sprague-Dawley rats treated with bilateral surgery to repair the supraspinatus tendon at its insertion site into 3 groups: group 1 = suture-only group; group 2 = suture and gelatin hydrogel sheets impregnated with phosphate-buffered saline (PBS); and group 3 = suture and gelatin hydrogel sheets impregnated with PDGF-BB (0.5 μg). Semiquantitative histologic evaluation was carried out 2, 6, and 12 weeks later; cell proliferation was assessed 2 and 6 weeks postoperatively by immunostaining for proliferating cell nuclear antigen (PCNA), and biomechanical testing, including ultimate load to failure, stiffness, and ultimate stress to failure, was performed 12 weeks after the operation. At 2 weeks, the average percentage of PCNA-positive cells at the insertion site was significantly higher in group 3 (40.5% ± 2.4%) than in group 1 (32.1% ± 6.9%; P = .03) and group 2 (31.9% ± 3.7%; P = .02). At 2 and 6 weeks, the histologic scores were similar among the 3 groups. At 12 weeks, the histologic score was significantly higher in group 3 (10.3 ± 0.8) than in group 1 (8.5 ± 0.5; P = .002) or group 2 (8.8 ± 0.8; P = .009), whereas ultimate load to failure, stiffness, and ultimate load to stress (normal control population, 44.73 ± 9.75 N, 27.59 ± 4.32 N/mm, and 21.33 ± 4.65 N/mm(2), respectively) were significantly higher in group 3 (28.28 ± 6.28 N, 11.05 ± 2.37 N/mm, and 7.99 ± 2.13 N/mm(2), respectively) than in group 1 (10.44 ± 1.98 N, 4.74 ± 1.31 N/mm, and 3.28 ± 1.27 N/mm(2), respectively; all P < .001) or group 2 (11.85 ± 2.89 N, 5.86 ± 1.75 N/mm, and 3.31 ± 0.80 N/mm(2), respectively; all P < .001). The placement of a PDGF

The Physiological Mechanisms of Effect of Vitamins and Amino Acids on Tendon and Muscle Healing: A Systematic Review.

PubMed

Tack, Christopher; Shorthouse, Faye; Kass, Lindsy

2018-05-01

To evaluate the current literature via systematic review to ascertain whether amino acids/vitamins provide any influence on musculotendinous healing and if so, by which physiological mechanisms. EBSCO, PubMed, ScienceDirect, Embase Classic/Embase, and MEDLINE were searched using terms including "vitamins," "amino acids," "healing," "muscle," and "tendon." The primary search had 479 citations, of which 466 were excluded predominantly due to nonrandomized design. Randomized human and animal studies investigating all supplement types/forms of administration were included. Critical appraisal of internal validity was assessed using the Cochrane risk of Bias Tool or the Systematic Review Centre for Laboratory Animal Experimentation Risk of Bias Tool for human and animal studies, respectively. Two reviewers performed duel data extraction. Twelve studies met criteria for inclusion: eight examined tendon healing and four examined muscle healing. All studies used animal models, except two human trials using a combined integrator. Narrative synthesis was performed via content analysis of demonstrated statistically significant effects and thematic analysis of proposed physiological mechanisms of intervention. Vitamin C/taurine demonstrated indirect effects on tendon healing through antioxidant activity. Vitamin A/glycine showed direct effects on extracellular matrix tissue synthesis. Vitamin E shows an antiproliferative influence on collagen deposition. Leucine directly influences signaling pathways to promote muscle protein synthesis. Preliminary evidence exists, demonstrating that vitamins and amino acids may facilitate multilevel changes in musculotendinous healing; however, recommendations on clinical utility should be made with caution. All animal studies and one human study showed high risk of bias with moderate interobserver agreement (k = 0.46). Currently, there is limited evidence to support the use of vitamins and amino acids for musculotendinous injury. Both

Failed healing of rotator cuff repair correlates with altered collagenase and gelatinase in supraspinatus and subscapularis tendons.

PubMed

Robertson, Catherine M; Chen, Christopher T; Shindle, Michael K; Cordasco, Frank A; Rodeo, Scott A; Warren, Russell F

2012-09-01

Despite improvements in arthroscopic rotator cuff repair technique and technology, a significant rate of failed tendon healing persists. Improving the biology of rotator cuff repairs may be an important focus to decrease this failure rate. The objective of this study was to determine the mRNA biomarkers and histological characteristics of repaired rotator cuffs that healed or developed persistent defects as determined by postoperative ultrasound. Increased synovial inflammation and tendon degeneration at the time of surgery are correlated with the failed healing of rotator cuff tendons. Case-control study; Level of evidence, 3. Biopsy specimens from the subscapularis tendon, supraspinatus tendon, glenohumeral synovium, and subacromial bursa of 35 patients undergoing arthroscopic rotator cuff repair were taken at the time of surgery. Expression of proinflammatory cytokines, tissue remodeling genes, and angiogenesis factors was evaluated by quantitative real-time polymerase chain reaction. Histological characteristics of the affected tissue were also assessed. Postoperative (>6 months) ultrasound was used to evaluate the healing of the rotator cuff. General linear modeling with selected mRNA biomarkers was used to predict rotator cuff healing. Thirty patients completed all analyses, of which 7 patients (23%) had failed healing of the rotator cuff. No differences in demographic data were found between the defect and healed groups. American Shoulder and Elbow Surgeons shoulder scores collected at baseline and follow-up showed improvement in both groups, but there was no significant difference between groups. Increased expression of matrix metalloproteinase 1 (MMP-1) and MMP-9 was found in the supraspinatus tendon in the defect group versus the healed group (P = .006 and .02, respectively). Similar upregulation of MMP-9 was also found in the subscapularis tendon of the defect group (P = .001), which was consistent with the loss of collagen organization as determined by

Treatment of mallet finger deformity with a modified palmaris longus tendon graft through a bone tunnel.

PubMed

Liu, Zengbing; Ma, Kai; Huang, Dong

2018-01-01

To investigate the clinical effect of treating mallet finger deformity using a modified palmaris longus tendon graft through a bone tunnel. Altogether, 21 patients with mallet finger deformity (16 men, 5 women; average age 31 years, range 19-47 years) were treated with a modified palmaris longus tendon graft through a bone tunnel during 18 months (2014-2016). Four index fingers, seven middle fingers, eight ring fingers, and two little fingers were treated for four cutting injuries, eleven finger sprains, four crush injuries, and two twist injuries (7 open and 14 closed injuries). Duration from injury to surgery was 9 h to 13 weeks. Three patients underwent surgery after 6 weeks of unsuccessful conservative treatment. No tendon was attached to the extensor tendon insertion in 16 patients, and 5 had residual tendon of <0.2 cm attached. All patients had distal segment flexion deformity and dorsiflexion disorder. Surgery comprised transverse penetration and vertical drilling of the base of the distal phalanx (2.0 and 2.5 mm diameter drills). Equal shallow semitendinosus pieces of the palmaris longus tendon (4 cm) were obtained from the sagittal end and were passed through a dorsal bone hole, emerging from a transverse bone hole. The two bundles were sutured to the main tendon. Tension was adjusted, and the broken ends were sutured. The distal interphalangeal joints were fixed in hyperextension. All patients were followed for 7-16 months (average 6.0 ± 0.3 months) postoperatively. All 21 patients had grade A wound healing, with no complications (e.g., necrotic wound, recurrence, joint stiffness). The mallet finger deformity was corrected with good appearance, no obvious abnormalities, and satisfactory flexion and extension. Two patients had a superficial wound infection. Each recovered after symptomatic treatment. One patient had a mild result, with limited extension. There were no recurrences. Results were evaluated according to Patel et al.'s system, which revealed

Human multipotent mesenchymal stem cells improve healing after collagenase tendon injury in the rat

PubMed Central

2014-01-01

Background Mesenchymal stromal cells attract much interest in tissue regeneration because of their capacity to differentiate into mesodermal origin cells, their paracrine properties and their possible use in autologous transplantations. The aim of this study was to investigate the safety and reparative potential of implanted human mesenchymal stromal cells (hMSCs), prepared under Good Manufacturing Practice (GMP) conditions utilizing human mixed platelet lysate as a culture supplement, in a collagenase Achilles tendon injury model in rats. Methods Eighty-one rats with collagenase-induced injury were divided into two groups. The first group received human mesenchymal stromal cells injected into the site of injury 3 days after lesion induction, while the second group received saline. Biomechanical testing, morphometry and semiquantitative immunohistochemistry of collagens I, II and III, versican and aggrecan, neovascularization, and hMSC survival were performed 2, 4, and 6 weeks after injury. Results Human mesenchymal stromal cell-treated rats had a significantly better extracellular matrix structure and a larger amount of collagen I and collagen III. Neovascularization was also increased in hMSC-treated rats 2 and 4 weeks after tendon injury. MTCO2 (Cytochrome c oxidase subunit II) positivity confirmed the presence of hMSCs 2, 4 and 6 weeks after transplantation. Collagen II deposits and alizarin red staining for bone were found in 6 hMSC- and 2 saline-treated tendons 6 weeks after injury. The intensity of anti-versican and anti-aggrecan staining did not differ between the groups. Conclusions hMSCs can support tendon healing through better vascularization as well as through larger deposits and better organization of the extracellular matrix. The treatment procedure was found to be safe; however, cartilage and bone formation at the implantation site should be taken into account when planning subsequent in vivo and clinical trials on tendinopathy as an expected

Healing of rotator cuff tendons using botulinum toxin A and immobilization in a rat model.

PubMed

Gilotra, Mohit N; Shorofsky, Michael J; Stein, Jason A; Murthi, Anand M

2016-03-15

We evaluated effects of botulinum toxin A (Botox) and cast immobilization on tendon healing in a rat model. Injection of Botox into rat supraspinatus was hypothesized to reduce muscle active force and improved healing. Eighty-four supraspinatus tendons were surgically transected and repaired in 42 Sprague-Dawley rats (transosseous technique). After repair, supraspinatus muscle was injected with saline or Botox (3 or 6 U/kg). Half the shoulders were cast-immobilized for the entire postoperative period; half were allowed free cage activity. Histology was examined at 2, 4, 8, and 12 weeks. A healing zone cross-sectional area was measured, and biomechanical testing of repair strength and tendon viscoelastic properties was conducted at 4 and 12 weeks. Botox alone and cast immobilization alone exhibited increased ultimate load compared with controls (saline injection, no immobilization) at 4 weeks. No difference in ultimate load occurred between Botox-only and cast-only groups. At 12 weeks, the Botox (6 U/kg) plus cast immobilization group was significantly weakest (p < 0.05). A trend was shown toward decreased healing zone cross-sectional areas in casted groups. Supraspinatus Botox injection after rotator cuff repair might help protect the repair. However, cast immobilization plus Botox administration is harmful to rotator cuff healing in a rat tendon model.

Treatment with vacuum-assisted closure and cryo-preserved homologous de-epidermalised dermis of complex traumas to the lower limbs with loss of substance, and bones and tendons exposure.

PubMed

Brandi, C; Grimaldi, L; Nisi, G; Silvestri, A; Brafa, A; Calabrò, M; D'Aniello, C

2008-12-01

Lower-limb injuries with loss of tissue and exposure of bones and tendons are an increasing problem. The condition of the wound locally and the patient in general does not always allow immediate and adequate coverage of the structures exposed by the trauma. Therefore, new therapeutic solutions are needed. A reduction in the time that bones and tendons are exposed is essential to achieve complete healing of bone fractures, with reduced risks of infection and less disabling outcomes. The effectiveness of vacuum-assisted closure (VAC) therapy in supporting wound healing and of cryopreserved homologous de-epidermalised dermis (DED) in providing an effective template for re-epithelialisation has been previously reported. We carried out a study to evaluate the effectiveness of the synergistic and combined use of the two methodologies. Eighteen patients with traumatic loss of tissue in the lower limbs, involving exposure of bone and tendon structures, were enrolled in the study. All participants had local, general contraindications to first-instance reconstructions, or both. All patients received a combination of VAC therapy and DED implants. Granulation tissue was obtained in all wounds, with complete coverage of exposed structures. No infections were detected in the cohort, and all patients were prepared for further necessary reconstructive treatments. In our experience, the combination of VAC therapy and DED could, in selected cases, constitute an effective treatment for complex lower limb traumatic injuries with bone and tendon exposure.

Extended healing validation of an artificial tendon to connect the quadriceps muscle to the Tibia: 180-day study.

PubMed

Melvin, Alan J; Litsky, Alan S; Mayerson, Joel L; Stringer, Keith; Juncosa-Melvin, Natalia

2012-07-01

Whenever a tendon or its bone insertion is disrupted or removed, existing surgical techniques provide a temporary connection or scaffolding to promote healing, but the interface of living to non-living materials soon breaks down under the stress of these applications, if it must bear the load more than acutely. Patients are thus disabled whose prostheses, defect size, or mere anatomy limit the availability or outcomes of such treatments. Our group developed the OrthoCoupler™ device to join skeletal muscle to prosthetic or natural structures without this interface breakdown. In this study, the goat knee extensor mechanism (quadriceps tendon, patella, and patellar tendon) was removed from the right hind limb in 16 goats. The device connected the quadriceps muscle to a stainless steel bone plate on the tibia. Mechanical testing and histology specimens were collected from each operated leg and contralateral unoperated control legs at 180 days. Maximum forces in the operated leg (vs. unoperated) were 1,400 ± 93 N (vs. 1,179 ± 61 N), linear stiffnesses were 33 ± 3 N/mm (vs. 37 ± 4 N/mm), and elongations at failure were 92.1 ± 5.3 mm (vs. 68.4 ± 3.8 mm; mean ± SEM). Higher maximum forces (p = 0.02) and elongations at failure (p=0.008) of legs with the device versus unoperated controls were significant; linear stiffnesses were not (p=0.3). We believe this technology will yield improved procedures for clinical challenges in orthopedic oncology, revision arthroplasty, tendon transfer, and tendon injury reconstruction. Copyright © 2011 Orthopaedic Research Society.

Effect of single- and double-row rotator cuff repair at the tendon-to-bone interface: preliminary results using an in vivo sheep model.

PubMed

Baums, M H; Schminke, B; Posmyk, A; Miosge, N; Klinger, H-M; Lakemeier, S

2015-01-01

The clinical superiority of the double-row technique is still a subject of controversial debate in rotator cuff repair. We hypothesised that the expression of different collagen types will differ between double-row and single-row rotator cuff repair indicating a faster healing response by the double-row technique. Twenty-four mature female sheep were randomly assembled to two different groups in which a surgically created acute infraspinatus tendon tear was fixed using either a modified single- or double-row repair technique. Shoulder joints from female sheep cadavers of identical age, bone maturity, and weight served as untreated control cluster. Expression of type I, II, and III collagen was observed in the tendon-to-bone junction along with recovering changes in the fibrocartilage zone after immunohistological tissue staining at 1, 2, 3, 6, 12, and 26 weeks postoperatively. Expression of type III collagen remained positive until 6 weeks after surgery in the double-row group, whereas it was detectable for 12 weeks in the single-row group. In both groups, type I collagen expression increased after 12 weeks. Type II collagen expression was increased after 12 weeks in the double-row versus single-row group. Clusters of chondrocytes were only visible between week 6 and 12 in the double-row group. The study demonstrates differences regarding the expression of type I and type III collagen in the tendon-to-bone junction following double-row rotator cuff repair compared to single-row repair. The healing response in this acute repair model is faster in the double-row group during the investigated healing period.

Histological study of the influence of plasma rich in growth factors (PRGF) on the healing of divided Achilles tendons in sheep.

PubMed

Fernández-Sarmiento, J Andrés; Domínguez, Juan M; Granados, María M; Morgaz, Juan; Navarrete, Rocío; Carrillo, José M; Gómez-Villamandos, Rafael J; Muñoz-Rascón, Pilar; Martín de Las Mulas, Juana; Millán, Yolanda; García-Balletbó, Montserrat; Cugat, Ramón

2013-02-06

The use of plasma rich in growth factors (PRGF) has been proposed to improve the healing of Achilles tendon injuries, but there is debate about the effectiveness of this therapy. The objective of the present study was to evaluate the histological effects of PRGF, which is a type of leukocyte-poor platelet-rich plasma, on tendon healing. The Achilles tendons of twenty-eight sheep were divided surgically. The animals were randomly divided into four groups of seven animals each. The repaired tendons in two groups received an infiltration of PRGF intraoperatively and every week for the following three weeks under ultrasound guidance. The tendons in the other two groups received injections with saline solution. The animals in one PRGF group and one saline solution group were killed at four weeks, and the animals in the remaining two groups were killed at eight weeks. The Achilles tendons were examined histologically, and the morphometry of fibroblast nuclei was calculated. The fibroblast nuclei of the PRGF-treated tendons were more elongated and more parallel to the tendon axis than the fibroblast nuclei of the tendons in the saline solution group at eight weeks. PRGF-treated tendons showed more packed and better oriented collagen bundles at both four and eight weeks. In addition to increased maturation of the collagen structure, fibroblast density was significantly lower in PRGF-infiltrated tendons. PRGF-treated tendons exhibited faster vascular regression than tendons in the control groups, as demonstrated by a lower vascular density at eight weeks. PRGF was associated with histological changes consistent with an accelerated early healing process in repaired Achilles tendons in sheep after experimental surgical disruption. PRGF-treated tendons showed improvements in the morphometric features of fibroblast nuclei, suggesting a more advanced stage of healing. At eight weeks, histological examination revealed more mature organization of collagen bundles, lower vascular

Modulatory effect of gastric pentadecapeptide BPC 157 on angiogenesis in muscle and tendon healing.

PubMed

Brcic, L; Brcic, I; Staresinic, M; Novinscak, T; Sikiric, P; Seiwerth, S

2009-12-01

Angiogenesis is a natural and complex process controlled by angiogenic and angiostatic molecules, with a central role in healing process. One of the most important modulating factors in angiogenesis is the vascular endothelial growth factor (VEGF). Pentadecapeptide BPC 157 promotes healing demonstrating particular angiogenic/angiomodulatory potential. We correlated the angiogenic effect of BPC 157 with VEGF expression using in vitro (cell culture) and in vivo (crushed muscle and transected muscle and tendon) models. Results revealed that there is no direct angiogenic effect of BPC 157 on cell cultures. On the other hand, immunohistochemical analysis of muscle and tendon healing using VEGF, CD34 and FVIII antibodies showed adequately modulated angiogenesis in BPC 157 treated animals, resulting in a more adequate healing. Therefore the angiogenic potential of BPC 157 seems to be closely related to the healing process in vivo with BPC 157 stimulating angiogenesis by up-regulating VEGF expression.

Effect of diet-induced vitamin D deficiency on rotator cuff healing in a rat model.

PubMed

Angeline, Michael E; Ma, Richard; Pascual-Garrido, Cecilia; Voigt, Clifford; Deng, Xiang Hua; Warren, Russell F; Rodeo, Scott A

2014-01-01

Few studies have considered hormonal influences, particularly vitamin D, on healing. Vitamin D deficiency would have a negative effect on the structure of the healing tendon-bone interface in a rat model and would result in decreased tendon attachment strength. Controlled laboratory study. Vitamin D deficiency was induced in 28 male Sprague-Dawley rats using a specialized vitamin D-deficient diet and ultraviolet light restriction. Serum levels of vitamin D were measured after 6 weeks. These vitamin D-deficient animals (experimental group) plus 32 rats with normal vitamin D levels (controls) underwent unilateral detachment of the right supraspinatus tendon from the greater tuberosity of the humerus, followed by immediate repair using bone tunnel suture fixation. The animals were sacrificed at 2- and 4-week intervals after surgery for biomechanical analysis. A paired t test was used to compare serum vitamin D levels at day 0 and at 6 weeks. A nonparametric Mann-Whitney U test was used to compare load-to-failure and stiffness values between the experimental group and controls. Bone density and new bone formation at the tendon insertion site on the greater tuberosity were assessed with micro-computed tomography (CT). The organization of collagen tissue, new bone formation, vascularity at the tendon-bone interface, fibrocartilage at the tendon-bone interface, and collagen fiber continuity between the tendon and bone tissue were evaluated with safranin O and picrosirius red staining. Blood draws confirmed vitamin D deficiency at 6 weeks compared with time zero/baseline for rats in the experimental group (10.9 ng/mL vs 6.5 ng/mL, respectively; P < .001). Biomechanical testing demonstrated a significant decrease in load to failure in the experimental group compared with controls at 2 weeks (5.8 ± 2.0 N vs 10.5 ± 4.4 N, respectively; P < .006). There was no difference in stiffness at 2 weeks between the control and experimental groups. At 4 weeks, there was no significant

Experimental evaluation of multiscale tendon mechanics.

PubMed

Fang, Fei; Lake, Spencer P

2017-07-01

Tendon's primary function is a mechanical link between muscle and bone. The hierarchical structure of tendon and specific compositional constituents are believed to be critical for proper mechanical function. With increased appreciation for tendon importance and the development of various technological advances, this review paper summarizes recent experimental approaches that have been used to study multiscale tendon mechanics, includes an overview of studies that have evaluated the role of specific tissue constituents, and also proposes challenges/opportunities facing tendon study. Tendon has been demonstrated to have specific structural characteristics (e.g., multi-level hierarchy, crimp pattern, helix) and complex mechanical properties (e.g., non-linearity, anisotropy, viscoelasticity). Physical mechanisms including uncrimping, fiber sliding, and collagen reorganization have been shown to govern tendon mechanical responses under both static and dynamic loading. Several tendon constituents with relatively small quantities have been suggested to play a role in its mechanics, although some results are conflicting. Further research should be performed to understand the interplay and communication of tendon mechanical properties across levels of the hierarchical structure, and further show how each of these components contribute to tendon mechanics. The studies summarized and discussed in this review have helped elucidate important aspects of multiscale tendon mechanics, which is a prerequisite for analyzing stress/strain transfer between multiple scales and identifying key principles of mechanotransduction. This information could further facilitate interpreting the functional diversity of tendons from different species, different locations, and even different developmental stages, and then better understand and identify fundamental concepts related to tendon degeneration, disease, and healing. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc

rhPDGF-BB promotes early healing in a rat rotator cuff repair model.

PubMed

Kovacevic, David; Gulotta, Lawrence V; Ying, Liang; Ehteshami, John R; Deng, Xiang-Hua; Rodeo, Scott A

2015-05-01

Tendon-bone healing after rotator cuff repair occurs by fibrovascular scar tissue formation, which is weaker than a normal tendon-bone insertion site. Growth factors play a role in tissue formation and have the potential to augment soft tissue healing in the perioperative period. Our study aim was to determine if rhPDGF-BB delivery on a collagen scaffold can improve tendon-to-bone healing after supraspinatus tendon repair compared with no growth factor in rats as measured by (1) gross observations; (2) histologic analysis; and (3) biomechanical testing. Ninety-five male Sprague-Dawley rats underwent acute repair of the supraspinatus tendon. Rats were randomized into one of five groups: control (ie, repair only), scaffold only, and three different platelet-derived growth factor (PDGF) doses on the collagen scaffold. Animals were euthanized 5 days after surgery to assess cellular proliferation and angiogenesis. The remaining animals were analyzed at 4 weeks to assess repair site integrity by gross visualization, fibrocartilage formation with safranin-O staining, and collagen fiber organization with picrosirius red staining, and to determine the biomechanical properties (ie, load-to-failure testing) of the supraspinatus tendon-bone construct. The repaired supraspinatus tendon was in continuity with the bone in all animals. At 5 days, rhPDGF-BB delivery on a scaffold demonstrated a dose-dependent response in cellular proliferation and angiogenesis compared with the control and scaffold groups. At 28 days, with the numbers available, rhPDGF-BB had no effect on increasing fibrocartilage formation or improving collagen fiber maturity at the tendon-bone insertion site compared with controls. The control group had higher tensile loads to failure and stiffness (35.5 ± 8.8 N and 20.3 ± 4.5 N/mm) than all the groups receiving the scaffold, including the PDGF groups (scaffold: 27 ± 6.4 N, p = 0.021 and 13 ± 5.7 N/mm, p = 0.01; 30 µg/mL PDGF: 26.5 ± 7.5 N, p = 0.014 and 13

Stem Cell Applications in Tendon Disorders: A Clinical Perspective

PubMed Central

Young, Mark

2012-01-01

Tendon injuries are a common cause of morbidity and a significant health burden on society. Tendons are structural tissues connecting muscle to bone and are prone to tearing and tendinopathy, an overuse or degenerative condition that is characterized by failed healing and cellular depletion. Current treatments, for tendon tear are conservative, surgical repair or surgical scaffold reconstruction. Tendinopathy is treated by exercises, injection therapies, shock wave treatments or surgical tendon debridement. However, tendons usually heal with fibrosis and scar tissue, which has suboptimal tensile strength and is prone to reinjury, resulting in lifestyle changes with activity restriction. Preclinical studies show that cell therapies have the potential to regenerate rather than repair tendon tissue, a process termed tenogenesis. A number of different cell lines, with varying degrees of differentiation, have being evaluated including stem cells, tendon derived cells and dermal fibroblasts. Even though cellular therapies offer some potential in treating tendon disorders, there have been few published clinical trials to determine the ideal cell source, the number of cells to administer, or the optimal bioscaffold for clinical use. PMID:22448174

Repair of insertional achilles tendinosis with a bone-quadriceps tendon graft.

PubMed

Philippot, Rémi; Wegrzyn, Julien; Grosclaude, Sophie; Besse, Jean Luc

2010-09-01

While conservative treatment may be successful in most cases, partial rupture at the calcaneal insertion point is a significant concern with insertional Achilles tendinopathy. We report on the outcomes of a surgical technique for Achilles tendon augmentation using a bone-tendon graft harvested from the knee extensor system. Our retrospective case series includes 25 surgical procedures performed in 24 patients, 19 males and five females, with a mean age of 47 (range, 30 to 59) years, 18 of whom were athletes. The mean followup period was 52 (range, 12 to 156) months. All patients underwent MRI examination prior to surgery which showed partial Achilles tendon rupture. The Achilles tendon was debrided through a posterolateral approach. The bone-quadriceps tendon graft was harvested, then the bone plug of the graft was inserted into a blind tunnel drilled into the calcaneus and fixed with an interference screw. The fibers of the quadriceps tendon were sutured to the residual part of the Achilles tendon with the foot at an angle of 90 degrees. Patients were able to resume their sporting activity after an average of 6.7 months. At last followup examination, physical activity was scored 5.2 on the 10-point Tegner Scale; the mean AOFAS score was 98.4. MRI examination showed good graft integration 1 year postoperatively. The bone-quadriceps tendon grafting technique was a good alternative for the insertional Achilles lesions with partial detachment which we felt required augmentation.

Free Bone Plug Quadriceps Tendon Harvest and Suspensory Button Attachment for Anterior Cruciate Ligament Reconstruction.

PubMed

Todor, Adrian; Caterev, Sergiu; Nistor, Dan Viorel; Khallouki, Youssef

2016-06-01

The most commonly used autografts for anterior cruciate ligament reconstruction are the bone-patellar tendon-bone and hamstring tendons. Each has its advantages and limitations. The bone-patellar tendon-bone autograft can lead to more donor-site morbidity, and the hamstring autograft can be unpredictable in size. The quadriceps tendon, with or without a bone block, has been described as an alternative graft source and has been used especially in revision cases, but in recent years, it has attracted attention even for primary cases. We report a technique for harvesting a free bone quadriceps tendon graft and attaching an extracortical button for femoral fixation for anterior cruciate ligament reconstruction.

Tendon Tissue Engineering and Its Role on Healing of the Experimentally Induced Large Tendon Defect Model in Rabbits: A Comprehensive In Vivo Study

PubMed Central

Meimandi-Parizi, Abdolhamid; Oryan, Ahmad; Moshiri, Ali

2013-01-01

Healing of large tendon defects is challenging. We studied the role of collagen implant with or without polydioxanone (PDS) sheath on the healing of a large Achilles tendon defect model, in rabbits. Sixty rabbits were divided into three groups. A 2 cm gap was created in the left Achilles tendon of all rabbits. In the control lesions, no implant was used. The other two groups were reconstructed by collagen and collagen-PDS implants respectively. The animals were clinically examined at weekly intervals and their lesions were observed by ultrasonography. Blood samples were obtained from the animals and were assessed for hematological analysis and determination of serum PDGF level, at 60 days post injury (DPI). The animals were then euthanized and their lesions were assessed for gross and histopathology, scanning electron microscopy, biomechanical testing, dry matter and hydroxyproline content. Another 65 pilot animals were also studied grossly and histopathologically to define the host implant interaction and graft incorporation at serial time points. The treated animals gained significantly better clinical scoring compared to the controls. Treatment with collagen and collagen-PDS implants significantly increased the biomechanical properties of the lesions compared to the control tendons at 60DPI (P<0.05). The tissue engineered implants also reduced peritendinous adhesion, muscle fibrosis and atrophy, and increased ultrasonographical echogenicity and homogenicity, maturation and differentiation of the collagen fibrils and fibers, tissue alignment and volume of the regenerated tissue compared to those of the control lesions (P<0.05). The implants were gradually absorbed and substituted by the new tendon. Implantation of the bioimplants had a significant role in initiating tendon healing and the implants were biocompatible, biodegradable and safe for application in tendon reconstructive surgery. The results of the present study may be valuable in clinical practice. PMID

Chronic Degeneration Leads to Poor Healing of Repaired Massive Rotator Cuff Tears in Rats.

PubMed

Killian, Megan L; Cavinatto, Leonardo M; Ward, Samuel R; Havlioglu, Necat; Thomopoulos, Stavros; Galatz, Leesa M

2015-10-01

Chronic rotator cuff tears present a clinical challenge, often with poor outcomes after surgical repair. Degenerative changes to the muscle, tendon, and bone are thought to hinder healing after surgical repair; additionally, the ability to overcome degenerative changes after surgical repair remains unclear. The purpose of this study was to evaluate healing outcomes of muscle, tendon, and bone after tendon repair in a model of chronic rotator cuff disease and to compare these outcomes to those of acute rotator cuff injuries and repair. The hypothesis was that degenerative rotator cuff changes associated with chronic multitendon tears and muscle unloading would lead to poor structural and mechanical outcomes after repair compared with acute injuries and repair. Controlled laboratory study. Chronic rotator cuff injuries, induced via detachment of the supraspinatus (SS) and infraspinatus (IS) tendons and injection of botulinum toxin A into the SS and IS muscle bellies, were created in the shoulders of rats. After 8 weeks of injury, tendons were surgically reattached to the humeral head, and an acute, dual-tendon injury and repair was performed on the contralateral side. After 8 weeks of healing, muscles were examined histologically, and tendon-to-bone samples were examined microscopically, histologically, and biomechanically and via micro-computed tomography. All repairs were intact at the time of dissection, with no evidence of gapping or ruptures. Tendon-to-bone healing after repair in our chronic injury model led to reduced bone quality and morphological disorganization at the repair site compared with acute injuries and repair. SS and IS muscles were atrophic at 8 weeks after repair of chronic injuries, indicating incomplete recovery after repair, whereas SS and IS muscles exhibited less atrophy and degeneration in the acute injury group at 8 weeks after repair. After chronic injuries and repair, humeral heads had decreased total mineral density and an altered

[Experimental study of tendon graft fixation in anterior cruciate ligament reconstruction with cortical press-fit bolt in rabbits].

PubMed

Qi, Wei; Li, Chun-bao; Wang, Jun-liang; Zhu, Juan-li; Liu, Yu-jie

2013-05-21

To explore the histological outcomes of tendon-bone healing in anterior cruciate ligament (ACL) reconstruction with cortical press-fit bolt (CPB). Twenty-four healthy female or male New Zealand White rabbits (2-3 months old) underwent bilateral ACL reconstruction with extensor digitorum longus tendon. A random method was used to decide one knee would receive the routine ACL reconstruction (control group) and another cortical press-fit bolt fixation (experimental group). After general anesthesia, extensor digitorum longus tendon was harvested and ACL reconstruction performed. All animals were sacrificed at 4, 8 and 12 weeks postoperation. Radiological and histological examinations were made at each timepoint. The specimens were stained with different methods to observe the pathological changes of tendon graft, bone tunnel and cortical press-fit bolt. More revascularization and massive new bone were found in tendon-bone junction of experimental group at 4, 8 and 12 weeks postoperation. The circum-graft new vessel proportion of the experimental and control groups were 0.48 ± 0.12 and 0.26 ± 0.05 respectively (P < 0.05). In the experimental group, more cartilage cells were present in tendon-bone junction at 12 weeks and the circum-graft new bone areas in two groups were 0.41 ± 0.11 and 0.21 ± 0.10 mm(2) respectively (P < 0.05). Cortical press-fit blot may improve tendon-bone healing after ACL reconstruction in rabbits. The application prospects of this procedure are promising.

Structural and Ultrastructural Characteristics of Bone-Tendon Junction of the Calcaneal Tendon of Adult and Elderly Wistar Rats

PubMed Central

Cury, Diego Pulzatto; Dias, Fernando José; Miglino, Maria Angélica; Watanabe, Ii-sei

2016-01-01

Tendons are transition tissues that transfer the contractile forces generated by the muscles to the bones, allowing movement. The region where the tendon attaches to the bone is called bone-tendon junction or enthesis and may be classified as fibrous or fibrocartilaginous. This study aims to analyze the collagen fibers and the cells present in the bone-tendon junction using light microscopy and ultrastructural techniques as scanning electron microscopy and transmission electron microscopy. Forty male Wistar rats were used in the experiment, being 20 adult rats at 4 months-old and 20 elderly rats at 20 months-old. The hind limbs of the rats were removed, dissected and prepared to light microscopy, transmission electron microscopy and scanning electron microscopy. The aging process showed changes in the collagen fibrils, with a predominance of type III fibers in the elderly group, in addition to a decrease in the amount of the fibrocartilage cells, fewer and shorter cytoplasmic processes and a decreased synthetic capacity due to degradation of the organelles involved in synthesis. PMID:27078690

Structural and Ultrastructural Characteristics of Bone-Tendon Junction of the Calcaneal Tendon of Adult and Elderly Wistar Rats.

PubMed

Cury, Diego Pulzatto; Dias, Fernando José; Miglino, Maria Angélica; Watanabe, Ii-sei

2016-01-01

Tendons are transition tissues that transfer the contractile forces generated by the muscles to the bones, allowing movement. The region where the tendon attaches to the bone is called bone-tendon junction or enthesis and may be classified as fibrous or fibrocartilaginous. This study aims to analyze the collagen fibers and the cells present in the bone-tendon junction using light microscopy and ultrastructural techniques as scanning electron microscopy and transmission electron microscopy. Forty male Wistar rats were used in the experiment, being 20 adult rats at 4 months-old and 20 elderly rats at 20 months-old. The hind limbs of the rats were removed, dissected and prepared to light microscopy, transmission electron microscopy and scanning electron microscopy. The aging process showed changes in the collagen fibrils, with a predominance of type III fibers in the elderly group, in addition to a decrease in the amount of the fibrocartilage cells, fewer and shorter cytoplasmic processes and a decreased synthetic capacity due to degradation of the organelles involved in synthesis.

Functional grading of mineral and collagen in the attachment of tendon to bone.

PubMed

Genin, Guy M; Kent, Alistair; Birman, Victor; Wopenka, Brigitte; Pasteris, Jill D; Marquez, Pablo J; Thomopoulos, Stavros

2009-08-19

Attachment of dissimilar materials is a major challenge because high levels of localized stress may develop at their interfaces. An effective biologic solution to this problem exists at one of nature's most extreme interfaces: the attachment of tendon (a compliant, structural "soft tissue") to bone (a stiff, structural "hard tissue"). The goal of our study was to develop biomechanical models to describe how the tendon-to-bone insertion derives its mechanical properties. We examined the tendon-to-bone insertion and found two factors that give the tendon-to-bone transition a unique grading in mechanical properties: 1), a gradation in mineral concentration, measured by Raman spectroscopy; and 2), a gradation in collagen fiber orientation, measured by polarized light microscopy. Our measurements motivate a new physiological picture of the tissue that achieves this transition, the tendon-to-bone insertion, as a continuous, functionally graded material. Our biomechanical model suggests that the experimentally observed increase in mineral accumulation within collagen fibers can provide significant stiffening of the partially mineralized fibers, but only for concentrations of mineral above a "percolation threshold" corresponding to formation of a mechanically continuous mineral network within each collagen fiber (e.g., the case of mineral connectivity extending from one end of the fiber to the other). Increasing dispersion in the orientation distribution of collagen fibers from tendon to bone is a second major determinant of tissue stiffness. The combination of these two factors may explain the nonmonotonic variation of stiffness over the length of the tendon-to-bone insertion reported previously. Our models explain how tendon-to-bone attachment is achieved through a functionally graded material composition, and provide targets for tissue engineered surgical interventions and biomimetic material interfaces.

Parathyroid hormone and bone healing.

PubMed

Ellegaard, M; Jørgensen, N R; Schwarz, P

2010-07-01

Fracture healing is a complex process, and a significant number of fractures are complicated by impaired healing and non-union. Impaired healing is prevalent in certain risk groups, such as the elderly, osteoporotics, people with malnutrition, and women after menopause. Currently, no pharmacological treatments are available. There is therefore an unmet need for medications that can stimulate bone healing. Parathyroid hormone (PTH) is the first bone anabolic drug approved for the treatment of osteoporosis, and intriguingly a number of animal studies suggest that PTH could be beneficial in the treatment of fractures and could thus be a potentially new treatment option for induction of fracture healing in humans. Furthermore, fractures in animals with experimental conditions of impaired healing such as aging, estrogen withdrawal, and malnutrition can heal in an expedited manner after PTH treatment. Interestingly, fractures occurring at both cancellous and cortical sites can be treated successfully, indicating that both osteoporotic and nonosteoporotic fractures can be the target of PTH-induced healing. Finally, the data suggest that PTH partly prevents the delay in fracture healing caused by aging. Recently, the first randomized, controlled clinical trial investigating the effect of PTH on fracture healing was published, indicating a possible clinical benefit of PTH treatment in inducing fracture healing. The aim of this article is therefore to review the evidence for the potential of PTH in bone healing, including the underlying mechanisms for this, and to provide recommendations for the clinical testing and use of PTH in the treatment of impaired fracture healing in humans.

Effects of boric acid on the healing of Achilles tendons of rats.

PubMed

Kaymaz, Burak; Gölge, Umut Hatay; Ozyalvaclı, Gulzade; Kömürcü, Erkam; Goksel, Ferdi; Mermerkaya, Musa Ugur; Doral, Mahmut Nedim

2016-12-01

Tendinous lesions are among the most frequent pathologies encountered in sportsmen. The objectives of new treatments are to improve the healing process and reduce the recovery time. Boron plays an important role in the wound repair process by increasing components of extracellular matrix and angiogenesis. This animal study aimed to investigate the effect of boric acid on healing of the Achilles tendon. The right Achilles tendons of 40 rats were completely sectioned, and the rats were randomly divided into five groups. Each group consisted of eight rats. Groups 1 and 2 were oral boric acid groups with the doses of 4 and 8 mg/kg/day boric acid, respectively. Group 3 was the local boric acid group (8 mg/kg boric acid intratendinous injection). Group 4 was administered both oral and local boric acid (8 mg/kg/day orally and 8 mg/kg boric acid intratendinous injection), and group 5 was the control group with no boric acid application. At the end of the fourth week, all the rats were killed and histopathological examination of the Achilles tendon repair site was made. Histopathological examination of the tissue sections revealed more properly oriented collagen fibres, more normal cellular distribution of tenocytes and more properly organized vascular bundles in group 1 and group 2, which were the groups administered oral boric acid. Pathological sum scores of groups 1 and 2 were less than those of the other groups, and the differences between the oral boric acid groups (group 1 and group 2) and the other three groups (groups 3, 4 and 5) were statistically significant (p = 0.001). As boric acid is safe and toxicity even after very high doses is unusual, oral boric acid may be used as an agent to improve the healing process of tendon injuries. However, biomechanical tests should also be performed to show the effect of boric acid on strength and endurance of the tendon before it can be used in clinical practice.

Radioprotection provides functional mechanics but delays healing of irradiated tendon allografts after ACL reconstruction in sheep.

PubMed

Seto, Aaron U; Culp, Brian M; Gatt, Charles J; Dunn, Michael

2013-12-01

Successful protection of tissue properties against ionizing radiation effects could allow its use for terminal sterilization of musculoskeletal allografts. In this study we functionally evaluate Achilles tendon allografts processed with a previously developed radioprotective treatment based on (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) crosslinking and free radical scavenging using ascorbate and riboflavin, for ovine anterior cruciate ligament reconstruction. Arthroscopic anterior cruciate ligament (ACL) reconstruction was performed using double looped allografts, while comparing radioprotected irradiated and fresh frozen allografts after 12 and 24 weeks post-implantation, and to control irradiated grafts after 12 weeks. Radioprotection was successful at preserving early subfailure mechanical properties comparable to fresh frozen allografts. Twelve week graft stiffness and anterior-tibial (A-T) translation for radioprotected and fresh frozen allografts were comparable at 30 % of native stiffness, and 4.6 and 5 times native A-T translation, respectively. Fresh frozen allograft possessed the greatest 24 week peak load at 840 N and stiffness at 177 N/mm. Histological evidence suggested a delay in tendon to bone healing for radioprotected allografts, which was reflected in mechanical properties. There was no evidence that radioprotective treatment inhibited intra-articular graft healing. This specific radioprotective method cannot be recommended for ACL reconstruction allografts, and data suggest that future efforts to improve allograft sterilization procedures should focus on modifying or eliminating the pre-crosslinking procedure.

Tendon and Ligament Regeneration and Repair: Clinical Relevance and Developmental Paradigm

PubMed Central

Tuan, Rocky S.

2014-01-01

Tendon and ligament (T/L) are dense connective tissues connecting bone to muscle and bone to bone, respectively. Similar to other musculoskeletal tissues, T/L arise from the somitic mesoderm, but they are derived from a recently discovered somitic compartment, the syndetome. The adjacent sclerotome and myotome provide inductive signals to the interposing syndetome, thereby upregulating the expression of the transcription factor Scleraxis, which in turn leads to further tenogenic and ligamentogenic differentiation. These advances in the understanding of T/L development have been sought to provide a knowledge base for improving the healing of T/L injuries, a common clinical challenge due to the intrinsically poor natural healing response. Specifically, the three most common tendon injuries involve tearing of the rotator cuff of the shoulder, the flexor tendon of the hand, and the Achilles tendon. At present, injuries to these tissues are treated by surgical repair and/or conservative approaches, including biophysical modalities such as physical rehabilitation and cryotherapy. Unfortunately, the healing tissue forms fibrovascular scar and possesses inferior mechanical and biochemical properties as compared to native T/L. Therefore, tissue engineers have sought to improve upon the natural healing response by augmenting the injured tissue with cells, scaffolds, bioactive agents, and mechanical stimulation. These strategies show promise, both in vitro and in vivo, for improving T/L healing. However, several challenges remain in restoring full T/L function following injury, including uncertainties over the optimal combination of these biological agents as well how to best deliver tissue engineered elements to the injury site. A greater understanding of the molecular mechanisms involved in T/L development and natural healing, coupled with the capability of producing complex biomaterials to deliver multiple growth factors with high spatiotemporal resolution and specificity

The role of animal models in tendon research

PubMed Central

Hast, M. W.; Zuskov, A.; Soslowsky, L. J.

2014-01-01

Tendinopathy is a debilitating musculoskeletal condition which can cause significant pain and lead to complete rupture of the tendon, which often requires surgical repair. Due in part to the large spectrum of tendon pathologies, these disorders continue to be a clinical challenge. Animal models are often used in this field of research as they offer an attractive framework to examine the cascade of processes that occur throughout both tendon pathology and repair. This review discusses the structural, mechanical, and biological changes that occur throughout tendon pathology in animal models, as well as strategies for the improvement of tendon healing. Cite this article: Bone Joint Res 2014;3:193–202. PMID:24958818

Chronic Degeneration Leads to Poor Healing of Repaired Massive Rotator Cuff Tears in Rats

PubMed Central

Killian, Megan L.; Cavinatto, Leonardo M.; Ward, Samuel R.; Havlioglu, Necat; Thomopoulos, Stavros; Galatz, Leesa M.

2016-01-01

Background Chronic rotator cuff tears present a clinical challenge, often with poor outcomes after surgical repair. Degenerative changes to the muscle, tendon, and bone are thought to hinder healing after surgical repair; additionally, the ability to overcome degenerative changes after surgical repair remains unclear. Purpose/Hypothesis The purpose of this study was to evaluate healing outcomes of muscle, tendon, and bone after tendon repair in a model of chronic rotator cuff disease and to compare these outcomes to those of acute rotator cuff injuries and repair. The hypothesis was that degenerative rotator cuff changes associated with chronic multitendon tears and muscle unloading would lead to poor structural and mechanical outcomes after repair compared with acute injuries and repair. Study Design Controlled laboratory study. Methods Chronic rotator cuff injuries, induced via detachment of the supraspinatus (SS) and infraspinatus (IS) tendons and injection of botulinum toxin A into the SS and IS muscle bellies, were created in the shoulders of rats. After 8 weeks of injury, tendons were surgically reattached to the humeral head, and an acute, dual-tendon injury and repair was performed on the contralateral side. After 8 weeks of healing, muscles were examined histologically, and tendon-to-bone samples were examined microscopically, histologically, and biomechanically and via micro–computed tomography. Results All repairs were intact at the time of dissection, with no evidence of gapping or ruptures. Tendon-to-bone healing after repair in our chronic injury model led to reduced bone quality and morphological disorganization at the repair site compared with acute injuries and repair. SS and IS muscles were atrophic at 8 weeks after repair of chronic injuries, indicating incomplete recovery after repair, whereas SS and IS muscles exhibited less atrophy and degeneration in the acute injury group at 8 weeks after repair. After chronic injuries and repair, humeral

Nanotechnology and bone healing.

PubMed

Harvey, Edward J; Henderson, Janet E; Vengallatore, Srikar T

2010-03-01

Nanotechnology and its attendant techniques have yet to make a significant impact on the science of bone healing. However, the potential benefits are immediately obvious with the result that hundreds of researchers and firms are performing the basic research needed to mature this nascent, yet soon to be fruitful niche. Together with genomics and proteomics, and combined with tissue engineering, this is the new face of orthopaedic technology. The concepts that orthopaedic surgeons recognize are fabrication processes that have resulted in porous implant substrates as bone defect augmentation and medication-carrier devices. However, there are dozens of applications in orthopaedic traumatology and bone healing for nanometer-sized entities, structures, surfaces, and devices with characteristic lengths ranging from 10s of nanometers to a few micrometers. Examples include scaffolds, delivery mechanisms, controlled modification of surface topography and composition, and biomicroelectromechanical systems. We review the basic science, clinical implications, and early applications of the nanotechnology revolution and emphasize the rich possibilities that exist at the crossover region between micro- and nanotechnology for developing new treatments for bone healing.

Femoral press-fit fixation in ACL reconstruction using bone-patellar tendon-bone autograft: results at 15 years follow-up.

PubMed

Widuchowski, Wojciech; Widuchowska, Malgorzata; Koczy, Bogdan; Dragan, Szymon; Czamara, Andrzej; Tomaszewski, Wieslaw; Widuchowski, Jerzy

2012-06-27

If anterior cruciate ligament (ACL) reconstruction is to be performed, decision regarding graft choice and its fixation remains one of the most controversial. Multiple techniques for ACL reconstruction are available. To avoid disadvantages related to fixation devices, a hardware-free, press-fit ACL reconstruction technique was developed. The aim of this study was to evaluate clinical outcome and osteoarthritis progression in long term after ACL reconstruction with central third patellar-tendon autograft fixed to femur by press-fit technique. Fifty two patients met inclusion/excusion criteria for this study. The patients were assessed preoperatively and at 15 years after surgery with International Knee Documentation Committee Knee Ligament Evaluation Form, Lysholm knee score, Tegner activity scale and radiographs. Good overall clinical outcomes and self-reported assessments were documented, and remained good at 15 years. The mean Lysholm and Tegner scores improved from 59.7 ± 18.5 and 4.2 ± 1.0 preoperatively to 86.4 ± 5.6 (p = 0.004) and 6.9 ± 1.4 (p = 0.005) respectively at follow-up. The IKDC subjective score improved from 60.1 ± 9.2 to 80.2 ± 8.1 (p = 0.003). According to IKDC objective score, 75% of patients had normal or nearly normal knee joints at follow-up. Grade 0 or 1 results were seen in 85% of patients on laxity testing. Degenerative changes were found in 67% of patients. There was no correlation between arthritic changes and stability of knee and subjective evaluation (p > 0.05). ACL reconstruction with patellar tendon autograft fixed to femur with press-fit technique allows to achieve good self-reported assessments and clinical ligament evaluation up to 15 years. Advantages of the bone-patellar-tendon-bone (BPTB) press-fit fixation include unlimited bone-to-bone healing, cost effectiveness, avoidance of disadvantages associated with hardware, and ease for revision surgery. BPTB femoral press-fit fixation technique can be safely applied in

Bone healing in 2016

PubMed Central

Buza, John A.; Einhorn, Thomas

2016-01-01

Summary Delayed fracture healing and nonunion occurs in up to 5–10% of all fractures, and can present a challenging clinical scenario for the treating physician. Methods for the enhancement of skeletal repair may benefit patients that are at risk of, or have experienced, delayed healing or nonunion. These methods can be categorized into either physical stimulation therapies or biological therapies. Physical stimulation therapies include electrical stimulation, low-intensity pulsed ultrasonography, or extracorporeal shock wave therapy. Biological therapies can be further classified into local or systemic therapy based on the method of delivery. Local methods include autologous bone marrow, autologous bone graft, fibroblast growth factor-2, platelet-rich plasma, platelet-derived growth factor, and bone morphogenetic proteins. Systemic therapies include parathyroid hormone and bisphosphonates. This article reviews the current applications and supporting evidence for the use of these therapies in the enhancement of fracture healing. PMID:27920804

Does immobilization after arthroscopic rotator cuff repair increase tendon healing? A systematic review and meta-analysis.

PubMed

Shen, Chong; Tang, Zhi-Hong; Hu, Jun-Zu; Zou, Guo-Yao; Xiao, Rong-Chi; Yan, Dong-Xue

2014-09-01

To determine whether immobilization after arthroscopic rotator cuff repair improved tendon healing compared with early passive motion. A systematic electronic literature search was conducted to identify randomized controlled trials (RCTs) comparing early passive motion with immobilization after arthroscopic rotator cuff repair. The primary outcome assessed was tendon healing in the repaired cuff. Secondary outcome measures were range of motion (ROM) and American Shoulder and Elbow Surgeons (ASES) shoulder scale, Simple Shoulder Test (SST), Constant, and visual analog scale (VAS) for pain scores. Pooled analyses were performed using a random effects model to obtain summary estimates of treatment effect with 95% confidence intervals. Heterogeneity among included studies was quantified. Three RCTs examining 265 patients were included. Meta-analysis revealed no significant difference in tendon healing in the repaired cuff between the early-motion and immobilization groups. A significant difference in external rotation at 6 months postoperatively favored early motion over immobilization, but no significant difference was observed at 1 year postoperatively. In one study, Constant scores were slightly higher in the early-motion group than in the immobilization group. Two studies found no significant difference in ASES, SST, or VAS score between groups. We found no evidence that immobilization after arthroscopic rotator cuff repair was superior to early-motion rehabilitation in terms of tendon healing or clinical outcome. Patients in the early-motion group may recover ROM more rapidly. Level II; systematic review of levels I and II studies.

Optimization of intrinsic and extrinsic tendon healing through controllable water-soluble mitomycin-C release from electrospun fibers by mediating adhesion-related gene expression.

PubMed

Zhao, Xin; Jiang, Shichao; Liu, Shen; Chen, Shuai; Lin, Zhi Yuan William; Pan, Guoqing; He, Fan; Li, Fengfeng; Fan, Cunyi; Cui, Wenguo

2015-08-01

To balance intrinsic and extrinsic healing during tendon repair is challenging in tendon surgery. We hypothesized that by mediating apoptotic gene and collagen synthesis of exogenous fibroblasts, the adhesion formation induced by extrinsic healing could be inhibited. With the maintenance of intrinsic healing, the tendon could be healed with proper function with no adhesion. In this study, we loaded hydrophilic mitomycin-C (MMC) into hyaluronan (HA) hydrosols, which were then encapsulated in poly(L-lactic acid) (PLLA) fibers by micro-sol electrospinning. This strategy successfully provided a controlled release of MMC to inhibit adhesion formations with no detrimental effect on intrinsic healing. We found that micro-sol electrospinning was an effective and facile approach to incorporate and control hydrophilic drug release from hydrophobic polyester fibers. MMC exhibited an initially rapid, and gradually steadier release during 40 days, and the release rates could be tuned by its concentration. In vitro studies revealed that low concentrations of MMC could inhibit fibroblast adhesion and proliferation. When lacerate tendons were healed using the MMC-HA loaded PLLA fibers in vivo, they exhibited comparable mechanical strength to the naturally healed tendons but with no significant presence of adhesion formation. We further identified the up-regulation of apoptotic protein Bax expression and down-regulation of proteins Bcl2, collage I, collagen III and α-SMA during the healing process associated with minimum adhesion formations. This approach presented here leverages new advances in drug delivery and nanotechnology and offers a promising strategy to balance intrinsic and extrinsic tendon healing through modulating genes associated with fibroblast apoptosis and collagen synthesis. Copyright © 2015 Elsevier Ltd. All rights reserved.

Distal Triceps Tendon Injuries.

PubMed

Keener, Jay D; Sethi, Paul M

2015-11-01

Acute triceps ruptures are an uncommon entity, occurring mainly in athletes, weight lifters (especially those taking anabolic steroids), and following elbow trauma. Accurate diagnosis is made clinically, although MRI may aid in confirmation and surgical planning. Acute ruptures are classified on an anatomic basis based on tear location and the degree of tendon involvement. Most complete tears are treated surgically in medically fit patients. Partial-thickness tears are managed according to the tear severity, functional demands, and response to conservative treatment. We favor an anatomic footprint repair of the triceps to provide optimal tendon to bone healing and, ultimately, functional outcome. Copyright © 2015 Elsevier Inc. All rights reserved.

Monitoring the mechanical properties of healing bone.

PubMed

Claes, L E; Cunningham, J L

2009-08-01

Fracture healing is normally assessed through an interpretation of radiographs, clinical evaluation, including pain on weight bearing, and a manual assessment of the mobility of the fracture. These assessments are subjective and their accuracy in determining when a fracture has healed has been questioned. Viewed in mechanical terms, fracture healing represents a steady increase in strength and stiffness of a broken bone and it is only when these values are sufficiently high to support unrestricted weight bearing that a fracture can be said to be healed. Information on the rate of increase of the mechanical properties of a healing bone is therefore valuable in determining both the rate at which a fracture will heal and in helping to define an objective and measurable endpoint of healing. A number of techniques have been developed to quantify bone healing in mechanical terms and these are described and discussed in detail. Clinical studies, in which measurements of fracture stiffness have been used to identify a quantifiable end point of healing, compare different treatment methods, predictably determine whether a fracture will heal, and identify factors which most influence healing, are reviewed and discussed.

Mechanisms of tendon injury and repair

PubMed Central

Thomopoulos, Stavros; Parks, William C.; Rifkin, Daniel B.; Derwin, Kathleen A.

2015-01-01

Tendon disorders are common and lead to significant disability, pain, healthcare cost, and lost productivity. A wide range of injury mechanisms exist leading to tendinopathy or tendon rupture. Tears can occur in healthy tendons that are acutely overloaded (e.g., during a high speed or high impact event) or lacerated (e.g., a knife injury). Tendinitis or tendinosis can occur in tendons exposed to overuse conditions (e.g., an elite swimmer’s training regimen) or intrinsic tissue degeneration (e.g., age-related degeneration). The healing potential of a torn or pathologic tendon varies depending on anatomic location (e.g., Achilles vs. rotator cuff) and local environment (e.g., intrasynovial vs. extrasynovial). Although healing occurs to varying degrees, in general healing of repaired tendons follows the typical wound healing course, including an early inflammatory phase, followed by proliferative and remodeling phases. Numerous treatment approaches have been attempted to improve tendon healing, including growth factor- and cell-based therapies and rehabilitation protocols. This review will describe the current state of knowledge of injury and repair of the three most common tendinopathies-- flexor tendon lacerations, Achilles tendon rupture, and rotator cuff disorders-- with a particular focus on the use of animal models for understanding tendon healing. PMID:25641114

Transcription factor EGR1 directs tendon differentiation and promotes tendon repair

PubMed Central

Guerquin, Marie-Justine; Charvet, Benjamin; Nourissat, Geoffroy; Havis, Emmanuelle; Ronsin, Olivier; Bonnin, Marie-Ange; Ruggiu, Mathilde; Olivera-Martinez, Isabel; Robert, Nicolas; Lu, Yinhui; Kadler, Karl E.; Baumberger, Tristan; Doursounian, Levon; Berenbaum, Francis; Duprez, Delphine

2013-01-01

Tendon formation and repair rely on specific combinations of transcription factors, growth factors, and mechanical parameters that regulate the production and spatial organization of type I collagen. Here, we investigated the function of the zinc finger transcription factor EGR1 in tendon formation, healing, and repair using rodent animal models and mesenchymal stem cells (MSCs). Adult tendons of Egr1–/– mice displayed a deficiency in the expression of tendon genes, including Scx, Col1a1, and Col1a2, and were mechanically weaker compared with their WT littermates. EGR1 was recruited to the Col1a1 and Col2a1 promoters in postnatal mouse tendons in vivo. Egr1 was required for the normal gene response following tendon injury in a mouse model of Achilles tendon healing. Forced Egr1 expression programmed MSCs toward the tendon lineage and promoted the formation of in vitro–engineered tendons from MSCs. The application of EGR1-producing MSCs increased the formation of tendon-like tissues in a rat model of Achilles tendon injury. We provide evidence that the ability of EGR1 to promote tendon differentiation is partially mediated by TGF-β2. This study demonstrates EGR1 involvement in adult tendon formation, healing, and repair and identifies Egr1 as a putative target in tendon repair strategies. PMID:23863709

Delayed early passive motion is harmless to shoulder rotator cuff healing in a rabbit model.

PubMed

Zhang, Shurong; Li, Hong; Tao, Hongyue; Li, Hongyun; Cho, Samson; Hua, Yinghui; Chen, Jiwu; Chen, Shiyi; Li, Yunxia

2013-08-01

Postoperative passive motion is the most widely accepted rehabilitation protocol after rotator cuff repair; however, a rotator cuff retear remains a frequent surgical complication. Clinical outcomes indicate that early passive motion is harmless to rotator cuff healing, but no laboratory evidence supports this proposition. (1) Immediate postoperative immobilization improves rotator cuff healing in rabbits. (2) Early passive motion after short-term immobilization does not harm rotator cuff healing in rabbits. Controlled laboratory study. An injury to the supraspinatus tendon was created and repaired in 90 New Zealand White rabbits, after which they were randomly separated into 3 groups: (1) nonimmobilization (NI; n = 30), (2) continuous immobilization (IM; n = 30), and (3) immobilization with early passive motion (IP; n = 30). At 3, 6, and 12 weeks postoperatively, 5 rabbits from each group were sacrificed for histological evaluation, biomechanical testing, and magnetic resonance imaging. The histological study demonstrated better postoperative healing in the IM and IP groups, with clusters of chondrocytes accumulated at the tendon-bone junction. Magnetic resonance imaging illustrated that the tendon-bone junction was intact in the IM and IP groups. The magnetic resonance quantification analysis showed that the signal-to-noise quotient (SNQ) of the NI group was not significantly higher than that of the immobilization groups at 3 weeks (P = .232) or 6 weeks (P = .117), but it was significantly different at 12 weeks (NI vs IM, P = .006; NI vs IP, P = .009). At 12 weeks, the failure load was significantly higher in the IM and IP groups than in the NI group (NI vs IM, P = .002; NI vs IP, P = .002), but no difference was found between the IM and IP groups (P = .599). Immediate postoperative immobilization led to better tendon-bone healing than immediate postoperative mobilization, and under immobilization, early passive motion was harmless to tendon-bone healing in this

Gastric pentadecapeptide BPC 157 accelerates healing of transected rat Achilles tendon and in vitro stimulates tendocytes growth.

PubMed

Staresinic, M; Sebecic, B; Patrlj, L; Jadrijevic, S; Suknaic, S; Perovic, D; Aralica, G; Zarkovic, N; Borovic, S; Srdjak, M; Hajdarevic, K; Kopljar, M; Batelja, L; Boban-Blagaic, A; Turcic, I; Anic, T; Seiwerth, S; Sikiric, P

2003-11-01

In studies intended to improve healing of transected Achilles tendon, effective was a stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, M.W. 1419). Currently in clinical trials for inflammatory bowel disease (PLD-116, PL 14736, Pliva), it ameliorates internal and external wound healing. In rats, the right Achilles tendon transected (5 mm proximal to its calcaneal insertion) presents with a large tendon defect between cut ends. Agents (/kg b.w., i.p., once time daily) (BPC 157 (dissolved in saline, with no carrier addition) (10 microg, 10 ng or 10 pg) or saline (5.0 ml)), were firstly applied at 30 min after surgery, the last application at 24 h before autopsy. Achilles functional index (AFI) was assessed once time daily. Biomechanical, microscopical and macroscopical assessment was on day 1, 4, 7, 10 and 14. Controls generally have severely compromised healing. In comparison, pentadecapeptide BPC 157 fully improves recovery: (i) biomechanically, increased load of failure, load of failure per area and Young's modulus of elasticity; (ii) functionally, significantly higher AFI-values; (iii) microscopically, more mononuclears and less granulocytes, superior formation of fibroblasts, reticulin and collagen; (iv) macroscopically, smaller size and depth of tendon defect, and subsequently the reestablishment of full tendon integrity. Likewise, unlike TGF-beta, pentadecapeptide BPC 157, presenting with no effect on the growth of cultured cell of its own, consistently opposed 4-hydroxynonenal (HNE), a negative modulator of the growth. HNE-effect is opposed in both combinations: BPC 157+HNE (HNE growth inhibiting effect reversed into growth stimulation of cultured tendocytes) and HNE+BPC 157(abolished inhibiting activity of the aldehyde), both in the presence of serum and serum deprived conditions. In conclusion, these findings, particularly, Achilles tendon transection fully recovered in rats, peptide stability suitable delivery, usefully favor gastric

Synthesis, development, characterization and effectiveness of bovine pure platelet gel-collagen-polydioxanone bioactive graft on tendon healing

PubMed Central

Moshiri, Ali; Oryan, Ahmad; Meimandi-Parizi, Abdolhamid

2015-01-01

Bovine platelet gel (BPG) is an accessible and cost-effective source of growth factors which may have a value in tendon regenerative medicine. We produced a collagen implant (CI) as a tendon proper, covered it with polydioxanone (PDS) sheath to simulate paratenon and finally embedded the BPG as an active source of growth factor within the bioimplant to test whether BPG would be able to accelerate and enhance tendon regeneration and repair. After in vitro characterization of the bioactive grafts, the grafts were implanted in rabbit large tendon defect model. Untreated tendons and tendons treated with either CI or CI-PDS were served as controls for the CI-PDS-BPG. The animals were investigated clinically, ultrasonographically and haematologically for 120 days. After euthanasia, dry matter content, water uptake and delivery characteristics and also gross morphological, histopathological and scanning electron microscopic features of the healing tendons were assessed. In vitro, the activated platelets in the scaffold, released their growth factors significantly more than the controls. BPG also increased cell viability, and enhanced cellular differentiation, maturation and proliferation inside the CI-PDS compared with the controls. In vivo, the BPG modulated inflammation, increased quality and rate of fibroplasia and produced a remodelled tendon that had significantly higher collagen content and superior collagen fibril and fibre differentiation than controls. Treatment also significantly improved tendon water uptake and delivery characteristics, animals’ serum PDGF level, CI-PDS biocompatibility and biodegradability and reduced peritendinous adhesions, muscle fibrosis and atrophy. BPG was effective on tendon healing and CI-PDS-BPG may be a valuable bioscaffold in tendon reconstructive surgery. PMID:25702535

The role of three-dimensional pure bovine gelatin scaffolds in tendon healing, modeling, and remodeling: an in vivo investigation with potential clinical value.

PubMed

Oryan, Ahmad; Sharifi, Pardis; Moshiri, Ali; Silver, Ian A

2017-09-01

Large tendon defects involving extensive tissue loss present complex clinical problems. Surgical reconstruction of such injuries is normally performed by transplanting autogenous and allogenous soft tissues that are expected to remodel to mimic a normal tendon. However, the use of grafts has always been associated with significant limitations. Tissue engineering employing artificial scaffolds may provide acceptable alternatives. Gelatin is a hydrolyzed form of collagen that is bioactive, biodegradable, and biocompatible. The present study has investigated the suitability of gelatin scaffold for promoting healing of a large tendon-defect model in rabbits. An experimental model of a large tendon defect was produced by partial excision of the Achilles tendon of the left hind leg in adult rabbits. To standardize and stabilize the length of the tendon defect a modified Kessler core suture was anchored in the sectioned tendon ends. The defects were either left untreated or filled with three-dimensional gelatin scaffold. Before euthanasia 60 days after injury, the progress of healing was evaluated clinically. Samples of healing tendon were harvested at autopsy and evaluated by gross, histopathologic, scanning, and transmission electron microscopy, and by biomechanical testing. The treated animals showed superior weight-bearing and physical activity compared with those untreated, while frequency of peritendinous adhesions around the healing site was reduced. The gelatin scaffold itself was totally degraded and replaced by neo-tendon that morphologically had significantly greater numbers, diameters, density, and maturation of collagen fibrils, fibers, and fiber bundles than untreated tendon scar tissue. It also had mechanically higher ultimate load, yield load, stiffness, maximum stress and elastic modulus, when compared to the untreated tendons. Gelatin scaffold may be a valuable option in surgical reconstruction of large tendon defects.

Reversibility of Supraspinatus Muscle Atrophy in Tendon-Bone Healing After Arthroscopic Rotator Cuff Repair.

PubMed

Park, Yong Bok; Ryu, Ho Young; Hong, Jin Ho; Ko, Young Hoo; Yoo, Jae Chul

2016-04-01

final follow-up (P = .077). After successful arthroscopic rotator cuff repair, there was a slight (11.3%-13.9%) increase in muscle volume from preoperatively to final follow-up, as seen on serial MRI. Fatty infiltration according to the Goutallier grade was not reversed (P = .077). Some reversibility of supraspinatus muscle atrophy may exist in tendon-bone healing after arthroscopic rotator cuff repair; further follow-up is needed to better elucidate this result. © 2016 The Author(s).

The effect of layer-by-layer chitosan-hyaluronic acid coating on graft-to-bone healing of a poly(ethylene terephthalate) artificial ligament.

PubMed

Li, Hong; Ge, Yunsheng; Zhang, Pengyun; Wu, Lingxiang; Chen, Shiyi

2012-01-01

Surface coating with an organic layer-by-layer self-assembled template of chitosan and hyaluronic acid on a poly(ethylene terephthalate) (PET) artificial ligament was designed for the promotion and enhancement of graft-to-bone healing after artificial ligament implantation in a bone tunnel. The results of in vitro culturing of MC3T3-E1 mouse osteoblastic cells supported the hypothesis that the layer-by-layer coating of chitosan and hyaluronic acid could promote the cell compatibility of grafts and could promote osteoblast proliferation. A rabbit extra-articular tendon-to-bone healing model was used to evaluate the effect of this kind of surface-modified stainless artificial ligament in vivo. The final results proved that this organic compound coating could significantly promote and enhance new bone formation at the graft-bone interface histologically and, correspondingly, the experimental group with coating had significantly higher biomechanical properties compared with controls at 8 weeks (P < 0.05).

Shock wave-enhanced neovascularization at the tendon-bone junction: an experiment in dogs.

PubMed

Wang, Ching-Jen; Huang, Hsuan-Ying; Pai, Chun-Hwan

2002-01-01

The purpose of the research was to study the phenomenon of neovascularization at the Achilles tendon-bone junction after low-energy shock wave application. The study was performed on eight mongrel dogs. The control specimens were obtained from the medial one-third of the right Achilles tendon-bone unit before shock wave application. Low-energy shock waves of 1000 impulses at 14 kV (equivalent to 0.18 mJ/mm2 energy flux density) were applied to the right Achilles bone-tendon junction. Biopsies were taken from the middle one-third of the Achilles tendon-bone junction at 4 weeks and from the lateral one-third at 8 weeks, respectively, after shock wave application. The features of microscopic examination included the number of new capillaries and muscularized vessels, the presence and arrangements of myofibroblasts, and the changes in bone. New capillary and muscularized vessels were seen in the study specimens which were obtained in 4 weeks and in 8 weeks after shock wave application, but none were seen in the control specimens before shock wave application. There was a considerable geographic variation in the number of new vessels within the same specimen. Myofibroblasts were not seen in the control specimens. Myofibroblasts with haphazard appearance and intermediate orientation fibers were seen in all study specimens obtained at 4 weeks and predominantly intermediate orientation myofibroblast fibers at 8 weeks. There were no changes in bone matrix, osteocyte activity, and vascularization within the bone. Two pathologists reviewed each specimen and concurrence was achieved in all cases. The results of the study suggested that low-energy shock wave enhanced the phenomenon of neovascularization at the bone-tendon junction in dogs.

Composition and structure of porcine digital flexor tendon-bone insertion tissues.

PubMed

Chandrasekaran, Sandhya; Pankow, Mark; Peters, Kara; Huang, Hsiao-Ying Shadow

2017-11-01

Tendon-bone insertion is a functionally graded tissue, transitioning from 200 MPa tensile modulus at the tendon end to 20 GPa tensile modulus at the bone, across just a few hundred micrometers. In this study, we examine the porcine digital flexor tendon insertion tissue to provide a quantitative description of its collagen orientation and mineral concentration by using Fast Fourier Transform (FFT) based image analysis and mass spectrometry, respectively. Histological results revealed uniformity in global collagen orientation at all depths, indicative of mechanical anisotropy, although at mid-depth, the highest fiber density, least amount of dispersion, and least cellular circularity were evident. Collagen orientation distribution obtained through 2D FFT of histological imaging data from fluorescent microscopy agreed with past measurements based on polarized light microscopy. Results revealed global fiber orientation across the tendon-bone insertion to be preserved along direction of physiologic tension. Gradation in the fiber distribution orientation index across the insertion was reflective of a decrease in anisotropy from the tendon to the bone. We provided elemental maps across the fibrocartilage for its organic and inorganic constituents through time-of-flight secondary ion mass spectrometry (TOF-SIMS). The apatite intensity distribution from the tendon to bone was shown to follow a linear trend, supporting past results based on Raman microprobe analysis. The merit of this study lies in the image-based simplified approach to fiber distribution quantification and in the high spatial resolution of the compositional analysis. In conjunction with the mechanical properties of the insertion tissue, fiber, and mineral distribution results for the insertion from this may potentially be incorporated into the development of a structural constitutive approach toward computational modeling. Characterizing the properties of the native insertion tissue would provide the

Inhibition of 5-LOX, COX-1, and COX-2 increases tendon healing and reduces muscle fibrosis and lipid accumulation after rotator cuff repair.

PubMed

Oak, Nikhil R; Gumucio, Jonathan P; Flood, Michael D; Saripalli, Anjali L; Davis, Max E; Harning, Julie A; Lynch, Evan B; Roche, Stuart M; Bedi, Asheesh; Mendias, Christopher L

2014-12-01

The repair and restoration of function after chronic rotator cuff tears are often complicated by muscle atrophy, fibrosis, and fatty degeneration of the diseased muscle. The inflammatory response has been implicated in the development of fatty degeneration after cuff injuries. Licofelone is a novel anti-inflammatory drug that inhibits 5-lipoxygenase (5-LOX), as well as cyclooxygenase (COX)-1 and COX-2 enzymes, which play important roles in inducing inflammation after injuries. While previous studies have demonstrated that nonsteroidal anti-inflammatory drugs and selective inhibitors of COX-2 (coxibs) may prevent the proper healing of muscles and tendons, studies about bone and cartilage have demonstrated that drugs that inhibit 5-LOX concurrently with COX-1 and COX-2 may enhance tissue regeneration. After the repair of a chronic rotator cuff tear in rats, licofelone would increase the load to failure of repaired tendons and increase the force production of muscle fibers. Controlled laboratory study. Rats underwent supraspinatus release followed by repair 28 days later. After repair, rats began a treatment regimen of either licofelone or a vehicle for 14 days, at which time animals were euthanized. Supraspinatus muscles and tendons were then subjected to contractile, mechanical, histological, and biochemical analyses. Compared with controls, licofelone-treated rats had a grossly apparent decrease in inflammation and increased fibrocartilage formation at the enthesis, along with a 62% increase in the maximum load to failure and a 51% increase in peak stress to failure. Licofelone resulted in a marked reduction in fibrosis and lipid content in supraspinatus muscles as well as reduced expression of several genes involved in fatty infiltration. Despite the decline in fibrosis and fat accumulation, muscle fiber specific force production was reduced by 23%. The postoperative treatment of cuff repair with licofelone may reduce fatty degeneration and enhance the development

Ultrasonographic assessment of the equine palmar tendons

PubMed Central

Padaliya, N. R.; Ranpariya, J. J.; Kumar, Dharmendra; Javia, C. B.; Barvalia, D. R.

2015-01-01

Aim: The present study was conducted to evaluate the equine palmar tendon by ultrasonography (USG) in standing the position. Materials and Methods: USG of palmar tendons was performed in 40 adult horses using linear transducer having frequency of 10-18 MHz (e-soate, My Lab FIVE) and L52 linear array transducer (Titan, SonoSite) with frequencies ranging from 8 to 10 MHz. Palmar tendon was divided into 7 levels from distal to accessory carpal bone up to ergot in transverse scanning and 3 levels in longitudinal scanning. Results: The USG evaluation was very useful for diagnosis of affections of the conditions such as chronic bowed tendon, suspensory ligament desmitis, carpal sheath tenosynovitis and digital sheath effusions. The mean cross-sectional area (cm2) of affected tendons was significantly increased in affected than normal tendons. The echogenicity was also found reduced in affected tendons and ligaments along with disorganization of fiber alignment depending on the severity of lesion and injury. Conclusion: USG proved ideal diagnostic tool for diagnosis and post-treatment healing assessment of tendon injuries in horses. PMID:27047074

Tendon injuries of the hand

PubMed Central

Schöffl, Volker; Heid, Andreas; Küpper, Thomas

2012-01-01

Tendon injuries are the second most common injuries of the hand and therefore an important topic in trauma and orthopedic patients. Most injuries are open injuries to the flexor or extensor tendons, but less frequent injuries, e.g., damage to the functional system tendon sheath and pulley or dull avulsions, also need to be considered. After clinical examination, ultrasound and magnetic resonance imaging have proved to be important diagnostic tools. Tendon injuries mostly require surgical repair, dull avulsions of the distal phalanges extensor tendon can receive conservative therapy. Injuries of the flexor tendon sheath or single pulley injuries are treated conservatively and multiple pulley injuries receive surgical repair. In the postoperative course of flexor tendon injuries, the principle of early passive movement is important to trigger an “intrinsic” tendon healing to guarantee a good outcome. Many substances were evaluated to see if they improved tendon healing; however, little evidence was found. Nevertheless, hyaluronic acid may improve intrinsic tendon healing. PMID:22720265

Are bone turnover markers capable of predicting callus consolidation during bone healing?

PubMed

Klein, P; Bail, H J; Schell, H; Michel, R; Amthauer, H; Bragulla, H; Duda, G N

2004-07-01

The aim of this study was to determine the ability of the following bone turnover markers to monitor the course of callus consolidation during bone healing: Carboxy-terminal propeptide of procollagen type I (PICP), skeletal alkaline phosphatase (sALP), and amino-terminal propeptide of type III procollagen (PIlINP). Since interfragmentary movements have been proven to possess the ability to document the progression of bone healing in experimental studies, correlations between bone turnover markers and interfragmentary movements in vivo were investigated. Therefore, two different types of osteosyntheses representing different mechanical situations at the fracture site were compared in an ovine osteotomy model. Blood samples were taken preoperatively and postoperatively in weekly intervals over a nine-week healing period. At the same intervals, interfragmentary movements were measured in all sheep. After nine weeks, animals were sacrificed and the tibiae were evaluated both mechanically and histologically. Wide interindividual ranges were observed for all bone turnover markers. The systemic PICP level did not increase with callus consolidation. The bone-healing model seemed to influence the systemic level of PIIINP and sALP but no general correlation between bone turnover markers and interfragmentary movements could be detected. No differences between the different types of osteosyntheses and thus the different mechanical situations were observed. All analyzed markers failed as general predictors for the course of callus consolidation during bone healing.

Eccentric Training for Tendon Healing After Acute Lesion: A Rat Model.

PubMed

Kaux, Jean-François; Libertiaux, Vincent; Leprince, Pierre; Fillet, Marianne; Denoel, Vincent; Wyss, Clémence; Lecut, Christelle; Gothot, André; Le Goff, Caroline; Croisier, Jean-Louis; Crielaard, Jean-Michel; Drion, Pierre

2017-05-01

The tendon is a dynamic entity that remodels permanently. Platelet-rich plasma (PRP) injection has been shown to have a beneficial effect on tendon healing after lesion in rats. Furthermore, eccentric exercise seems to improve the mechanical quality of the tendon. A combination of PRP injection and eccentric training might be more effective than either treatment alone. Controlled laboratory study. Adult male rats were anesthetized, an incision was performed in the middle of their left patellar tendon and an injection of physiological fluid (PF) or homologous PRP was randomly made at the lesion level. The rats were then divided into 2 groups: the eccentric group, undergoing eccentric training 3 times a week, and the untrained group, without any training. Thus, 4 groups were compared. After 5 weeks, the tendons were removed and their ultimate tensile strength and energy were measured. Tendons were frozen for proteomic analyses when all biomechanical tests were completed. Statistical analysis was performed with linear mixed effect models. No significant difference was found between the treatments using PF injection or PRP injection alone. However, the value of the ultimate tensile force at rupture was increased by 4.5 N (108% of control, P = .006) when eccentric training was performed. An intragroup analysis revealed that eccentric training significantly improved the ultimate force values for the PRP group. Proteomic analysis revealed that eccentric training led to an increase in abundance of several cytoskeletal proteins in the PF group, while a decrease in abundance of enzymes of the glycolytic pathway occurred in the PRP-treated groups, indicating that this treatment might redirect the exercise-driven metabolic plasticity of the tendon. Eccentric training altered the metabolic plasticity of tendon and led to an improvement of injured tendon resistance regardless of the treatment injected (PF or PRP). This study demonstrates the necessity of eccentric rehabilitation

Novel engineered tendon-fibrocartilage-bone composite with cyclic tension for rotator cuff repair.

PubMed

Liu, Qian; Hatta, Taku; Qi, Jun; Liu, Haoyu; Thoreson, Andrew R; Amadio, Peter C; Moran, Steven L; Steinmann, Scott P; Gingery, Anne; Zhao, Chunfeng

2018-05-15

Surgical repair of rotator cuff tears presents a significant clinical challenge with high failure rates and inferior functional outcomes. Graft augmentation improves repair outcomes, however currently available grafting materials have limitations. While cell-seeded decellularized tendon slices may facilitate cell infiltration, promote tendon incorporation and preserve original mechanical strength, the unique fibrocartilage zone is yet to be successfully reestablished. In this study, we investigated the biological and mechanical properties of an engineered tendon-fibrocartilage-bone composite (TFBC) with cyclic tension (3% strain, 0.2 Hz). Decellularized TFBCs seeded with bone marrow-derived mesenchymal stem cell (BMSCs) sheets and subjected to mechanical stimulation for up to 7 days, were characterized by histology, immunohistochemistry, scanning electron microscopy, mechanical testing, and transcriptional regulation. The decellularized TFBC maintained native enthesis structure and properties. Mechanically stimulated TFBC-BMSC constructs displayed increased cell migration after 7 days of culture compared to static groups. The seeded cell sheet not only integrated well with tendon scaffold but also distributed homogeneously and aligned to the direction of stretch under dynamic culture. Developmental genes were regulated including, scleraxis which was significantly upregulated with mechanical stimulation. The Young's modulus of the cell-seeded constructs was significantly higher compared to the non-cell-seeded controls. In conclusion, the results of this study reveal that the TFBC-BMSC composite provides an ideal multilayer construct for cell seeding and growth, with mechanical preconditioning further enhances cell penetration and differentiation. The BMSC cell sheet revitalized TFBC in conjunction with mechanical stimulation could serve as a novel and primed biological patch to improve rotator cuff repair. This article is protected by copyright. All rights reserved.

Inter-species investigation of the mechano-regulation of bone healing: comparison of secondary bone healing in sheep and rat.

PubMed

Checa, Sara; Prendergast, Patrick J; Duda, Georg N

2011-04-29

Inter-species differences in regeneration exist in various levels. One aspect is the dynamics of bone regeneration and healing, e.g. small animals show a faster healing response when compared to large animals. Mechanical as well as biological factors are known to play a key role in the process. However, it remains so far unknown whether different animals follow at all comparable mechano-biological rules during tissue regeneration, and in particular during bone healing. In this study, we investigated whether differences observed in vivo in the dynamics of bone healing between rat and sheep are only due to differences in the animal size or whether these animals have a different mechano-biological response during the healing process. Histological sections from in vivo experiments were compared to in silico predictions of a mechano-biological computer model for the simulation of bone healing. Investigations showed that the healing processes in both animal models occur under significantly different levels of mechanical stimuli within the callus region, which could explain histological observations of early intramembranous ossification at the endosteal side. A species-specific adaptation of a mechano-biological model allowed a qualitative match of model predictions with histological observations. Specifically, when keeping cell activity processes at the same rate, the amount of tissue straining defining favorable mechanical conditions for the formation of bone had to be increased in the large animal model, with respect to the small animal, to achieve a qualitative agreement of model predictions with histological data. These findings illustrate that geometrical (size) differences alone cannot explain the distinctions seen in the histological appearance of secondary bone healing in sheep and rat. It can be stated that significant differences in the mechano-biological regulation of the healing process exist between these species. Future investigations should aim towards

Pentadecapeptide BPC 157 enhances the growth hormone receptor expression in tendon fibroblasts.

PubMed

Chang, Chung-Hsun; Tsai, Wen-Chung; Hsu, Ya-Hui; Pang, Jong-Hwei Su

2014-11-19

BPC 157, a pentadecapeptide derived from human gastric juice, has been demonstrated to promote the healing of different tissues, including skin, muscle, bone, ligament and tendon in many animal studies. However, the underlying mechanism has not been fully clarified. The present study aimed to explore the effect of BPC 157 on tendon fibroblasts isolated from Achilles tendon of male Sprague-Dawley rat. From the result of cDNA microarray analysis, growth hormone receptor was revealed as one of the most abundantly up-regulated genes in tendon fibroblasts by BPC 157. BPC 157 dose- and time-dependently increased the expression of growth hormone receptor in tendon fibroblasts at both the mRNA and protein levels as measured by RT/real-time PCR and Western blot, respectively. The addition of growth hormone to BPC 157-treated tendon fibroblasts dose- and time-dependently increased the cell proliferation as determined by MTT assay and PCNA expression by RT/real-time PCR. Janus kinase 2, the downstream signal pathway of growth hormone receptor, was activated time-dependently by stimulating the BPC 157-treated tendon fibroblasts with growth hormone. In conclusion, the BPC 157-induced increase of growth hormone receptor in tendon fibroblasts may potentiate the proliferation-promoting effect of growth hormone and contribute to the healing of tendon.

A unified theory of bone healing and nonunion: BHN theory.

PubMed

Elliott, D S; Newman, K J H; Forward, D P; Hahn, D M; Ollivere, B; Kojima, K; Handley, R; Rossiter, N D; Wixted, J J; Smith, R M; Moran, C G

2016-07-01

This article presents a unified clinical theory that links established facts about the physiology of bone and homeostasis, with those involved in the healing of fractures and the development of nonunion. The key to this theory is the concept that the tissue that forms in and around a fracture should be considered a specific functional entity. This 'bone-healing unit' produces a physiological response to its biological and mechanical environment, which leads to the normal healing of bone. This tissue responds to mechanical forces and functions according to Wolff's law, Perren's strain theory and Frost's concept of the "mechanostat". In response to the local mechanical environment, the bone-healing unit normally changes with time, producing different tissues that can tolerate various levels of strain. The normal result is the formation of bone that bridges the fracture - healing by callus. Nonunion occurs when the bone-healing unit fails either due to mechanical or biological problems or a combination of both. In clinical practice, the majority of nonunions are due to mechanical problems with instability, resulting in too much strain at the fracture site. In most nonunions, there is an intact bone-healing unit. We suggest that this maintains its biological potential to heal, but fails to function due to the mechanical conditions. The theory predicts the healing pattern of multifragmentary fractures and the observed morphological characteristics of different nonunions. It suggests that the majority of nonunions will heal if the correct mechanical environment is produced by surgery, without the need for biological adjuncts such as autologous bone graft. Cite this article: Bone Joint J 2016;98-B:884-91. ©2016 The British Editorial Society of Bone & Joint Surgery.

In vivo study of magnesium plate and screw degradation and bone fracture healing.

PubMed

Chaya, Amy; Yoshizawa, Sayuri; Verdelis, Kostas; Myers, Nicole; Costello, Bernard J; Chou, Da-Tren; Pal, Siladitya; Maiti, Spandan; Kumta, Prashant N; Sfeir, Charles

2015-05-01

Each year, millions of Americans suffer bone fractures, often requiring internal fixation. Current devices, like plates and screws, are made with permanent metals or resorbable polymers. Permanent metals provide strength and biocompatibility, but cause long-term complications and may require removal. Resorbable polymers reduce long-term complications, but are unsuitable for many load-bearing applications. To mitigate complications, degradable magnesium (Mg) alloys are being developed for craniofacial and orthopedic applications. Their combination of strength and degradation make them ideal for bone fixation. Previously, we conducted a pilot study comparing Mg and titanium devices with a rabbit ulna fracture model. We observed Mg device degradation, with uninhibited healing. Interestingly, we observed bone formation around degrading Mg, but not titanium, devices. These results highlighted the potential for these fixation devices. To better assess their efficacy, we conducted a more thorough study assessing 99.9% Mg devices in a similar rabbit ulna fracture model. Device degradation, fracture healing, and bone formation were evaluated using microcomputed tomography, histology and biomechanical tests. We observed device degradation throughout, and calculated a corrosion rate of 0.40±0.04mm/year after 8 weeks. In addition, we observed fracture healing by 8 weeks, and maturation after 16 weeks. In accordance with our pilot study, we observed bone formation surrounding Mg devices, with complete overgrowth by 16 weeks. Bend tests revealed no difference in flexural load of healed ulnae with Mg devices compared to intact ulnae. These data suggest that Mg devices provide stabilization to facilitate healing, while degrading and stimulating new bone formation. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Can Grafts Provide Superior Tendon Healing and Clinical Outcomes After Rotator Cuff Repairs?

PubMed Central

Ono, Yohei; Dávalos Herrera, Diego Alejandro; Woodmass, Jarret M.; Boorman, Richard S.; Thornton, Gail M.; Lo, Ian K. Y.

2016-01-01

Background: Arthroscopic repair of large to massive rotator cuff tears commonly retear. To improve healing rates, a number of different approaches have been utilized, including the use of grafts, which may enhance the biomechanical and biologic aspects of the repair construct. However, the outcomes after the use of grafts are diverse. Purpose: To systematically review the literature for large to massive rotator cuff tears to determine whether the use of grafts generally provides superior tendon healing and clinical outcomes to the repairs without grafts. Study Design: Systematic review; Level of evidence, 3. Methods: A systematic review of the literature was performed. Clinical studies comparing the repairs with (graft group) and without grafts (control group) were included and analyzed. The primary outcome was tendon healing on either magnetic resonance imaging or ultrasound. The secondary outcome measures included visual analog scale for pain, University of California at Los Angles (UCLA) score, and forward elevation range. Differences between groups in all outcome measures were statistically analyzed. Results: Six comparative studies (level of evidence 2 or 3) with 13 study groups were included. A total of 242 repairs in the graft group (mean age, 62.5 ± 4.6 years) and 185 repairs in the control group (mean age, 62.5 ± 5.0 years) were analyzed. The graft types utilized included autograft (fascia lata) in 1 study, allograft (human dermis) in 2 studies, xenograft (bovine pericardium, porcine small intestine submucosa) in 2 studies, synthetic graft (polypropylene) in 1 study, and a combination of autograft (the long head of biceps) and synthetic graft (polypropylene) in 1 study. The overall mean follow-up time was 28.4 ± 9.0 months. When 1 or 2 studies/study groups were excluded due to practical or statistical reasons, the graft group demonstrated significantly improved healing (odds ratio, 2.48; 95% CI, 1.58-3.90; P < .0001) and all clinical outcome measures at

Bone healing and bone substitutes.

PubMed

Costantino, Peter D; Hiltzik, David; Govindaraj, Satish; Moche, Jason

2002-02-01

With the advent of new biomaterials and surgical techniques, the reconstructive surgeon has a wider range of treatment modalities for the rehabilitation and reconstruction of craniofacial skeletal deformities than ever before. These innovative substances act as true bone graft substitutes, thereby allowing the surgeon to avoid the use of autogenous bone grafts and their associated donor site morbidity. Surgeons have long been interested in producing a composite graft that can heal faster by induction, incorporate with surrounding tissues, and be remodeled to resemble native bone. Currently, there are a host of bone graft substitutes available that vary in both their composition and properties. Craniomaxillofacial surgeons must therefore become comfortable with numerous biomaterials to best tailor the treatment for each patient individually. Ongoing investigations into the next phase of tissue engineering will continue to bring us closer to the ability to regenerate or replace bone.

Anti-DKK1 antibody promotes bone fracture healing through activation of β-catenin signaling

PubMed Central

Jin, Hongting; Wang, Baoli; Li, Jia; Xie, Wanqing; Mao, Qiang; Li, Shan; Dong, Fuqiang; Sun, Yan; Ke, Hua-Zhu; Babij, Philip; Tong, Peijian; Chen, Di

2015-01-01

In this study we investigated if Wnt/β-catenin signaling in mesenchymal progenitor cells plays a role in bone fracture repair and if DKK1-Ab promotes fracture healing through activation of β-catenin signaling. Unilateral open transverse tibial fractures were created in CD1 mice and in β-cateninPrx1ER conditional knockout (KO) and Cre-negative control mice (C57BL/6 background). Bone fracture callus tissues were collected and analyzed by radiography, micro-CT (μCT), histology, biomechanical testing and gene expression analysis. The results demonstrated that treatment with DKK1-Ab promoted bone callus formation and increased mechanical strength during the fracture healing processinCD1 mice. DKK1-Ab enhanced fracture repair by activation of endochondral ossification. The normal rate of bone repair was delayed when the β-catenin gene was conditionally deleted in mesenchymal progenitor cells during the early stages of fracture healing. DKK1-Ab appeared to act through β-catenin signaling to enhance bone repair since the beneficial effect of DKK1-Ab was abrogated in β-cateninPrx1ER conditional KO mice. Further understanding of the signaling mechanism of DKK1-Ab in bone formation and bone regeneration may facilitate the clinical translation of this anabolic agent into therapeutic intervention. PMID:25263522

Experimental models for cancellous bone healing in the rat

PubMed Central

Bernhardsson, Magnus; Sandberg, Olof; Aspenberg, Per

2015-01-01

Background and purpose — Cancellous bone appears to heal by mechanisms different from shaft fracture healing. There is a paucity of animal models for fractures in cancellous bone, especially with mechanical evaluation. One proposed model consists of a screw in the proximal tibia of rodents, evaluated by pull-out testing. We evaluated this model in rats by comparing it to the healing of empty drill holes, in order to explain its relevance for fracture healing in cancellous bone. To determine the sensitivity to external influences, we also compared the response to drugs that influence bone healing. Methods — Mechanical fixation of the screws was measured by pull-out test and related to the density of the new bone formed around similar, but radiolucent, PMMA screws. The pull-out force was also related to the bone density in drill holes at various time points, as measured by microCT. Results — The initial bone formation was similar in drill holes and around the screw, and appeared to be reflected by the pull-out force. Both models responded similarly to alendronate or teriparatide (PTH). Later, the models became different as the bone that initially filled the drill hole was resorbed to restore the bone marrow cavity, whereas on the implant surface a thin layer of bone remained, making it change gradually from a trauma-related model to an implant fixation model. Interpretation — The similar initial bone formation in the different models suggests that pull-out testing in the screw model is relevant for assessment of metaphyseal bone healing. The subsequent remodeling would not be of clinical relevance in either model. PMID:26200395

Injection of demineralized bone matrix with bone marrow concentrate improves healing in unicameral bone cyst.

PubMed

Di Bella, Claudia; Dozza, Barbara; Frisoni, Tommaso; Cevolani, Luca; Donati, Davide

2010-11-01

Unicameral bone cysts are benign lesions that usually spontaneously regress with skeletal maturity; however, the high risk of pathologic fractures often justifies treatment that could reinforce a weakened bone cortex. Various treatments have been proposed but there is no consensus regarding the best procedure. We compared the healing rates and failures of two methods of cure based on multiple injections of corticosteroid or a single injection of demineralized bone matrix (DBM) in association with bone marrow concentrate (BMC). We retrospectively reviewed 184 patients who had one of the two treatments for unicameral bone cysts with cortical erosion. Clinical records were reviewed for treatment failures and radiographs for healing in all patients. The minimum followup was 12 months for the Steroids Group (mean, 48 months; range, 12-120 months) and 12 months for the DBM + BMC Group (mean, 20 months; range, 12-28 months). After one treatment we observed a lower healing rate of cysts treated with multiple injections of steroids compared with the healing after the first injection of DBM + BMC (21% versus 58%, respectively). At last followup, 38% healed with steroids and 71% with DBM + BMC. The rate of failure after one steroid injection was higher than after a single injection of BDM + BMC (63% versus 24%, respectively). We observed no difference in fracture rates after treatment between the two groups. A single injection of DBM added with autologous bone marrow concentrate appears to provide a higher healing rate with a lower number of failures compared with a single injection of steroids.

Evaluation of the potential application of three different biomaterials combined with bone morphological proteins for enhancing tendon-bone integration.

PubMed

Pan, Weimin; Cao, Zheng; Li, Dan; Zhang, Mingjun

2013-04-01

Secure tendon-bone integration is crucial for successful anterior cruciate ligament (ACL) reconstruction. Previous studies have applied different types of biomaterial or biomaterial combined with bone-growth factors to enhance tendon-bone integration. However, which approach is better remains controversial. This comparison evaluation could help identify a suitable composite biomaterial for osteointegration of grafted tendon. Three different composite biomaterials mixed with bone morphological proteins (BMPs) were fabricated. The in vitro study investigates cell metabolism, osteogenic gene expression and the growth behaviour of bone marrow stromal cells (BMSCs) on fibrin glue-BMPs (FGB), calcium phosphate cement-BMPs (CPCB) and recombined bone xenograft (RBX), which are commercially, clinically available biomaterials. Meanwhile, the changes in the physical, morphological and mechanical properties between the three composites and the original biomaterials were also observed. The in vivo study mainly examined the osteogenic ability of the three composites through rat ectopic testing. The porosity structure of three biomaterials was improved after being combined with BMPs powder for SEM observation, and the setting times of the injectable composites were not significantly delayed. More importantly, there were no significant decreases in compressive strength between the three composite biomaterials and the original biomaterials. The highest proliferation rate of BMSCs was found in the RBX group, followed by the CPCB and FGB groups. BMSCs seeded onto an RBX showed the highest alkaline phosphatase (ALPase) activity and gene expression of collagen I (P < 0.05). Histological examination showed endochondral new bone formation in the specimens of all groups, but the ALPase activity of newly formed tissue in the RBX group showed the highest level (P < 0.01). Our results indicate that RBX seems to be a very good choice for accelerating tendon-bone integration, and CPCB also has

Comparison of Autograft and Allograft with Surface Modification for Flexor Tendon Reconstruction: A Canine in Vivo Model.

PubMed

Wei, Zhuang; Reisdorf, Ramona L; Thoreson, Andrew R; Jay, Gregory D; Moran, Steven L; An, Kai-Nan; Amadio, Peter C; Zhao, Chunfeng

2018-04-04

Flexor tendon injury is common, and tendon reconstruction is indicated clinically if the primary repair fails or cannot be performed immediately after tendon injury. The purpose of the current study was to compare clinically standard extrasynovial autologous graft (EAG) tendon and intrasynovial allogeneic graft (IAG) that had both undergone biolubricant surface modification in a canine in vivo model. Twenty-four flexor digitorum profundus (FDP) tendons from the second and fifth digits of 12 dogs were used for this study. In the first phase, a model of failed FDP tendon repair was created. After 6 weeks, the ruptured FDP tendons with a scarred digit were reconstructed with the use of either EAG or IAG tendons treated with carbodiimide-derivatized hyaluronic acid and lubricin. At 12 weeks after tendon reconstruction, the digits were harvested for functional, biomechanical, and histologic evaluations. The tendon failure model was a clinically relevant and reproducible model for tendon reconstruction. The IAG group demonstrated improved digit function with decreased adhesion formation, lower digit work of flexion, and improved graft gliding ability compared with the EAG group. However, the IAG group had decreased healing at the distal tendon-bone junction. Our histologic findings verified the biomechanical evaluations and, further, showed that cellular repopulation of allograft at 12 weeks after reconstruction is still challenging. FDP tendon reconstruction using IAG with surface modification has some beneficial effects for reducing adhesions but demonstrated inferior healing at the distal tendon-bone junction compared with EAG. These mixed results indicate that vitalization and turnover acceleration are crucial to reducing failure of reconstruction with allograft. Flexor tendon reconstruction is a common surgical procedure. However, postoperative adhesion formation may lead to unsatisfactory clinical outcomes. In this study, we developed a potential flexor tendon

Effects of PDGF-BB delivery from heparinized collagen sutures on the healing of lacerated chicken flexor tendon in vivo.

PubMed

Younesi, Mousa; Knapik, Derrick M; Cumsky, Jameson; Donmez, Baris Ozgur; He, Ping; Islam, Anowarul; Learn, Greg; McClellan, Philip; Bohl, Michael; Gillespie, Robert J; Akkus, Ozan

2017-11-01

Flexor tendon lacerations are traditionally repaired by using non-absorbable monofilament sutures. Recent investigations have explored to improve the healing process by growth factor delivery from the sutures. However, it is difficult to conjugate growth factors to nylon or other synthetic sutures. This study explores the performance of a novel electrochemically aligned collagen suture in a flexor tendon repair model with and without platelet derived growth factor following complete tendon laceration in vivo. Collagen suture was fabricated via electrochemical alignment process. Heparin was covalently bound to electrochemically aligned collagen sutures (ELAS) to facilitate affinity bound delivery of platelet-derived growth factor-BB (PDGF-BB). Complete laceration of the flexor digitorum profundus in the third digit of the foot was performed in 36 skeletally mature White Leghorn chickens. The left foot was used as the positive control. Animals were randomly divided into three groups: control specimens treated with standard nylon suture (n=12), specimens repaired with heparinated ELAS suture without PDGF-BB (n=12) and specimens repaired with heparinated ELAS suture with affinity bound PDGF-BB (n=12). Specimens were harvested at either 4weeks or 12weeks following tendon repair. Differences between groups were evaluated by the degree of gross tendon excursion, failure load/stress, stiffness/modulus, absorbed energy at failure, elongation/strain at failure. Quantitative histological scoring was performed to assess cellularity and vascularity. Closed flexion angle measurements demonstrated no significant differences in tendon excursion between the study groups at 4 or 12weeks. Biomechanical testing showed that the group treated with PDGF-BB bound heparinated ELAS suture had significantly higher stiffness and failure load (p<0.05) at 12-weeks relative to both heparinated ELAS suture and nylon suture. Similarly, the group treated with PDGF-BB bound suture had significantly

The relationships among spatiotemporal collagen gene expression, histology, and biomechanics following full-length injury in the murine patellar tendon.

PubMed

Dyment, Nathaniel A; Kazemi, Namdar; Aschbacher-Smith, Lindsey E; Barthelery, Nicolas J; Kenter, Keith; Gooch, Cynthia; Shearn, Jason T; Wylie, Christopher; Butler, David L

2012-01-01

Tendon injuries are major orthopedic problems that worsen as the population ages. Type-I (Col1) and type-II (Col2) collagens play important roles in tendon midsubstance and tendon-to-bone insertion healing, respectively. Using double transgenic mice, this study aims to spatiotemporally monitor Col1 and Col2 gene expression, histology, and biomechanics up to 8 weeks following a full-length patellar tendon injury. Gene expression and histology were analyzed weekly for up to 5 weeks while mechanical properties were measured at 1, 2, 5, and 8 weeks. At week 1, the healing region displayed loose granulation tissue with little Col1 expression. Col1 expression peaked at 2 weeks, but the ECM was highly disorganized and hypercellular. By 3 weeks, Col1 expression had reduced and by 5 weeks, the ECM was generally aligned along the tendon axis. Col2 expression was not seen in the healing midsubstance or insertion at any time point. The biomechanics of the healing tissue was inadequate at all time points, achieving ultimate loads and stiffnesses of 48% and 63% of normal values by 8 weeks. Future studies will further characterize the cells within the healing midsubstance and insertion using tenogenic markers and compare these results to those of tendon cells during normal development. Copyright © 2011 Orthopaedic Research Society.

Bone Marrow Aspirate Concentrate in Animal Long Bone Healing: An Analysis of Basic Science Evidence.

PubMed

Gianakos, Arianna; Ni, Amelia; Zambrana, Lester; Kennedy, John G; Lane, Joseph M

2016-01-01

Long bone fractures that fail to heal or show a delay in healing can lead to increased morbidity. Bone marrow aspirate concentrate (BMAC) containing bone mesenchymal stem cells (BMSCs) has been suggested as an autologous biologic adjunct to aid long bone healing. The purpose of this study was to systematically review the basic science in vivo evidence for the use of BMAC with BMSCs in the treatment of segmental defects in animal long bones. The PubMed/MEDLINE and EMBASE databases were screened in July 14-25, 2014. The following search criteria were used: [("bmac" OR "bone marrow aspirate concentrate" OR "bmc" OR "bone marrow concentrate" OR "mesenchymal stem cells") AND ("bone" OR "osteogenesis" OR "fracture healing" OR "nonunion" OR "delayed union")]. Three authors extracted data and analyzed for trends. Quality of evidence score was given to each study. Results are presented as Hedge G standardized effect sizes with 95% confidence intervals. The search yielded 35 articles for inclusion. Of studies reporting statistics, 100% showed significant increase in bone formation in the BMAC group on radiograph. Ninety percent reported significant improvement in earlier bone healing on histologic/histomorphometric assessment. Eighty-one percent reported a significant increase in bone area on micro-computed tomography. Seventy-eight percent showed a higher torsional stiffness for the BMAC-treated defects. In the in vivo studies evaluated, BMAC confer beneficial effects on the healing of segmental defects in animal long bone models when compared with a control. Proof-of-concept has been established for BMAC in the treatment of animal segmental bone defects.

Nutritional Aspects of Bone Health and Fracture Healing

PubMed Central

Karpouzos, Athanasios; Diamantis, Evangelos; Farmaki, Paraskevi

2017-01-01

Introduction Fractures are quite common, especially among the elderly. However, they can increase in prevalence in younger ages too if the bone health is not good. This may happen as a result of bad nutrition. Methods A customized, retrospective review of available literature was performed using the following keywords: bone health, nutrition, and fractures. Results Insufficient intake of certain vitamins, particularly A and D, and other nutrients, such as calcium, may affect bone health or even the time and degree of bone healing in case of fracture. The importance of different nutrients, both dietary and found in food supplements, is discussed concerning bone health and fracture healing. Conclusion A healthy diet with adequate amounts of both macro- and micronutrients is essential, for both decreasing fracture risk and enhancing the healing process after fracture. PMID:29464131

A Comparative Animal Study of Tendon Grafts Healing After Remnant-Preserving Versus Conventional Anterior Cruciate Ligament Reconstruction

PubMed Central

Zhang, Lei; Jiang, Kan; Chai, Hao; Zhou, Mei; Bai, Jingping

2016-01-01

Background The aim of this study was to determine if anterior cruciate ligament (ACL) reconstruction by remnant preservation promotes cell proliferation, vascularization, proprioception recovery, and improved biomechanical properties of the tendon grafts. Material/Methods 75 New Zealand rabbits were randomly assigned into the control group (group A), conventional ACL reconstruction group (group B), ACL reconstruction using remnant preservation and graft through remnant sleeve technique group (group C), and ACL reconstruction using remnant preservation and remnant tensioning technique group (group D). The remnant and healing of tendon grafts in groups C and D were observed at 3, 6, and 12 weeks after surgery, and the mRNA expression levels of VEGF, NT-3 and GAP-43 in ACL (group A) or tendon graft samples (groups B, C, and D) were determined by real-time PCR. Tendon graft cell count, microvessel density (MVD), and proprioceptors were determined by H&E staining, CD34, and S-100 immunohistochemical staining. The biomechanical properties of the tendon graft at week 12 in groups B, C, and D were examined by using a tensile strength test. Results Remnant and tendon grafts were not healed at 3, 6, and 12 weeks after the operation in groups C and D. VEGF, NT-3, and GAP-43 mRNA expressions in groups B, C, and D were higher than those in group A (P<0.05), but no significant difference was observed between groups B, C, and D (P>0.05). Furthermore, tendon graft cell count, MVD, proprioception, and biomechanical properties showed no significant differences (P>0.05) among groups B, C, and D at various time points. Conclusions There was no significant difference in cell proliferation, vascularization, proprioception recovery, or biomechanical properties of the tendon grafts between remnant-preserving and conventional ACL reconstruction methods. PMID:27669454

Effect of adipose-derived mesenchymal stromal cells on tendon healing in aging and estrogen deficiency: an in vitro co-culture model.

PubMed

Veronesi, Francesca; Della Bella, Elena; Torricelli, Paola; Pagani, Stefania; Fini, Milena

2015-11-01

Aging and estrogen deficiency play a pivotal role in reducing tenocyte proliferation, collagen turnover and extracellular matrix remodeling. Mesenchymal stromal cells are being studied as an alternative for tendon regeneration, but little is known about the molecular events of adipose-derived mesenchymal stromal cells (ADSCs) on tenocytes in tendons compromised by aging and estrogen deficiency. The present in vitro study aims to compare the potential therapeutic effects of ADSCs, harvested from healthy young (sham) and aged estrogen-deficient (OVX) subjects, for tendon healing. An indirect co-culture system was set up with ADSCs, isolated from OVX or sham rats, and tenocytes from OVX rats. Cell proliferation, healing rate and gene expression were evaluated in both a standard culture condition and a microwound-healing model. It was observed that tenocyte proliferation, healing rate and collagen expression improved after the addition of sham ADSCs in both culture situations. OVX ADSCs also increased tenocyte proliferation and healing rate but less compared with sham ADSCs. Decorin and Tenascin C expression increased in the presence of OVX ADSCs. Findings suggest that ADSCs might be a promising treatment for tendon regeneration in advanced age and estrogen deficiency. However, some differences between allogenic and autologous cells were found and should be investigated in further in vivo studies. It appears that allogenic ADSCs improve tenocyte proliferation, collagen expression and the healing rate more than autologous cells. Autologous cells increase collagen expression only in the absence of an injury and increase Decorin and Tenascin C more than allogenic cells. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Gene therapy for bone healing.

PubMed

Evans, Christopher H

2010-06-23

Clinical problems in bone healing include large segmental defects, spinal fusions, and the nonunion and delayed union of fractures. Gene-transfer technologies have the potential to aid healing by permitting the local delivery and sustained expression of osteogenic gene products within osseous lesions. Key questions for such an approach include the choice of transgene, vector and gene-transfer strategy. Most experimental data have been obtained using cDNAs encoding osteogenic growth factors such as bone morphogenetic protein-2 (BMP-2), BMP-4 and BMP-7, in conjunction with both nonviral and viral vectors using in vivo and ex vivo delivery strategies. Proof of principle has been convincingly demonstrated in small-animal models. Relatively few studies have used large animals, but the results so far are encouraging. Once a reliable method has been developed, it will be necessary to perform detailed pharmacological and toxicological studies, as well as satisfy other demands of the regulatory bodies, before human clinical trials can be initiated. Such studies are very expensive and often protracted. Thus, progress in developing a clinically useful gene therapy for bone healing is determined not only by scientific considerations, but also by financial constraints and the ambient regulatory environment.

ACL reconstruction using bone-patella tendon-bone autograft: press-fit technique vs. interference screw fixation.

PubMed

Sarzaeem, M M; Najafi, F; Razi, M; Najafi, M A

2014-07-01

The gold standard in ACL reconstructions has been the bone-patellar tendon-bone autograft fixed with interference screws. This prospective, randomized clinical trial aimed to compare two methods of fixation for BPTB grafts: press-fit fixation vs. interference screw, over a 12-month follow-up interval. 158 patients with an average age of 29.8 years, between 2011 and 2012, were treated for torn ACL. 82 patients underwent reconstruction with BPTB autograft with a press fit fixation technique, and in 76 cases an interference screw was used. At the time of final follow-up, 71 patients in press-fit group and 65 patients in interference screw group were evaluated in terms of return to pre-injury activity level, pain, knee stability, range of motion, IKDC score and complications. At 12-month follow-up, 59 (83 %) and 55 (85 %) in press-fit and screw group, respectively had good-to-excellent IKDC score (p > 0.05). The mean laxity assessed using a KT-1000 arthrometer improved to 2.7 and 2.5 mm in press-fit and screw group, respectively. Regarding Lachman and pivot shift test, there was a statistically significant improvement in the integrity of the ACL in both the groups, but no significant differences was noted between groups. There were no significant differences in terms of femur circumference difference, effusion, knee range of motion, pain and complications. The press-fit technique is an efficient procedure. Its outcome was comparable with the interference screw group. Furthermore it has unlimited bone-to-bone healing, no need for removal of hardware, ease for revision and cost effectiveness.

Formation of blood clot on biomaterial implants influences bone healing.

PubMed

Shiu, Hoi Ting; Goss, Ben; Lutton, Cameron; Crawford, Ross; Xiao, Yin

2014-12-01

The first step in bone healing is forming a blood clot at injured bones. During bone implantation, biomaterials unavoidably come into direct contact with blood, leading to a blood clot formation on its surface prior to bone regeneration. Despite both situations being similar in forming a blood clot at the defect site, most research in bone tissue engineering virtually ignores the important role of a blood clot in supporting healing. Dental implantology has long demonstrated that the fibrin structure and cellular content of a peri-implant clot can greatly affect osteoconduction and de novo bone formation on implant surfaces. This article reviews the formation of a blood clot during bone healing in relation to the use of platelet-rich plasma (PRP) gels. It is implicated that PRP gels are dramatically altered from a normal clot in healing, resulting in conflicting effect on bone regeneration. These results indicate that the effect of clots on bone regeneration depends on how the clots are formed. Factors that influence blood clot structure and properties in relation to bone healing are also highlighted. Such knowledge is essential for developing strategies to optimally control blood clot formation, which ultimately alter the healing microenvironment of bone. Of particular interest are modification of surface chemistry of biomaterials, which displays functional groups at varied composition for the purpose of tailoring blood coagulation activation, resultant clot fibrin architecture, rigidity, susceptibility to lysis, and growth factor release. This opens new scope of in situ blood clot modification as a promising approach in accelerating and controlling bone regeneration.

* Fabrication and Characterization of Biphasic Silk Fibroin Scaffolds for Tendon/Ligament-to-Bone Tissue Engineering.

PubMed

Font Tellado, Sònia; Bonani, Walter; Balmayor, Elizabeth R; Foehr, Peter; Motta, Antonella; Migliaresi, Claudio; van Griensven, Martijn

2017-08-01

Tissue engineering is an attractive strategy for tendon/ligament-to-bone interface repair. The structure and extracellular matrix composition of the interface are complex and allow for a gradual mechanical stress transfer between tendons/ligaments and bone. Thus, scaffolds mimicking the structural features of the native interface may be able to better support functional tissue regeneration. In this study, we fabricated biphasic silk fibroin scaffolds designed to mimic the gradient in collagen molecule alignment present at the interface. The scaffolds had two different pore alignments: anisotropic at the tendon/ligament side and isotropic at the bone side. Total porosity ranged from 50% to 80% and the majority of pores (80-90%) were <100-300 μm. Young's modulus varied from 689 to 1322 kPa depending on the type of construct. In addition, human adipose-derived mesenchymal stem cells were cultured on the scaffolds to evaluate the effect of pore morphology on cell proliferation and gene expression. Biphasic scaffolds supported cell attachment and influenced cytoskeleton organization depending on pore alignment. In addition, the gene expression of tendon/ligament, enthesis, and cartilage markers significantly changed depending on pore alignment in each region of the scaffolds. In conclusion, the biphasic scaffolds fabricated in this study show promising features for tendon/ligament-to-bone tissue engineering.

The combined use of kartogenin and platelet-rich plasma promotes fibrocartilage formation in the wounded rat Achilles tendon entheses.

PubMed

Zhang, J; Yuan, T; Zheng, N; Zhou, Y; Hogan, M V; Wang, J H-C

2017-04-01

After an injury, the biological reattachment of tendon to bone is a challenge because healing takes place between a soft (tendon) and a hard (bone) tissue. Even after healing, the transition zone in the enthesis is not completely regenerated, making it susceptible to re-injury. In this study, we aimed to regenerate Achilles tendon entheses (ATEs) in wounded rats using a combination of kartogenin (KGN) and platelet-rich plasma (PRP). Wounds created in rat ATEs were given three different treatments: kartogenin platelet-rich plasma (KGN-PRP); PRP; or saline (control), followed by histological and immunochemical analyses, and mechanical testing of the rat ATEs after three months of healing. Histological analysis showed well organised arrangement of collagen fibres and proteoglycan formation in the wounded ATEs in the KGN-PRP group. Furthermore, immunohistochemical analysis revealed fibrocartilage formation in the KGN-PRP-treated ATEs, evidenced by the presence of both collagen I and II in the healed ATE. Larger positively stained collagen III areas were found in both PRP and saline groups than those in the KGN-PRP group. Chondrocyte-related genes, SOX9 and collagen II, and tenocyte-related genes, collagen I and scleraxis (SCX), were also upregulated by KGN-PRP. Moreover, mechanical testing results showed higher ultimate tensile strength in the KGN-PRP group than in the saline control group. In contrast, PRP treatment appeared to have healed the injured ATE but induced no apparent formation of fibrocartilage. The saline-treated group showed poor healing without fibrocartilage tissue formation in the ATEs. Our results show that injection of KGN-PRP induces fibrocartilage formation in the wounded rat ATEs. Hence, KGN-PRP may be a clinically relevant, biological approach to regenerate injured enthesis effectively. Cite this article: J. Zhang, T. Yuan, N. Zheng, Y. Zhou, M. V. Hogan, J. H-C. Wang. The combined use of kartogenin and platelet-rich plasma promotes

The Ameloblastin extracellular matrix molecule enhances bone fracture resistance and promotes rapid bone fracture healing

PubMed Central

Lu, Xuanyu; Li, Wenjin; Fukumoto, Satoshi; Yamada, Yoshihiko; Evans, Carla; Diekwisch, Thomas G.H.; Luan, Xianghong

2016-01-01

The extracellular matrix (ECM) provides structural support, cell migration anchorage, cell differentiation cues, and fine-tuned cell proliferation signals during all stages of bone fracture healing, including cartilaginous callus formation, callus remodeling, and bony bridging of the fracture gap. In the present study we have defined the role of the extracellular matrix protein ameloblastin (AMBN) in fracture resistance and fracture healing of mouse long bones. To this end, long bones from WT and AMBNΔ5-6 truncation model mice were subjected to biomechanical analysis, fracture healing assays, and stem cell colony formation comparisons. The effect of exogenous AMBN addition to fracture sites was also determined. Our data indicate that lack of a functional AMBN in the bone matrix resulted in 31% decreased femur bone mass and 40% reduced energy to failure. On a cellular level, AMBN function inhibition diminished the proliferative capacity of fracture repair callus cells, as evidenced by a 58% reduction in PCNA and a 40% reduction in Cyclin D1 gene expression, as well as PCNA immunohistochemistry. In terms of fracture healing, AMBN truncation was associated with an enhanced and prolonged chondrogenic phase, resulting in delayed mineralized tissue gene expression and delayed ossification of the fracture repair callus. Underscoring a role of AMBN in fracture healing, there was a 6.9-fold increase in AMBN expression at the fracture site one week after fracture, and distinct AMBN immunolabeling in the fracture gap. Finally, application of exogenous AMBN protein to bone fracture sites accelerated callus formation and bone fracture healing (33% increase in bone volume and 19% increase in bone mineral density), validating the findings of our AMBN loss of function studies. Together, these data demonstrate the functional importance of the AMBN extracellular matrix protein in bone fracture prevention and rapid fracture healing. PMID:26899203

Platelet-rich plasma for bone healing and regeneration.

PubMed

Oryan, Ahmad; Alidadi, Soodeh; Moshiri, Ali

2016-01-01

Successful healing of large bone defects (LBDs) is a complicated phenomenon because the body's natural ability often fails to effectively repair the LBDs. New modalities should be utilized to increase the quality and accelerate bone healing. Platelet concentrates in different forms can be considered an attractive option for such purpose. Platelets as a natural source of growth factors, cytokines, and other micro and macromolecules are hypothesized to improve bone healing. This review has covered important concepts regarding platelet-rich plasma (PRP) including mechanisms of action, preparation protocols and their differences, and factors affecting the PRP efficacy during bone healing. In addition, the most recent studies in different levels which evaluated the role of PRP on bone repair has been reviewed and discussed to clarify the controversies and conflicts, and to illustrate a future prospective and directions for orthopedic surgeons to overcome current limitations and difficulties. As the efficacy of PRP is dependent on various factors, the outcome of PRP therapy is variable and unpredictable in orthopedic patients. Therefore, it is still too soon to suggest PRP as the first line treatment option in complicated bone injuries such as LBDs and nonunions. However, combination of PRP with natural and synthetic biomaterials can enhance the effectiveness of PRP.

Augmentation of autologous hamstring graft during anterior cruciate ligament reconstruction using the bone chip technique.

PubMed

Nha, Kyung Wook; Shetty, Gautam M; Ahn, Jin Hwan; Lee, Yong Seuk; Chae, Dong Ju; Nam, Hyok Woo; Lee, Dae Hee

2010-01-01

The use of autologous quadrupled hamstring tendon graft is a well-known technique for anterior cruciate ligament reconstruction. In cases where the diameter of the graft is inadequate, the stability of graft fixation and subsequent bone to tendon healing may be compromised. We describe a new technique to augment the autologous double looped hamstring tendon graft during anterior cruciate ligament reconstruction using cancellous bone chips. This simple technique effectively enhances graft fixation and stability.

Human growth hormone may be detrimental when used to accelerate recovery from acute tendon-bone interface injuries.

PubMed

Baumgarten, Keith M; Oliver, Harvey A; Foley, Jack; Chen, Ding-Geng; Autenried, Peter; Duan, Shanzhong; Heiser, Patrick

2013-05-01

There have been few scientific studies that have examined usage of human growth hormone to accelerate recovery from injury. The hypothesis of this study was that human growth hormone would accelerate tendon-to-bone healing compared with control animals treated with placebo in a rat model of acute rotator cuff injury repair. Seventy-two rats underwent repair of acute rotator cuff injuries and were randomized into the following postoperative dosing regimens: placebo, and human growth hormone at 0.1, 1, 2, 5, and 10 mg/kg/day, administered subcutaneously once per day for fourteen days (Protocol 1). An additional twenty-four rats were randomized to receive either (1) placebo or (2) human growth hormone at 5 mg/kg, administered subcutaneously twice per day for seven days preoperatively and twenty-eight days postoperatively (Protocol 2). All rats were killed twenty-eight days postoperatively. Mechanical testing was performed. Ultimate stress, ultimate force, stiffness, energy to failure, and ultimate distension were determined. For Protocol 1, analysis of variance testing showed no significant difference between the groups with regard to ultimate stress, ultimate force, stiffness, energy to failure, or ultimate distension. In Protocol 2, ultimate force to failure was significantly worse in the human growth hormone group compared with the placebo group (21.1 ± 5.85 versus 26.3 ± 5.47 N; p = 0.035). Failure was more likely to occur through the bone than the tendon-bone interface in the human growth hormone group compared with the placebo group (p = 0.001). No significant difference was found for ultimate stress, ultimate force, stiffness, energy to failure, or ultimate distension between the groups in Protocol 2. In this rat model of acute tendon-bone injury repair, daily subcutaneous postoperative human growth hormone treatment for fourteen days failed to demonstrate a significant difference in any biomechanical parameter compared with placebo. Furthermore, subcutaneous

Bone fracture healing in mechanobiological modeling: A review of principles and methods.

PubMed

Ghiasi, Mohammad S; Chen, Jason; Vaziri, Ashkan; Rodriguez, Edward K; Nazarian, Ara

2017-06-01

Bone fracture is a very common body injury. The healing process is physiologically complex, involving both biological and mechanical aspects. Following a fracture, cell migration, cell/tissue differentiation, tissue synthesis, and cytokine and growth factor release occur, regulated by the mechanical environment. Over the past decade, bone healing simulation and modeling has been employed to understand its details and mechanisms, to investigate specific clinical questions, and to design healing strategies. The goal of this effort is to review the history and the most recent work in bone healing simulations with an emphasis on both biological and mechanical properties. Therefore, we provide a brief review of the biology of bone fracture repair, followed by an outline of the key growth factors and mechanical factors influencing it. We then compare different methodologies of bone healing simulation, including conceptual modeling (qualitative modeling of bone healing to understand the general mechanisms), biological modeling (considering only the biological factors and processes), and mechanobiological modeling (considering both biological aspects and mechanical environment). Finally we evaluate different components and clinical applications of bone healing simulation such as mechanical stimuli, phases of bone healing, and angiogenesis.

Effectiveness of xenogenous-based bovine-derived platelet gel embedded within a three-dimensional collagen implant on the healing and regeneration of the Achilles tendon defect in rabbits

PubMed Central

Moshiri, Ali; Oryan, Ahmad; Meimandi-Parizi, Abdolhamid; Koohi-Hosseinabadi, Omid

2014-01-01

Background and objective: Tissue engineering is an option in reconstructing large tendon defects and managing their healing and regeneration. We designed and produced a novel xenogeneic-based bovine platelet, embedded it within a tissue-engineered collagen implant (CI) and applied it in an experimentally induced large tendon defect model in rabbits to test whether bovine platelets could stimulate tendon healing and regeneration in vivo. Methods: One hundred twenty rabbits were randomly divided into two experimental and pilot groups. In all the animals, the left Achilles tendon was surgically excised and the tendon edges were aligned by Kessler suture. Each group was then divided into three groups of control (no implant), treated with CI and treated with collagen-platelet implant. The pilot groups were euthanized at 10, 15, 30 and 40 days post-injury (DPI), and their gross and histologic characteristics were evaluated to study host–graft interaction mechanism. To study the tendon healing and its outcome, the experimental animals were tested during the experiment using hematologic, ultrasonographic and various methods of clinical examinations and then euthanized at 60 DPI and their tendons were evaluated by gross pathologic, histopathologic, scanning electron microscopic, biophysical and biochemical methods. Results: Bovine platelets embedded within a CI increased inflammation at short term while it increased the rate of implant absorption and matrix replacement compared with the controls and CI alone. Treatment also significantly increased diameter, density, amount, alignment and differentiation of the collagen fibrils and fibers and approximated the water uptake and delivery behavior of the healing tendons to normal contralaterals (p < 0.05). Treatment also improved echogenicity and homogenicity of the tendons and reduced peritendinous adhesion, muscle fibrosis and atrophy, and therefore, it improved the clinical scores and physical activity related to the

Comparison of a novel bone-tendon allograft with a human dermis-derived patch for repair of chronic large rotator cuff tears using a canine model.

PubMed

Smith, Matthew J; Cook, James L; Kuroki, Keiichi; Jayabalan, Prakash S; Cook, Cristi R; Pfeiffer, Ferris M; Waters, Nicole P

2012-02-01

This study tested a bone-tendon allograft versus human dermis patch for reconstructing chronic rotator cuff repair by use of a canine model. Mature research dogs (N = 15) were used. Radiopaque wire was placed in the infraspinatus tendon (IST) before its transection. Three weeks later, radiographs showed IST retraction. Each dog then underwent 1 IST treatment: debridement (D), direct repair of IST to bone with a suture bridge and human dermis patch augmentation (GJ), or bone-tendon allograft (BT) reconstruction. Outcome measures included lameness grading, radiographs, and ultrasonographic assessment. Dogs were killed 6 months after surgery and both shoulders assessed biomechanically and histologically. BT dogs were significantly (P = .01) less lame than the other groups. BT dogs had superior bone-tendon, tendon, and tendon-muscle integrity compared with D and GJ dogs. Biomechanical testing showed that the D group had significantly (P = .05) more elongation than the other groups whereas BT had stiffness and elongation characteristics that most closely matched normal controls. Radiographically, D and GJ dogs showed significantly more retraction than BT dogs (P = .003 and P = .045, respectively) Histologically, GJ dogs had lymphoplasmacytic infiltrates, tendon degeneration and hypocellularity, and poor tendon-bone integration. BT dogs showed complete incorporation of allograft bone into host bone, normal bone-tendon junctions, and well-integrated allograft tendon. The bone-tendon allograft technique re-establishes a functional IST bone-tendon-muscle unit and maintains integrity of repair in this model. Clinical trials using this bone-tendon allograft technique are warranted. Copyright © 2012 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.

Osteoporotic Animal Models of Bone Healing: Advantages and Pitfalls.

PubMed

Calciolari, Elena; Donos, Nikolaos; Mardas, Nikos

2017-10-01

The aim of this review was to summarize the advantages and pitfalls of the available osteoporotic animal models of bone healing. A thorough literature search was performed in MEDLINE via OVID and EMBASE to identify animal studies investigating the effect of experimental osteoporosis on bone healing and bone regeneration. The osteotomy model in the proximal tibia is the most popular osseous defect model to study the bone healing process in osteoporotic-like conditions, although other well-characterized models, such as the post-extraction model, might be taken into consideration by future studies. The regenerative potential of osteoporotic bone and its response to biomaterials/regenerative techniques has not been clarified yet, and the critical size defect model might be an appropriate tool to serve this purpose. Since an ideal animal model for simulating osteoporosis does not exist, the type of bone remodeling, the animal lifespan, the age of peak bone mass, and the economic and ethical implications should be considered in our selection process. Furthermore, the influence of animal species, sex, age, and strain on the outcome measurement should be taken into account. In order to make future studies meaningful, standardized international guidelines for osteoporotic animal models of bone healing need to be set up.

The microstructure and micromechanics of the tendon-bone insertion

NASA Astrophysics Data System (ADS)

Rossetti, L.; Kuntz, L. A.; Kunold, E.; Schock, J.; Müller, K. W.; Grabmayr, H.; Stolberg-Stolberg, J.; Pfeiffer, F.; Sieber, S. A.; Burgkart, R.; Bausch, A. R.

2017-06-01

The exceptional mechanical properties of the load-bearing connection of tendon to bone rely on an intricate interplay of its biomolecular composition, microstructure and micromechanics. Here we identify that the Achilles tendon-bone insertion is characterized by an interface region of ~500 μm with a distinct fibre organization and biomolecular composition. Within this region, we identify a heterogeneous mechanical response by micromechanical testing coupled with multiscale confocal microscopy. This leads to localized strains that can be larger than the remotely applied strain. The subset of fibres that sustain the majority of loading in the interface area changes with the angle of force application. Proteomic analysis detects enrichment of 22 proteins in the interfacial region that are predominantly involved in cartilage and skeletal development as well as proteoglycan metabolism. The presented mechanisms mark a guideline for further biomimetic strategies to rationally design hard-soft interfaces.

Mineral distributions at the developing tendon enthesis.

PubMed

Schwartz, Andrea G; Pasteris, Jill D; Genin, Guy M; Daulton, Tyrone L; Thomopoulos, Stavros

2012-01-01

Tendon attaches to bone across a functionally graded interface, "the enthesis". A gradient of mineral content is believed to play an important role for dissipation of stress concentrations at mature fibrocartilaginous interfaces. Surgical repair of injured tendon to bone often fails, suggesting that the enthesis does not regenerate in a healing setting. Understanding the development and the micro/nano-meter structure of this unique interface may provide novel insights for the improvement of repair strategies. This study monitored the development of transitional tissue at the murine supraspinatus tendon enthesis, which begins postnatally and is completed by postnatal day 28. The micrometer-scale distribution of mineral across the developing enthesis was studied by X-ray micro-computed tomography and Raman microprobe spectroscopy. Analyzed regions were identified and further studied by histomorphometry. The nanometer-scale distribution of mineral and collagen fibrils at the developing interface was studied using transmission electron microscopy (TEM). A zone (∼20 µm) exhibiting a gradient in mineral relative to collagen was detected at the leading edge of the hard-soft tissue interface as early as postnatal day 7. Nanocharacterization by TEM suggested that this mineral gradient arose from intrinsic surface roughness on the scale of tens of nanometers at the mineralized front. Microcomputed tomography measurements indicated increases in bone mineral density with time. Raman spectroscopy measurements revealed that the mineral-to-collagen ratio on the mineralized side of the interface was constant throughout postnatal development. An increase in the carbonate concentration of the apatite mineral phase over time suggested possible matrix remodeling during postnatal development. Comparison of Raman-based observations of localized mineral content with histomorphological features indicated that development of the graded mineralized interface is linked to endochondral

Role of whole bone marrow, whole bone marrow cultured cells, and mesenchymal stem cells in chronic wound healing.

PubMed

Rodriguez-Menocal, Luis; Shareef, Shahjahan; Salgado, Marcela; Shabbir, Arsalan; Van Badiavas, Evangelos

2015-03-13

Recent evidence has shown that bone marrow cells play critical roles during the inflammatory, proliferative and remodeling phases of cutaneous wound healing. Among the bone marrow cells delivered to wounds are stem cells, which can differentiate into multiple tissue-forming cell lineages to effect, healing. Gaining insight into which lineages are most important in accelerating wound healing would be quite valuable in designing therapeutic approaches for difficult to heal wounds. In this report we compared the effect of different bone marrow preparations on established in vitro wound healing assays. The preparations examined were whole bone marrow (WBM), whole bone marrow (long term initiating/hematopoietic based) cultured cells (BMC), and bone marrow derived mesenchymal stem cells (BM-MSC). We also applied these bone marrow preparations in two murine models of radiation induced delayed wound healing to determine which had a greater effect on healing. Angiogenesis assays demonstrated that tube formation was stimulated by both WBM and BMC, with WBM having the greatest effect. Scratch wound assays showed higher fibroblast migration at 24, 48, and 72 hours in presence of WBM as compared to BM-MSC. WBM also appeared to stimulate a greater healing response than BMC and BM-MSC in a radiation induced delayed wound healing animal model. These studies promise to help elucidate the role of stem cells during repair of chronic wounds and reveal which cells present in bone marrow might contribute most to the wound healing process.

Effect of methotrexate on bone and wound healing.

PubMed

Pountos, Ippokratis; Giannoudis, Peter V

2017-05-01

Methotrexate (MTX) is one of the most commonly used disease modifying drugs administered for wide spectrum of conditions. Through the expansion of the indications of MTX use, an increasing number of patients nowadays attend orthopaedic departments receiving this pharmacological agent. The aim of this manuscript is to present our current understanding on the effect of MTX on bone and wound healing. Areas covered: The authors offer a comprehensive review of the existing literature on the experimental and clinical studies analysing the effect of MTX on bone and wound healing. The authors also analyse the available literature and describe the incidence of complications after elective orthopaedic surgery in patients receiving MTX. Expert opinion: The available experimental data and clinical evidence are rather inadequate to allow any safe scientific conclusions on the effect of MTX on bone healing. Regarding wound healing, in vitro and experimental animal studies suggest that MTX can adversely affect wound healing, whilst the clinical studies show that lose-dose MTX is safe and does not affect the incidence of postoperative wound complications.

Changes in bone microstructure and toughness during the healing process of long bones

NASA Astrophysics Data System (ADS)

Ishimoto, T.; Nakano, T.; Umakoshi, Y.; Tabata, Y.

2009-05-01

It is of great importance to understand how bone defects regain the microstructure and mechanical function of bone and how the microstructure affects the mechanical function during the bone healing process. In the present study on long bone defects, we investigated the relationship between the recovery process of fracture toughness and biological apatite (BAp)/collagen (Col) alignment as an index of the bone microstructure to clarify the bone toughening mechanisms. A 5-mm defect introduced in the rabbit ulna was allowed to heal naturally and a three-point bending test was conducted on the regenerated site to assess bone toughness. The bone toughness was quite low at the early stage of bone regeneration but increased during the postoperative period. The change in toughness agreed well with the characteristics of the fracture surface morphology, which reflected the history of the crack propagation. SEM and microbeam X-ray diffraction analyses indicated that the toughness was dominated by the degree and orientation of the preferred BAp/Col alignment, i.e. bundles aligned perpendicular to the crack propagation clearly contributed to the bone toughening owing to extra energy consumption for resistance to crack propagation. In conclusion, regenerated bone improves fracture toughness by reconstructing the preferred BAp/Col alignment along the bone longitudinal axis during the healing process of long bones.

The ameloblastin extracellular matrix molecule enhances bone fracture resistance and promotes rapid bone fracture healing.

PubMed

Lu, Xuanyu; Li, Wenjin; Fukumoto, Satoshi; Yamada, Yoshihiko; Evans, Carla A; Diekwisch, Tom; Luan, Xianghong

2016-01-01

The extracellular matrix (ECM) provides structural support, cell migration anchorage, cell differentiation cues, and fine-tuned cell proliferation signals during all stages of bone fracture healing, including cartilaginous callus formation, callus remodeling, and bony bridging of the fracture gap. In the present study we have defined the role of the extracellular matrix protein ameloblastin (AMBN) in fracture resistance and fracture healing of mouse long bones. To this end, long bones from WT and AMBN(Δ5-6) truncation model mice were subjected to biomechanical analysis, fracture healing assays, and stem cell colony formation comparisons. The effect of exogenous AMBN addition to fracture sites was also determined. Our data indicate that lack of a functional AMBN in the bone matrix resulted in 31% decreased femur bone mass and 40% reduced energy to failure. On a cellular level, AMBN function inhibition diminished the proliferative capacity of fracture repair callus cells, as evidenced by a 58% reduction in PCNA and a 40% reduction in Cyclin D1 gene expression, as well as PCNA immunohistochemistry. In terms of fracture healing, AMBN truncation was associated with an enhanced and prolonged chondrogenic phase, resulting in delayed mineralized tissue gene expression and delayed ossification of the fracture repair callus. Underscoring a role of AMBN in fracture healing, there was a 6.9-fold increase in AMBN expression at the fracture site one week after fracture, and distinct AMBN immunolabeling in the fracture gap. Finally, application of exogenous AMBN protein to bone fracture sites accelerated callus formation and bone fracture healing (33% increase in bone volume and 19% increase in bone mineral density), validating the findings of our AMBN loss of function studies. Together, these data demonstrate the functional importance of the AMBN extracellular matrix protein in bone fracture prevention and rapid fracture healing. Copyright © 2016 International Society of

Dual growth factor-immobilized asymmetrically porous membrane for bone-to-tendon interface regeneration on rat patellar tendon avulsion model.

PubMed

Kim, Joong-Hyun; Oh, Se Heang; Min, Hyun Ki; Lee, Jin Ho

2018-01-01

Insufficient repair of the bone-to-tendon interface (BTI) with structural/compositional gradients has been a significant challenge in orthopedics. In this study, dual growth factor (platelet-derived growth factor-BB [PDGF-BB] and bone morphogenetic protein-2 [BMP-2])-immobilized polycaprolactone (PCL)/Pluronic F127 asymmetrically porous membrane was fabricated to estimate its feasibility as a potential strategy for effective regeneration of BTI injury. The growth factors immobilized (via heparin-intermediated interactions) on the membrane were continuously released for up to ∼80% of the initial loading amount after 5 weeks without a significant initial burst. From the in vivo animal study using a rat patellar tendon avulsion model, it was observed that the PDGF-BB/BMP-2-immobilized membrane accelerates the regeneration of the BTI injury, probably because of the continuous release of both growth factors (biological stimuli) and their complementary effect to create a multiphasic structure (bone, fibrocartilage, and tendon) like a native structure, as well as the role of the asymmetrically porous membrane as a physical barrier (nanopore side; prevention of fibrous tissue invasion into the defect site) and scaffold (micropore side; guidance for tissue regeneration). © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 115-125, 2018. © 2017 Wiley Periodicals, Inc.

Marginal bone loss around non-submerged implants is associated with salivary microbiome during bone healing.

PubMed

Duan, Xiao-Bo; Wu, Ting-Xi; Guo, Yu-Chen; Zhou, Xue-Dong; Lei, Yi-Ling; Xu, Xin; Mo, An-Chun; Wang, Yong-Yue; Yuan, Quan

2017-06-01

Marginal bone loss during bone healing exists around non-submerged dental implants. The aim of this study was to identify the relationship between different degrees of marginal bone loss during bone healing and the salivary microbiome. One hundred patients were recruited, and marginal bone loss around their implants was measured using cone beam computed tomography during a 3-month healing period. The patients were divided into three groups according to the severity of marginal bone loss. Saliva samples were collected from all subjected and were analysed using 16S MiSeq sequencing. Although the overall structure of the microbial community was not dramatically altered, the relative abundance of several taxonomic groups noticeably changed. The abundance of species in the phyla Spirochaeta and Synergistetes increased significantly as the bone loss became more severe. Species within the genus Treponema also exhibited increased abundance, whereas Veillonella, Haemophilus and Leptotrichia exhibited reduced abundances, in groups with more bone loss. Porphyromonasgingivalis, Treponemadenticola and Streptococcus intermedius were significantly more abundant in the moderate group and/or severe group. The severity of marginal bone loss around the non-submerged implant was associated with dissimilar taxonomic compositions. An increased severity of marginal bone loss was related to increased proportions of periodontal pathogenic species. These data suggest a potential role of microbes in the progression of marginal bone loss during bone healing.

Relationship between tendon stiffness and failure: a metaanalysis

PubMed Central

LaCroix, Andrew S.; Duenwald-Kuehl, Sarah E.; Lakes, Roderic S.

2013-01-01

Tendon is a highly specialized, hierarchical tissue designed to transfer forces from muscle to bone; complex viscoelastic and anisotropic behaviors have been extensively characterized for specific subsets of tendons. Reported mechanical data consistently show a pseudoelastic, stress-vs.-strain behavior with a linear slope after an initial toe region. Many studies report a linear, elastic modulus, or Young's modulus (hereafter called elastic modulus) and ultimate stress for their tendon specimens. Individually, these studies are unable to provide a broader, interstudy understanding of tendon mechanical behavior. Herein we present a metaanalysis of pooled mechanical data from a representative sample of tendons from different species. These data include healthy tendons and those altered by injury and healing, genetic modification, allograft preparation, mechanical environment, and age. Fifty studies were selected and analyzed. Despite a wide range of mechanical properties between and within species, elastic modulus and ultimate stress are highly correlated (R2 = 0.785), suggesting that tendon failure is highly strain-dependent. Furthermore, this relationship was observed to be predictable over controlled ranges of elastic moduli, as would be typical of any individual species. With the knowledge gained through this metaanalysis, noninvasive tools could measure elastic modulus in vivo and reasonably predict ultimate stress (or structural compromise) for diseased or injured tendon. PMID:23599401

[Achilles tendon rupture].

PubMed

Thermann, H; Hüfner, T; Tscherne, H

2000-03-01

The treatment of acute of Achilles tendon rupture experienced a dynamic development in the last ten years. Decisive for this development was the application of MRI and above all the ultrasonography in the diagnostics of the pathological changes and injuries of tendons. The question of rupture morphology as well as different courses of healing could be now evaluated objectively. These advances led consequently to new modalities in treatment concepts and rehabilitation protocols. The decisive input for improvements of the outcome results and particularly the shortening of the rehabilitation period came with introduction of the early functional treatment in contrast to immobilizing plaster treatment. In a prospective randomized study (1987-1989) at the Trauma Dept. of the Hannover Medical School could show no statistical differences comparing functional non-operative with functional operative therapy with a special therapy boot (Variostabil/Adidas). The crucial criteria for therapy selection results from the sonographically measured position of the tendon stumps in plantar flexion (20 degrees). With complete adaptation of the tendons' ends surgical treatment does not achieve better results than non-operative functional treatment in term of tendon healing and functional outcome. Regarding the current therapeutic standards each method has is advantages and disadvantages. Both, the operative and non-operative functional treatment enable a stable tendon healing with a low risk of re-rupture (1-2%). Meanwhile there is consensus for early functional after-treatment of the operated Achilles' tendons. There seems to be a trend towards non-operative functional treatment in cases of adequate sonographical findings, or to minimal invasive surgical techniques.

A review of biomaterials in bone defect healing, remaining shortcomings and future opportunities for bone tissue engineering

PubMed Central

Winkler, T.; Sass, F. A.; Schmidt-Bleek, K.

2018-01-01

Despite its intrinsic ability to regenerate form and function after injury, bone tissue can be challenged by a multitude of pathological conditions. While innovative approaches have helped to unravel the cascades of bone healing, this knowledge has so far not improved the clinical outcomes of bone defect treatment. Recent findings have allowed us to gain in-depth knowledge about the physiological conditions and biological principles of bone regeneration. Now it is time to transfer the lessons learned from bone healing to the challenging scenarios in defects and employ innovative technologies to enable biomaterial-based strategies for bone defect healing. This review aims to provide an overview on endogenous cascades of bone material formation and how these are transferred to new perspectives in biomaterial-driven approaches in bone regeneration. Cite this article: T. Winkler, F. A. Sass, G. N. Duda, K. Schmidt-Bleek. A review of biomaterials in bone defect healing, remaining shortcomings and future opportunities for bone tissue engineering: The unsolved challenge. Bone Joint Res 2018;7:232–243. DOI: 10.1302/2046-3758.73.BJR-2017-0270.R1.

Interactions between MSCs and Immune Cells: Implications for Bone Healing

PubMed Central

Kovach, Tracy K.; Dighe, Abhijit S.; Lobo, Peter I.; Cui, Quanjun

2015-01-01

It is estimated that, of the 7.9 million fractures sustained in the United States each year, 5% to 20% result in delayed or impaired healing requiring therapeutic intervention. Following fracture injury, there is an initial inflammatory response that plays a crucial role in bone healing; however, prolonged inflammation is inhibitory for fracture repair. The precise spatial and temporal impact of immune cells and their cytokines on fracture healing remains obscure. Some cytokines are reported to be proosteogenic while others inhibit bone healing. Cell-based therapy utilizing mesenchymal stromal cells (MSCs) is an attractive option for augmenting the fracture repair process. Osteoprogenitor MSCs not only differentiate into bone, but they also exert modulatory effects on immune cells via a variety of mechanisms. In this paper, we review the current literature on both in vitro and in vivo studies on the role of the immune system in fracture repair, the use of MSCs in the enhancement of fracture healing, and interactions between MSCs and immune cells. Insight into this paradigm can provide valuable clues in identifying cellular and noncellular targets that can potentially be modulated to enhance both natural bone healing and bone repair augmented by the exogenous addition of MSCs. PMID:26000315

Adaptation of bone and tendon to prolonged hindlimb suspension in rats

NASA Technical Reports Server (NTRS)

Vailas, Arthur C.; Deluna, Diane M.; Lewis, Lisa L.; Curwin, Sandra L.; Roy, Roland R.

1988-01-01

The effect of a sustained deprivation of ground reaction forces on mineralized and soft connective tissues was investigated in rats subjected to 28-d-long hind-limb suspension. The results of morphological and biochemical studies carried out on femurs and patellar tendons obtained from suspended and nonsuspended 110-d-old rats showed that prolonged suspension led to an increase of the minimum diameter of the femur middiaphysis (by 12 percent), without any significant alterations in cortical area, density, mineral and collagen concentrations, femur wet weight, length, and DNA and uronic acid concentrations. However, in the patellar tendons of suspended rats, the collagen and proteoglycan concentrations were 28 percent lower than in tendons obtained from nonsuspended animals. These results suggest that ground reaction forces are important for the maintenance of cortical bone and patellar tendon homeostasis during weight-bearing conditions.

Early mechanical stimulation only permits timely bone healing in sheep.

PubMed

Tufekci, Pelin; Tavakoli, Aramesh; Dlaska, Constantin; Neumann, Mirjam; Shanker, Mihir; Saifzadeh, Siamak; Steck, Roland; Schuetz, Michael; Epari, Devakar

2018-06-01

Bone fracture healing is sensitive to the fixation stability. However, it is unclear which phases of healing are mechano-sensitive and if mechanical stimulation is required throughout repair. In this study, a novel bone defect model, which isolates an experimental fracture from functional loading, was applied in sheep to investigate if stimulation limited to the early proliferative phase is sufficient for bone healing. An active fixator controlled motion in the fracture. Animals of the control group were unstimulated. In the physiological-like group, 1 mm axial compressive movements were applied between day 5 and 21, thereafter the movements were decreased in weekly increments and stopped after 6 weeks. In the early stimulatory group, the movements were stopped after 3 weeks. The experimental fractures were evaluated with mechanical and micro-computed tomography methods after 9 weeks healing. The callus strength of the stimulated fractures (physiological-like and early stimulatory) was greater than the unstimulated control group. The control group was characterized by minimal external callus formation and a lack of bone bridging at 9 weeks. In contrast, the stimulated groups exhibited advanced healing with solid bone formation across the defect. This was confirmed quantitatively by a lower bone volume in the control group compared to the stimulated groups.The novel experimental model permits the application of a well-defined load history to an experimental bone fracture. The poor healing observed in the control group is consistent with under-stimulation. This study has shown early mechanical stimulation only is sufficient for a timely healing outcome. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1790-1796, 2018. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Bone sialoprotein, but not osteopontin, deficiency impairs the mineralization of regenerating bone during cortical defect healing.

PubMed

Monfoulet, Laurent; Malaval, Luc; Aubin, Jane E; Rittling, Susan R; Gadeau, Alain P; Fricain, Jean-Christophe; Chassande, Olivier

2010-02-01

Bone healing is a complex multi-step process, which depends on the position and size of the lesion, and on the mechanical stability of the wounded area. To address more specifically the mechanisms involved in cortical bone healing, we created drill-hole defects in the cortex of mouse femur, a lesion that triggers intramembranous repair, and compared the roles of bone sialoprotein (BSP) and osteopontin (OPN), two proteins of the extracellular matrix, in the repair process. Bone regeneration was analyzed by ex vivo microcomputerized X-ray tomography and histomorphometry of bones of BSP-deficient, OPN-deficient and wild-type mice. In all mouse strains, the cortical gap was bridged with woven bone within 2 weeks and no mineralized tissue was observed in the marrow. Within 3 weeks, lamellar cortical bone filled the gap. The amount and degree of mineralization of the woven bone was not affected by OPN deficiency, but cortical bone healing was delayed in BSP-deficient mice due to delayed mineralization. Gene expression studies showed a higher amount of BSP transcripts in the repair bone of OPN-deficient mice, suggesting a possible compensation of OPN function by BSP in OPN-null mice. Our data suggest that BSP, but not OPN, plays a role in primary bone formation and mineralization of newly formed bone during the process of cortical bone healing. (c) 2009 Elsevier Inc. All rights reserved.

Cellular response of healing tissue to DegraPol tube implantation in rabbit Achilles tendon rupture repair: an in vivo histomorphometric study.

PubMed

Buschmann, Johanna; Meier-Bürgisser, Gabriella; Bonavoglia, Eliana; Neuenschwander, Peter; Milleret, Vincent; Giovanoli, Pietro; Calcagni, Maurizio

2013-05-01

In tendon rupture repair, improvements such as higher primary repair strength, anti-adhesion and accelerated healing are needed. We developed a potential carrier system of an electrospun DegraPol tube, which was tightly implanted around a transected and conventionally sutured rabbit Achilles tendon. Histomorphometric analysis of the tendon tissue 12 weeks postoperation showed that the tenocyte density, tenocyte morphology and number of inflammation zones were statistically equivalent, whether or not DegraPol tube was implanted; only the collagen fibres were slightly less parallelly orientated in the tube-treated case. Comparison of rabbits that were operated on both hind legs with ones that were operated on only one hind leg showed that there were significantly more inflammation zones in the two-leg cases compared to the one-leg cases, while the implantation of a DegraPol tube had no such adverse effects. These findings are a prerequisite for using DegraPol tube as a carrier system for growth factors, cytokines or stem cells in order to accelerate the healing process of tendon tissue. Copyright © 2012 John Wiley & Sons, Ltd.

The combined use of kartogenin and platelet-rich plasma promotes fibrocartilage formation in the wounded rat Achilles tendon entheses

PubMed Central

Zhang, J.; Yuan, T.; Zheng, N.; Zhou, Y.; Hogan, M. V.

2017-01-01

Objectives After an injury, the biological reattachment of tendon to bone is a challenge because healing takes place between a soft (tendon) and a hard (bone) tissue. Even after healing, the transition zone in the enthesis is not completely regenerated, making it susceptible to re-injury. In this study, we aimed to regenerate Achilles tendon entheses (ATEs) in wounded rats using a combination of kartogenin (KGN) and platelet-rich plasma (PRP). Methods Wounds created in rat ATEs were given three different treatments: kartogenin platelet-rich plasma (KGN-PRP); PRP; or saline (control), followed by histological and immunochemical analyses, and mechanical testing of the rat ATEs after three months of healing. Results Histological analysis showed well organised arrangement of collagen fibres and proteoglycan formation in the wounded ATEs in the KGN-PRP group. Furthermore, immunohistochemical analysis revealed fibrocartilage formation in the KGN-PRP-treated ATEs, evidenced by the presence of both collagen I and II in the healed ATE. Larger positively stained collagen III areas were found in both PRP and saline groups than those in the KGN-PRP group. Chondrocyte-related genes, SOX9 and collagen II, and tenocyte-related genes, collagen I and scleraxis (SCX), were also upregulated by KGN-PRP. Moreover, mechanical testing results showed higher ultimate tensile strength in the KGN-PRP group than in the saline control group. In contrast, PRP treatment appeared to have healed the injured ATE but induced no apparent formation of fibrocartilage. The saline-treated group showed poor healing without fibrocartilage tissue formation in the ATEs. Conclusions Our results show that injection of KGN-PRP induces fibrocartilage formation in the wounded rat ATEs. Hence, KGN-PRP may be a clinically relevant, biological approach to regenerate injured enthesis effectively. Cite this article: J. Zhang, T. Yuan, N. Zheng, Y. Zhou, M. V. Hogan, J. H-C. Wang. The combined use of kartogenin and

Functional tissue engineering of ligament healing

PubMed Central

2010-01-01

Ligaments and tendons are dense connective tissues that are important in transmitting forces and facilitate joint articulation in the musculoskeletal system. Their injury frequency is high especially for those that are functional important, like the anterior cruciate ligament (ACL) and medial collateral ligament (MCL) of the knee as well as the glenohumeral ligaments and the rotator cuff tendons of the shoulder. Because the healing responses are different in these ligaments and tendons after injury, the consequences and treatments are tissue- and site-specific. In this review, we will elaborate on the injuries of the knee ligaments as well as using functional tissue engineering (FTE) approaches to improve their healing. Specifically, the ACL of knee has limited capability to heal, and results of non-surgical management of its midsubstance rupture have been poor. Consequently, surgical reconstruction of the ACL is regularly performed to gain knee stability. However, the long-term results are not satisfactory besides the numerous complications accompanied with the surgeries. With the rapid development of FTE, there is a renewed interest in revisiting ACL healing. Approaches such as using growth factors, stem cells and scaffolds have been widely investigated. In this article, the biology of normal and healing ligaments is first reviewed, followed by a discussion on the issues related to the treatment of ACL injuries. Afterwards, current promising FTE methods are presented for the treatment of ligament injuries, including the use of growth factors, gene delivery, and cell therapy with a particular emphasis on the use of ECM bioscaffolds. The challenging areas are listed in the future direction that suggests where collection of energy could be placed in order to restore the injured ligaments and tendons structurally and functionally. PMID:20492676

Prospective multicentre study of the clinical and functional outcomes following quadriceps tendon repair with suture anchors.

PubMed

Mille, F; Adam, A; Aubry, S; Leclerc, G; Ghislandi, X; Sergent, P; Garbuio, P

2016-01-01

Quadriceps tendon avulsions are typically treated by reattaching the tendon through bone tunnels, with or without tendon or hardware augmentation. The operated knee joint can be moved right away; however, tendon grafting or tension banding will be required to protect the repair, and the hardware must be removed later on. The goal of this study was to evaluate the clinical and functional outcomes when suture anchors are used to reattached torn quadriceps tendon, and also to assess tendon healing using MRI. Thirteen consecutive patients with avulsed quadriceps tendons were operated and then followed prospectively. The surgical technique consisted of tendon reattachment using at least three anchors, in addition to intratendinous weaving of the sutures. Weight bearing was allowed while using a splint. Rehabilitation was initiated immediately after surgery according to a set protocol. Eleven patients were followed for a mean of 14.7 months. Two retears occurred in patients who did not wear the splint. Eighty-two per cent of patients were satisfied or very satisfied with the outcome. The mean knee flexion was 124.5°. All patients were able to return to their pre-injury activity levels. The mean time for clinical and functional recovery was 3 months. MRI performed 6 months after the surgical repair revealed good tendon healing. This was the first prospective study performed on quadriceps avulsion patients undergoing suture anchor repair. Prior clinical case reports have shown that this method leads to predictable clinical and functional results. Our results were comparable to those in published cases. The procedure is simpler when only suture anchors are used. Tendon healing was observed on MRI in all cases. This simple, reproducible technique is free of the drawbacks associated with the typical repair augmentation.

Exposure of a tendon extracellular matrix to synovial fluid triggers endogenous and engrafted cell death: A mechanism for failed healing of intrathecal tendon injuries.

PubMed

Garvican, Elaine R; Salavati, Mazdak; Smith, Roger K W; Dudhia, Jayesh

2017-09-01

The purpose of this study was to investigate the effect of normal synovial fluid (SF) on exposed endogenous tendon-derived cells (TDCs) and engrafted mesenchymal stem cells (MSCs) within the tendon extracellular matrix. Explants from equine superficial digital flexor (extra-synovial) and deep digital flexor tendons (DDFTs) from the compressed, intra-synovial and the tensile, extra-synovial regions were cultured in allogeneic or autologous SF-media. Human hamstring explants were cultured in allogeneic SF. Explant viability was assessed by staining. Proliferation of equine monolayer MSCs and TDCs in SF-media and co-culture with DDFT explants was determined by alamarblue®. Non-viable Native Tendon matrices (NNTs) were re-populated with MSCs or TDCs and cultured in SF-media. Immunohistochemical staining of tendon sections for the apoptotic proteins caspase-3, -8, and -9 was performed. Contact with autologous or allogeneic SF resulted in rapid death of resident tenocytes in equine and human tendon. SF did not affect the viability of equine epitenon cells, or of MSCs and TDCs in the monolayer or indirect explant co-culture. MSCs and TDCs, engrafted into NNTs, died when cultured in SF. Caspase-3, -8, and -9 expression was the greatest in SDFT explants exposed to allogeneic SF. The efficacy of cells administered intra-synovially for tendon lesion repair is likely to be limited, since once incorporated into the matrix, cells become vlnerable to the adverse effects of SF. These observations could account for the poor success rate of intra-synovial tendon healing following damage to the epitenon and contact with SF, common with most soft tissue intra-synovial pathologies.

Nonsurgical treatment and early return to activity leads to improved Achilles tendon fatigue mechanics and functional outcomes during early healing in an animal model

PubMed Central

Freedman, BR; Gordon, JA; Bhatt, PB; Pardes, AM; Thomas, SJ; Sarver, JJ; Riggin, CN; Tucker, JJ; Williams, AW; Zanes, RC; Hast, MW; Farber, DC; Silbernagel, KG; Soslowsky, LJ

2016-01-01

Achilles tendon ruptures are common and devastating injuries; however, an optimized treatment and rehabilitation protocol has yet to be defined. Therefore, the objective of this study was to investigate the effects of surgical repair and return to activity on joint function and Achilles tendon properties after 3-weeks of healing. Sprague Dawley rats (N=100) received unilateral blunt transection of their Achilles tendon. Animals were then randomized into repaired or non-repaired treatments, and further randomized into groups that returned to activity after 1-week (RTA1) or after 3-weeks (RTA3) of limb casting in plantarflexion. Limb function, passive joint mechanics, and tendon properties (mechanical, organizational using high frequency ultrasound, histological, and compositional) were evaluated. Results showed that both treatment and return to activity collectively affected limb function, passive joint mechanics, and tendon properties. Functionally, RTA1 animals had increased dorsiflexion ROM and weight bearing of the injured limb compared to RTA3 animals 3-weeks post injury. Such functional improvements in RTA1 tendons were evidenced in their mechanical fatigue properties and increased cross sectional area compared to RTA3 tendons. When RTA1 was coupled with nonsurgical treatment, superior fatigue properties were achieved compared to repaired tendons. No differences in cell shape, cellularity, GAG, collagen type I, or TGF-β staining were identified between groups, but collagen type III was elevated in RTA3 repaired tendons. The larger tissue area and increased fatigue resistance created in RTA1 tendons may prove critical for optimized outcomes in early Achilles tendon healing following complete rupture. PMID:27038306

Differences of bone healing in metaphyseal defect fractures between osteoporotic and physiological bone in rats.

PubMed

Thormann, Ulrich; El Khawassna, Thaqif; Ray, Seemun; Duerselen, Lutz; Kampschulte, Marian; Lips, Katrin; von Dewitz, Helena; Heinemann, Sascha; Heiss, Christian; Szalay, Gabor; Langheinrich, Alexander C; Ignatius, Anita; Schnettler, Reinhard; Alt, Volker

2014-03-01

Discrepancies in bone healing between osteoporotic and non-osteoporotic bone remain uncertain. The focus of the current work is to evaluate potential healing discrepancies in a metaphyseal defect model in rat femora. Female Sprague-Dawley rats were either ovariectomized (OVX, n=14) and combined with a calcium-, phosphorus- and vitamin D3-, soy- and phytoestrogen-free diet or received SHAM operation with standard diet rat (SHAM, n=14). Three months post-ovariectomy, DEXA measurement showed a reduction of bone mineral density reflecting an osteoporotic bone status in OVX rats. Rats then underwent a 3 mm wedge-shaped osteotomy at the distal metaphyseal area of the left femur stabilized with a T-shaped mini-plate and allowed to heal for 6 weeks. Biomechanical competence by means of a non-destructive three-point bending test showed significant lower flexural rigidity in the OVX rats at 3 mm lever span compared to SHAM animals (p=0.048) but no differences at 10 mm lever span. Microcomputer tomography (μCT) showed bridging cortices and consolidation of the defect in both groups, however, no measurable differences were found in either total ossified tissue or vascular volume fraction. Furthermore, histology showed healing discrepancies that were characterized by cartilaginous remnant and more unmineralized tissue presence in the OVX rats compared to more mature consolidation appearance in the SHAM group. In summary, bone defect healing in metaphyseal bone slightly differs between osteoporotic and non-osteoporotic bone in the current 3 mm defect model in both 3mm lever span biomechanical testing and histology. Copyright © 2013 Elsevier Ltd. All rights reserved.

Incidence of bacterial contamination and predisposing factors during bone and tendon allograft procurement.

PubMed

Terzaghi, Clara; Longo, Alessia; Legnani, Claudio; Bernasconi, Davide Paolo; Faré, Maristella

2015-03-01

The aim of this study was to analyze factors contributing to bacteriological contamination of bone and tendon allograft. Between 2008 and 2011, 2,778 bone and tendon allografts obtained from 196 organ and tissue donors or tissue donors only were retrospectively analysed. Several variables were taken into account: donor type (organ and tissue donors vs. tissue donor), cause of death, time interval between death and tissue procurement, duration of the procurement procedure, type of allografts, number of team members, number of trainees members, associated surgical procedures, positivity to haemoculture, type of procurement. The overall incidence of graft contamination was 23 %. The cause of death, the procurement time, the duration of procurement, the associated surgical procedures were not associated with increased risk of contamination. Significant effect on contamination incidence was observed for the number of staff members performing the procurement. In addition, our study substantiated significantly higher contamination rate among bone allografts than from tendon grafts. According to these observations, in order to minimize the contamination rate of procured musculoskeletal allografts, we recommend appropriate donor selection, use of standard sterile techniques, immediate packaging of each allograft to reduce graft exposure. Allograft procurement should be performed by a small surgical team.

Osthole Promotes Bone Fracture Healing through Activation of BMP Signaling in Chondrocytes.

PubMed

Wang, Pinger; Ying, Jun; Luo, Cheng; Jin, Xing; Zhang, Shanxing; Xu, Taotao; Zhang, Lei; Mi, Meng; Chen, Di; Tong, Peijian; Jin, Hongting

2017-01-01

Osthole is a bioactive coumarin derivative and has been reported to be able to enhance bone formation and improve fracture healing. However, the molecular mechanism of Osthole in bone fracture healing has not been fully defined. In this study we determined if Osthole enhances bone fracture healing through activation of BMP2 signaling in mice. We performed unilateral open transverse tibial fracture procedure in 10-week-old C57BL/6 mice which were treated with or without Osthole. Our previous studies demonstrated that chondrocyte BMP signaling is required for bone fracture healing, in this study we also performed tibial fracture procedure in Cre-negative and Col2-Cre;Bmp2 flox/flox conditional knockout (KO) mice ( Bmp2 Col2Cre ) to determine if Osthole enhances fracture healing in a BMP2-dependent manner. Fracture callus tissues were collected and analyzed by X-ray, micro-CT (μCT), histology, histomorphometry, immunohistochemistry (IHC), biomechanical testing and quantitative gene expression analysis. In addition, mouse chondrogenic ATDC5 cells were cultured with or without Osthole and the expression levels of chondrogenic marker genes were examined. The results demonstrated that Osthole promotes bone fracture healing in wild-type (WT) or Cre - control mice. In contrast, Osthole failed to promote bone fracture healing in Bmp2 Col2Cre conditional KO mice. In the mice receiving Osthole treatment, expression of cartilage marker genes was significantly increased. We conclude that Osthole could promote bone strength and enhance fracture healing by activation of BMP2 signaling. Osthole may be used as an alternative approach in the orthopaedic clinic for the treatment of fracture healing.

Osthole Promotes Bone Fracture Healing through Activation of BMP Signaling in Chondrocytes

PubMed Central

Wang, Pinger; Ying, Jun; Luo, Cheng; Jin, Xing; Zhang, Shanxing; Xu, Taotao; Zhang, Lei; Mi, Meng; Chen, Di; Tong, Peijian; Jin, Hongting

2017-01-01

Osthole is a bioactive coumarin derivative and has been reported to be able to enhance bone formation and improve fracture healing. However, the molecular mechanism of Osthole in bone fracture healing has not been fully defined. In this study we determined if Osthole enhances bone fracture healing through activation of BMP2 signaling in mice. We performed unilateral open transverse tibial fracture procedure in 10-week-old C57BL/6 mice which were treated with or without Osthole. Our previous studies demonstrated that chondrocyte BMP signaling is required for bone fracture healing, in this study we also performed tibial fracture procedure in Cre-negative and Col2-Cre;Bmp2flox/flox conditional knockout (KO) mice (Bmp2Col2Cre) to determine if Osthole enhances fracture healing in a BMP2-dependent manner. Fracture callus tissues were collected and analyzed by X-ray, micro-CT (μCT), histology, histomorphometry, immunohistochemistry (IHC), biomechanical testing and quantitative gene expression analysis. In addition, mouse chondrogenic ATDC5 cells were cultured with or without Osthole and the expression levels of chondrogenic marker genes were examined. The results demonstrated that Osthole promotes bone fracture healing in wild-type (WT) or Cre- control mice. In contrast, Osthole failed to promote bone fracture healing in Bmp2Col2Creconditional KO mice. In the mice receiving Osthole treatment, expression of cartilage marker genes was significantly increased. We conclude that Osthole could promote bone strength and enhance fracture healing by activation of BMP2 signaling. Osthole may be used as an alternative approach in the orthopaedic clinic for the treatment of fracture healing. PMID:28924381

Differences between the Cell Populations from the Peritenon and the Tendon Core with Regard to Their Potential Implication in Tendon Repair

PubMed Central

Cadby, Jennifer A.; Buehler, Evelyne; Godbout, Charles; van Weeren, P. René; Snedeker, Jess G.

2014-01-01

The role of intrinsic and extrinsic healing in injured tendons is still debated. In this study, we characterized cell plasticity, proliferative capacity, and migration characteristics as proxy measures of healing potential in cells derived from the peritenon (extrinsic healing) and compared these to cells from the tendon core (intrinsic healing). Both cell populations were extracted from horse superficial digital flexor tendon and characterized for tenogenic and matrix remodeling markers as well as for rates of migration and replication. Furthermore, colony-forming unit assays, multipotency assays, and real-time quantitative polymerase chain reaction analyses of markers of osteogenic and adipogenic differentiation after culture in induction media were performed. Finally, cellular capacity for differentiation towards a myofibroblastic phenotype was assessed. Our results demonstrate that both tendon- and peritenon-derived cell populations are capable of adipogenic and osteogenic differentiation, with higher expression of progenitor cell markers in peritenon cells. Cells from the peritenon also migrated faster, replicate more quickly, and show higher differentiation potential toward a myofibroblastic phenotype when compared to cells from the tendon core. Based on these data, we suggest that cells from the peritenon have substantial potential to influence tendon-healing outcome, warranting further scrutiny of their role. PMID:24651449

Proteomic Analysis of Gingival Tissue and Alveolar Bone during Alveolar Bone Healing*

PubMed Central

Yang, Hee-Young; Kwon, Joseph; Kook, Min-Suk; Kang, Seong Soo; Kim, Se Eun; Sohn, Sungoh; Jung, Seunggon; Kwon, Sang-Oh; Kim, Hyung-Seok; Lee, Jae Hyuk; Lee, Tae-Hoon

2013-01-01

Bone tissue regeneration is orchestrated by the surrounding supporting tissues and involves the build-up of osteogenic cells, which orchestrate remodeling/healing through the expression of numerous mediators and signaling molecules. Periodontal regeneration models have proven useful for studying the interaction and communication between alveolar bone and supporting soft tissue. We applied a quantitative proteomic approach to analyze and compare proteins with altered expression in gingival soft tissue and alveolar bone following tooth extraction. For target identification and validation, hard and soft tissue were extracted from mini-pigs at the indicated times after tooth extraction. From triplicate experiments, 56 proteins in soft tissue and 27 proteins in alveolar bone were found to be differentially expressed before and after tooth extraction. The expression of 21 of those proteins was altered in both soft tissue and bone. Comparison of the activated networks in soft tissue and alveolar bone highlighted their distinct responsibilities in bone and tissue healing. Moreover, we found that there is crosstalk between identified proteins in soft tissue and alveolar bone with respect to cellular assembly, organization, and communication. Among these proteins, we examined in detail the expression patterns and associated networks of ATP5B and fibronectin 1. ATP5B is involved in nucleic acid metabolism, small molecule biochemistry, and neurological disease, and fibronectin 1 is involved in cellular assembly, organization, and maintenance. Collectively, our findings indicate that bone regeneration is accompanied by a profound interaction among networks regulating cellular resources, and they provide novel insight into the molecular mechanisms involved in the healing of periodontal tissue after tooth extraction. PMID:23824910

Hamstring tendon versus patellar tendon anterior cruciate ligament reconstruction using biodegradable interference fit fixation: a prospective matched-group analysis.

PubMed

Wagner, Michael; Kääb, Max J; Schallock, Jessica; Haas, Norbert P; Weiler, Andreas

2005-09-01

There are still controversies about graft selection for primary anterior cruciate ligament reconstruction, especially with respect to knee stability and functional outcome. Biodegradable interference screw fixation of hamstring tendon grafts provides clinical results similar to those achieved with identical fixation of bone-patellar tendon-bone grafts. Cohort study; Level of evidence, 2. In 1996 and 1997, primary isolated anterior cruciate ligament reconstruction using a bone-patellar tendon-bone autograft was performed in 72 patients. Since 1998, hamstring tendons were used as routine grafts. Matched patients with a hamstring tendon graft were selected from a database (n = 284). All patients were followed prospectively for a minimum of 2 years with KT-1000 arthrometer testing, International Knee Documentation Committee score, and Lysholm score. In the bone-patellar tendon-bone group, 9 patients were excluded because of bilateral rupture of the anterior cruciate ligament, 3 patients (4.2%) had a graft rupture, and 4 patients were lost to follow-up (follow-up rate, 92.1%), leaving 56 patients for a matched-group analysis. In the hamstring tendon database, the graft rupture rate was 5.6% (P = .698). The Lysholm score was 89.7 in the patellar tendon group and 94 in the hamstring tendon group (P = .003). The KT-1000 arthrometer side-to-side difference was 2.6 mm for the patellar tendon group and 2.1 mm for the hamstring tendon group (P = .041). There were significantly less positive pivot-shift test results in the hamstring tendon group (P = .005), and hamstring tendon patients showed lower thigh atrophy (P = .024) and patellofemoral crepitus (P = .003). Overall International Knee Documentation Committee scores were better (P = .001) in the hamstring tendon group (hamstring tendon: 34 x A, 21 x B, 0 x C, 0 x D; bone-patellar tendon-bone: 17 x A, 32 x B, 6 x C, 0 x D). In this comparison of anterior cruciate ligament reconstruction with bone-patellar tendon-bone and

Octacalcium phosphate collagen composite facilitates bone regeneration of large mandibular bone defect in humans.

PubMed

Kawai, Tadashi; Suzuki, Osamu; Matsui, Keiko; Tanuma, Yuji; Takahashi, Tetsu; Kamakura, Shinji

2017-05-01

Recently it was reported that the implantation of octacalcium phosphate (OCP) and collagen composite (OCP-collagen) was effective at promoting bone healing in small bone defects after cystectomy in humans. In addition, OCP-collagen promoted bone regeneration in a critical-sized bone defect of a rodent or canine model. In this study, OCP-collagen was implanted into a human mandibular bone defect with a longer axis of approximately 40 mm, which was diagnosed as a residual cyst with apical periodontitis. The amount of OCP-collagen implanted was about five times greater than the amounts implanted in previous clinical cases. Postoperative wound healing was satisfactory and no infection or allergic reactions occurred. The OCP-collagen-treated lesion was gradually filled with radio-opaque figures, and the alveolar region occupied the whole of the bone defect 12 months after implantation. This study suggests that OCP-collagen could be a useful bone substitute material for repairing large bone defects in humans that might not heal spontaneously. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

MMP inhibition as a potential method to augment the healing of skeletal muscle and tendon extracellular matrix

PubMed Central

Davis, Max E.; Gumucio, Jonathan P.; Sugg, Kristoffer B.; Bedi, Asheesh

2013-01-01

The extracellular matrix (ECM) of skeletal muscle and tendon is composed of different types of collagen molecules that play important roles in the transmission of forces throughout the body, and in the repair and regeneration of injured tissues. Fibroblasts are the primary cells in muscle and tendon that maintain, repair, and modify the ECM in response to mechanical loading, injury, and inactivity. Matrix metalloproteinases (MMPs) are enzymes that digest collagen and other structural molecules, which are synthesized and excreted by fibroblasts. MMPs are required for baseline ECM homeostasis, but disruption of MMP regulation due to injury or disease can alter the normal ECM architecture and prevent proper force transmission. Chronic injuries and diseases of muscles and tendons can be severely debilitating, and current therapeutic modalities to enhance healing are quite limited. This review will discuss the mechanobiology of MMPs, and the potential use of MMP inhibitors to improve the treatment of injured and diseased skeletal muscle and tendon tissue. PMID:23640595

Laser for bone healing after oral surgery: systematic review.

PubMed

Noba, Claudio; Mello-Moura, Anna Carolina Volpi; Gimenez, Thais; Tedesco, Tamara Kerber; Moura-Netto, Cacio

2018-04-01

The purpose of this study is to perform a systematic review on the use of lasers in oral surgery for bone healing. Selection of articles was carried out by two evaluators in Pubmed and Web of Science databases for published articles and OpenGray for gray literature. Search strategy was developed based on the PICO Question "Does the use of lasers after oral surgery improve bone healing?". Eligibility criteria were: being on laser; evaluate bone healing; involve oral surgery; do not be about implant, periodontics, orthodontics, osteonecrosis or radiotherapy, nor revisions, clinical cases, etc. Data were collected from each article in a structured spreadsheet and a descriptive analysis was performed. Risk assessment of bias of the articles was carried out through the tool elaborated by the Cochrane collaboration. A total of 827 potentially relevant references were identified. No articles were found in OpenGray. Eleven articles met the eligibility criteria and were included in the systematic review. Most of studies were in vivo and in jaw, being conducted with low-power lasers which were applied immediately after the surgical procedure of extraction. Neoformation and bone density were the outcomes of choice and there was a tendency of increase in bone density, neoformation, regeneration, mineralization, or bone condensation when laser was applied. Regarding the bias risk assessment, studies were not clear in reporting most of the parameters. Low-power laser therapy seems to reduce time of bone healing in oral surgery, although there are no defined protocols and the level of evidence is still considered weak.

Periosteal BMP2 activity drives bone graft healing.

PubMed

Chappuis, Vivianne; Gamer, Laura; Cox, Karen; Lowery, Jonathan W; Bosshardt, Dieter D; Rosen, Vicki

2012-10-01

Bone graft incorporation depends on the orchestrated activation of numerous growth factors and cytokines in both the host and the graft. Prominent in this signaling cascade is BMP2. Although BMP2 is dispensable for bone formation, it is required for the initiation of bone repair; thus understanding the cellular mechanisms underlying bone regeneration driven by BMP2 is essential for improving bone graft therapies. In the present study, we assessed the role of Bmp2 in bone graft incorporation using mice in which Bmp2 has been removed from the limb prior to skeletal formation (Bmp2(cKO)). When autograft transplantations were performed in Bmp2cKO mice, callus formation and bone healing were absent. Transplantation of either a vital wild type (WT) bone graft into a Bmp2(cKO) host or a vital Bmp2(cKO) graft into a WT host also resulted in the inhibition of bone graft incorporation. Histological analyses of these transplants show that in the absence of BMP2, periosteal progenitors remain quiescent and healing is not initiated. When we analyzed the expression of Sox9, a marker of chondrogenesis, on the graft surface, we found it significantly reduced when BMP2 was absent in either the graft itself or the host, suggesting that local BMP2 levels drive periosteal cell condensation and subsequent callus cell differentiation. The lack of integrated healing in the absence of BMP2 was not due to the inability of periosteal cells to respond to BMP2. Healing was achieved when grafts were pre-soaked in rhBMP2 protein, indicating that periosteal progenitors remain responsive in the absence of BMP2. In contrast to the requirement for BMP2 in periosteal progenitor activation in vital bone grafts, we found that bone matrix-derived BMP2 does not significantly enhance bone graft incorporation. Taken together, our data show that BMP2 signaling is not essential for the maintenance of periosteal progenitors, but is required for the activation of these progenitors and their subsequent

Smoking cessation and bone healing: optimal cessation timing.

PubMed

Truntzer, Jeremy; Vopat, Bryan; Feldstein, Michael; Matityahu, Amir

2015-02-01

Smoking is a worldwide epidemic. Complications related to smoking behavior generate an economic loss around $193 billion annually. In addition to impacting chronic health conditions, smoking is linked to increased perioperative complications in those with current or previous smoking history. Numerous studies have demonstrated more frequent surgical complications including higher rates of infection, poor wound healing, heightened pain complaints, and increased pulmonary morbidities in patients with a smoking history. Longer preoperative cessation periods also seem to correlate with reduced rates. At roughly 4 weeks of cessation prior to surgery, complication rates more closely reflect individuals without a smoking history in comparison with those that smoke within 4 weeks of surgery. In the musculoskeletal system, a similar trend has been observed in smokers with higher rates of fractures, nonunions, malunions, infections, osteomyelitis, and lower functional scores compared to non-smoking patients. Unfortunately, the present literature lacks robust data suggesting a temporal relationship between smoking cessation and bone healing. In our review, we analyze pseudoarthrosis rates following spinal fusion to suggest that bone healing in the context of smoking behavior follows a similar time sequence as observed in wound healing. We also discuss the implications for further clarity on bone healing and smoking cessation within orthopedics including improved risk stratification and better identification of circumstances where adjunct therapy is appropriate.

[Clinical application of peroneal muscles tendon transposition in repair of Achilles tendon rupture].

PubMed

Jin, Rihao; Jin, Yu; Fang, Xiulin

2006-07-01

To discuss applied anatomy, biomechanics and surgical procedures of long peroneal muscles tendon transposition in repair of occlusive achilles tendon rupture. The blood supply and the morphology of long peroneal muscles tendon were observed in the lower extremity of 50 sides adult specimens and the mechanical tests which stretch load on the tendon were carried out. The methods were designed on the basis of the anatomical characteristics and morphology. Ten patients suffering occlusive Achilles tendon rupture were treated by using long peroneal muscles tendon transposition from March 2001 to July 2004. Among 10 patients, there were 7 males and 3 females, aging 32 to 54 years including 6 cases of jump injury, 2 cases of bruise, 1 case of step vacancy and 1 case of spontaneity injury. The interval between injury and surgery was 6 hours to 7 days in 7 fresh rupture and 21 days to 3 months in 3 old rupture. All cases belonged to occlusive Achilles tendon rupture (8 cases of complete rupture and 2 cases of incomplete rupture). The origin of long peroneal muscles was proximal tibia and fibular head, the end of them was base of first metatarsal bones and medial cuboid. The length of tendon was 13.5 +/- 2.5 cm. The width of origin tendon was 0.9 +/- 0.2 cm and the thickness was 0.3 +/- 0.1 cm; the width on apex of lateral malleolus was 0.7 +/- 0.1 cm and the thickness was 0.4 +/- 0.1 cm, the width on head of cuboid was 0.7 +/- 0.1 cm and the thickness was 0.3 +/- 0.1 cm. The long peroneal muscles tendon had abundant blood supply. The results of mechanical test showed that the biggest load was 2,292.4 +/- 617.3 N on tendon calcaneus, 1,020.4 +/- 175.4 N on long peroneal muscles tendon, 752.0 +/- 165.4 N on peroneus brevis tendon and 938.2 +/- 216.7 N on tibialis posterior tendon. Ten cases of occlusive Achilles tendon rupture achieved healing by first intention and were followed up 18-24 months. No Achilles tendon re-rupture, necrosis of skin or other complications occurred

The Impact of Type 2 Diabetes on Bone Fracture Healing

PubMed Central

Marin, Carlos; Luyten, Frank P.; Van der Schueren, Bart; Kerckhofs, Greet; Vandamme, Katleen

2018-01-01

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease known by the presence of elevated blood glucose levels. Nowadays, it is perceived as a worldwide epidemic, with a very high socioeconomic impact on public health. Many are the complications caused by this chronic disorder, including a negative impact on the cardiovascular system, kidneys, eyes, muscle, blood vessels, and nervous system. Recently, there has been increasing evidence suggesting that T2DM also adversely affects the skeletal system, causing detrimental bone effects such as bone quality deterioration, loss of bone strength, increased fracture risk, and impaired bone healing. Nevertheless, the precise mechanisms by which T2DM causes detrimental effects on bone tissue are still elusive and remain poorly studied. The aim of this review was to synthesize current knowledge on the different factors influencing the impairment of bone fracture healing under T2DM conditions. Here, we discuss new approaches used in recent studies to unveil the mechanisms and fill the existing gaps in the scientific understanding of the relationship between T2DM, bone tissue, and bone fracture healing. PMID:29416527

Autonomic healing of acrylic bone cement.

PubMed

Gladman, A Sydney; Celestine, Asha-Dee N; Sottos, Nancy R; White, Scott R

2015-01-28

Self-healing in orthopedic bone cement is demonstrated with a novel thermoplastic solvent-bonding approach. Low toxicity solvent-filled microcapsules, embedded in a commercial acrylic bone cement matrix, enable recovery of up to 80% of the virgin fracture toughness of the cement at room and body temperature conditions without external stimuli or human intervention. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Fracture healing in osteoporotic bone.

PubMed

Cheung, Wing Hoi; Miclau, Theodore; Chow, Simon Kwoon-Ho; Yang, Frank F; Alt, Volker

2016-06-01

As the world population rises, osteoporotic fracture is an emerging global threat to the well-being of elderly patients. The process of fracture healing by intramembranous ossification or/and endochondral ossification involve many well-orchestrated events including the signaling, recruitment and differentiation of mesenchymal stem cells (MSCs) during the early phase; formation of a hard callus and extracellular matrix, angiogenesis and revascularization during the mid-phase; and finally callus remodeling at the late phase of fracture healing. Through clinical and animal research, many of these factors are shown to be impaired in osteoporotic bone. Animal studies related to post-menopausal estrogen deficient osteoporosis (type I) have shown healing to be prolonged with decreased levels of MSCs and decreased levels of angiogenesis. Moreover, the expression of estrogen receptor (ER) was shown to be delayed in ovariectomy-induced osteoporotic fracture. This might be related to the observed difference in mechanical sensitivity between normal and osteoporotic bones, which requires further experiments to elucidate. In mice fracture models related to senile osteoporosis (type II), it was observed that chondrocyte and osteoblast differentiation were impaired; and that transplantation of juvenile bone marrow would result in enhanced callus formation. Other factors related to angiogenesis and vasculogenesis have also been noted to be impaired in aged models, affecting the degradation of cartilaginous matrixes and vascular invasion; the result is changes in matrix composition and growth factors concentrations that ultimately impairs healing during age-related osteoporosis. Most osteoporotic related fractures occur at metaphyseal sites clinically, and reports have indicated that differences exist between diaphyseal and metaphyseal fractures. An animal model that satisfies three main criteria (metaphyseal region, plate fixation, osteoporosis) is suggested for future research for

In vivo assessment of bone healing following Piezotome® ultrasonic instrumentation.

PubMed

Reside, Jonathan; Everett, Eric; Padilla, Ricardo; Arce, Roger; Miguez, Patricia; Brodala, Nadine; De Kok, Ingeborg; Nares, Salvador

2015-04-01

This pilot study evaluated the molecular, histologic, and radiographic healing of bone to instrumentation with piezoelectric or high speed rotary (R) devices over a 3-week healing period. Fourteen Sprague-Dawley rats (Charles River Laboratories International, Inc., Wilmington, MA, USA) underwent bilateral tibial osteotomies prepared in a randomized split-leg design using Piezotome® (P1) (Satelec Acteon, Merignac, France), Piezotome 2® (P2) (Satelec Acteon), High-speed R instrumentation, or sham surgery (S). At 1 week, an osteogenesis array was used to evaluate differences in gene expression while quantitative analysis assessed percentage bone fill (PBF) and bone mineral density (BMD) in the defect, peripheral, and distant regions at 3 weeks. Qualitative histologic evaluation of healing osteotomies was also performed at 3 weeks. At 1 week, expression of 11 and 18 genes involved in bone healing was significantly (p < .05) lower following P1 and P2 instrumentation, respectively, relative to S whereas 16 and 4 genes were lower relative to R. No differences in PBF or BMD were detected between groups within the osteotomy defect. However, significant differences in PBF (p = .020) and BMD (p = .008) were noted along the peripheral region between P2 and R groups, being R the group with the lowest values. Histologically, smooth osteotomy margins were present following instrumentation using P1 or P2 relative to R. Piezoelectric instrumentation favors preservation of bone adjacent to osteotomies while variations in gene expression suggest differences in healing rates due to surgical modality. Bone instrumented by piezoelectric surgery appears less detrimental to bone healing than high-speed R device. © 2013 Wiley Periodicals, Inc.

Tendon transfer fixation: comparing a tendon to tendon technique vs. bioabsorbable interference-fit screw fixation.

PubMed

Sabonghy, Eric Peter; Wood, Robert Michael; Ambrose, Catherine Glauber; McGarvey, William Christopher; Clanton, Thomas Oscar

2003-03-01

Tendon transfer techniques in the foot and ankle are used for tendon ruptures, deformities, and instabilities. This fresh cadaver study compares the tendon fixation strength in 10 paired specimens by performing a tendon to tendon fixation technique or using 7 x 20-25 mm bioabsorbable interference-fit screw tendon fixation technique. Load at failure of the tendon to tendon fixation method averaged 279N (Standard Deviation 81N) and the bioabsorbable screw 148N (Standard Deviation 72N) [p = 0.0008]. Bioabsorbable interference-fit screws in these specimens show decreased fixation strength relative to the traditional fixation technique. However, the mean bioabsorbable screw fixation strength of 148N provides physiologic strength at the tendon-bone interface.

Biomaterial delivery of morphogens to mimic the natural healing cascade in bone

PubMed Central

Mehta, Manav; Schmidt-Bleek, Katharina; Duda, Georg N; Mooney, David J

2012-01-01

Complications in treatment of large bone defects using bone grafting still remain. Our understanding of the endogenous bone regeneration cascade has inspired the exploration of a wide variety of growth factors (GFs) in an effort to mimic the natural signaling that controls bone healing. Biomaterial-based delivery of single exogenous GFs has shown therapeutic efficacy, and this likely relates to its ability to recruit and promote replication of cells involved in tissue development and the healing process. However, as the natural bone healing cascade involves the action of multiple factors, each acting in a specific spatiotemporal pattern, strategies aiming to mimic the critical aspects of this process will likely benefit from the usage of multiple therapeutic agents. This article reviews the current status of approaches to deliver single GFs, as well as ongoing efforts to develop sophisticated delivery platforms to deliver multiple lineage-directing morphogens (multiple GFs) during bone healing. PMID:22626978

Biomaterial delivery of morphogens to mimic the natural healing cascade in bone.

PubMed

Mehta, Manav; Schmidt-Bleek, Katharina; Duda, Georg N; Mooney, David J

2012-09-01

Complications in treatment of large bone defects using bone grafting still remain. Our understanding of the endogenous bone regeneration cascade has inspired the exploration of a wide variety of growth factors (GFs) in an effort to mimic the natural signaling that controls bone healing. Biomaterial-based delivery of single exogenous GFs has shown therapeutic efficacy, and this likely relates to its ability to recruit and promote replication of cells involved in tissue development and the healing process. However, as the natural bone healing cascade involves the action of multiple factors, each acting in a specific spatiotemporal pattern, strategies aiming to mimic the critical aspects of this process will likely benefit from the usage of multiple therapeutic agents. This article reviews the current status of approaches to deliver single GFs, as well as ongoing efforts to develop sophisticated delivery platforms to deliver multiple lineage-directing morphogens (multiple GFs) during bone healing. Copyright © 2012 Elsevier B.V. All rights reserved.

Immature myeloid cells are critical for enhancing bone fracture healing through angiogenic cascade

PubMed Central

Levy, Seth; Feduska, Joseph M.; Sawant, Anandi; Gilbert, Shawn; Hensel, Jonathan A.; Ponnazhagan, Selvarangan

2016-01-01

Bone fractures heal with overlapping phases of inflammation, cell proliferation, and bone remodeling. Osteogenesis and angiogenesis work in concert to control many stages of this process, and when one is impaired it leads to failure of bone healing, termed a nonunion. During fracture repair, there is an infiltration of immune cells at the fracture site that not only mediate the inflammatory responses, but we hypothesize they also exert influence on neovasculature. Thus, further understanding the effects of immune cell participation throughout fracture healing will reveal additional knowledge as to why some fractures heal while others form nonunions, and lead to development of novel therapeutics modulating immune cells, to increase fracture healing and prevent nonunions. Using novel femoral segmental and critical-size defect models in mice, we identified a systemic and significant increase in immature myeloid cell (IMC) infiltration during the initial phase of fracture healing until boney union is complete. Using gemcitabine to specifically ablate the IMC population, we confirmed delayed bone healing. Further, adoptive transfer of IMC increased bone growth in a nonunion model, signifying the role of this unique cell population in fracture healing. We also identified IMC post-fracture have the ability to increase endothelial cell migration, and tube formation, signaling the essential communication between the immune system and angiogenesis as a requirement for proper bone healing. Based on this data we propose that IMC may play a significant role in fracture healing and therapeutic targeting of IMC after fracture would minimize the chances of eventual nonunion pathology. PMID:27664567

Immature myeloid cells are critical for enhancing bone fracture healing through angiogenic cascade.

PubMed

Levy, Seth; Feduska, Joseph M; Sawant, Anandi; Gilbert, Shawn R; Hensel, Jonathan A; Ponnazhagan, Selvarangan

2016-12-01

Bone fractures heal with overlapping phases of inflammation, cell proliferation, and bone remodeling. Osteogenesis and angiogenesis work in concert to control many stages of this process, and when one is impaired it leads to failure of bone healing, termed a nonunion. During fracture repair, there is an infiltration of immune cells at the fracture site that not only mediate the inflammatory responses, but we hypothesize they also exert influence on neovasculature. Thus, further understanding the effects of immune cell participation throughout fracture healing will reveal additional knowledge as to why some fractures heal while others form nonunions, and lead to development of novel therapeutics modulating immune cells, to increase fracture healing and prevent nonunions. Using novel femoral segmental and critical-size defect models in mice, we identified a systemic and significant increase in immature myeloid cell (IMC) infiltration during the initial phase of fracture healing until boney union is complete. Using gemcitabine to specifically ablate the IMC population, we confirmed delayed bone healing. Further, adoptive transfer of IMC increased bone growth in a nonunion model, signifying the role of this unique cell population in fracture healing. We also identified IMC post-fracture have the ability to increase endothelial cell migration, and tube formation, signaling the essential communication between the immune system and angiogenesis as a requirement for proper bone healing. Based on this data we propose that IMC may play a significant role in fracture healing and therapeutic targeting of IMC after fracture would minimize the chances of eventual nonunion pathology. Copyright © 2016 Elsevier Inc. All rights reserved.

Does microvascularization of the footprint play a role in rotator cuff healing of the shoulder?

PubMed

Bonnevialle, Nicolas; Bayle, Xavier; Faruch, Marie; Wargny, Matthieu; Gomez-Brouchet, Anne; Mansat, Pierre

2015-08-01

The aim of the study was to evaluate the relationship between bone microvascularization of the footprint and tendon integrity after rotator cuff repair of the shoulder. Forty-eight patients (mean age, 59 years; ±7.9) with a chronic rotator cuff tear underwent a tendon repair with a single-row technique and were studied prospectively. A core obtained from the footprint during the procedure allowed determination of the bone's microvascularization with an immunohistochemistry technique using anti-CD34 antibodies. Clinical evaluation was performed at a minimum of 12-month follow-up, and rotator cuff integrity was assessed with ultrasound according to Sugaya's classification. At a mean follow-up of 13 months, the Constant score improved from 40 to 75 points; American Shoulder and Elbow Surgeons score, from 59 to 89 points; and subjective shoulder value, from 38% to 83% (P < .001). Ultrasound identified 18 patients with Sugaya type I healing, 27 patients with type II, and 3 patients with type IV. No patients showed Sugaya type III or V repairs. The rate of microvascularization of the footprint was 15.6%, 13.9%, and 4.2% for type I, II, and IV tendon integrity, respectively (I vs. II, P = .22; II vs. IV, P = .02; I vs. IV, P = .0022). Patients with a history of corticosteroid injection had a lower rate of microvascularization than the others (10.3% vs. 16.2%; P = .03). Even if overall satisfactory clinical outcomes are achieved after a rotator cuff repair, bone microvascularization of the footprint plays a role in rotator cuff healing. A lower rate of microvessels decreases the tendon integrity and healing potential after repair. Copyright © 2015 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.

Involvement of Indian hedgehog signaling in mesenchymal stem cell-augmented rotator cuff tendon repair in an athymic rat model.

PubMed

Zong, Jian-Chun; Mosca, Michael J; Degen, Ryan M; Lebaschi, Amir; Carballo, Camila; Carbone, Andrew; Cong, Guang-Ting; Ying, Liang; Deng, Xiang-Hua; Rodeo, Scott A

2017-04-01

Bone marrow aspirate has been used in recent years to augment tendon-to-bone healing, including in rotator cuff repair. However, the healing mechanism in cell-based therapy has not been elucidated in detail. Sixteen athymic nude rats were randomly allocated to 2 groups: experimental (human mesenchymal stem cells in fibrin glue carrier) and control (fibrin glue only). Animals were sacrificed at 2 and 4 weeks. Immunohistochemical staining was performed to evaluate Indian hedgehog (Ihh) signaling and SOX9 signaling in the healing enthesis. Macrophages were identified using CD68 and CD163 staining, and proliferating cells were identified using proliferating cell nuclear antigen staining. More organized and stronger staining for collagen II and a higher abundance of SOX9 + cells were observed at the enthesis in the experimental group at 2 weeks. There was significantly higher Gli1 and Patched1 expression in the experimental group at the enthesis at 2 weeks and higher numbers of Ihh + cells in the enthesis of the experimental group vs control at both 2 weeks and 4 weeks postoperatively. There were more CD68 + cells localized to the tendon midsubstance at 2 weeks compared with 4 weeks, and there was a higher level of CD163 staining in the tendon midsubstance in the experimental group than in the control group at 4 weeks. Stem cell application had a positive effect on fibrocartilage formation at the healing rotator cuff repair site. Both SOX9 and Ihh signaling appear to play an important role in the healing process. Copyright © 2017 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.

Modeling the effects of inflammation in bone fracture healing

NASA Astrophysics Data System (ADS)

Kojouharov, H. V.; Trejo, I.; Chen-Charpentier, B. M.

2017-10-01

A new mathematical model is presented to study the early inflammatory effects in bone healing. It consists of a system of nonlinear ordinary differential equations that represents the interactions among macrophages, mesenchymal stem cells, and osteoblasts. A qualitative analysis of the model is performed to determine the equilibria and their corresponding stability properties. A set of numerical simulations is performed to support the theoretical results. The model is also used to numerically monitor the evolution of a broken bone for different types of fractures and to explore possible treatments to accelerate bone healing by administrating anti-inflammatory drugs.

Monitoring of bone healing by piezoelectric-EMI method

NASA Astrophysics Data System (ADS)

Mazlina, M. H.; Sarpinah, Bibi; Tawie, Rudy; Daho, Claira Dalislone; Annuar, Ishak

2016-02-01

Smart Piezoelectric devices which have excellent piezoelectric properties have been employed for various sensor and actuators applications. The work presented here is an attempt to demonstrate the feasibility of bone healing monitoring by using piezoelectric-electromechanical impedance (EMI) method that have several advantages such as low cost, portable, light weight and simplicity in measurement. A Piezoelectric sensor (PZT) has been widely used in damage detection of various structures including concrete, pipes and bones due to their unique sensing and actuating properties. The EMI technique has emerged as a universal Structural Health Monitoring (SHM) tool suitable for almost all engineering materials and structures. The method used for this proposed study consists of put healing agent in the host structure in particular cracks bone to be monitored by PZT-needle sensor which is embedded to the host structure. The measurements were taken in the frequency range between 0.04 to 100 kHz at 1 kHz interval using AD5933 evaluation board. The signals retrieved from the AD5933 evaluation board, were quantify and analyse to obtain Root Mean Square Deviation (RMSD) percentage value. Measurements were taken every hour for 12 hours. The result from the study shows the feasibility of the piezoelectric-EMI method to effectively detect changes during bone-cracks healing process until the cracks bone is fully recovered.

The response of bone, articular cartilage and tendon to exercise in the horse

PubMed Central

Firth, Elwyn C

2006-01-01

Horses can gallop within hours of birth, and may begin training for athletic competition while still growing. This review cites studies on the effects of exercise on bone, tendon and articular cartilage, as detected by clinical and research imaging techniques, tissue biochemical analysis and microscopy of various kinds. For bone, alterations in bone mineral content, mineral density and the morphology of the mineralized tissue are the most common end-points. Apparent bone density increases slightly after athletic training in the cortex, but substantially in the major load paths of the epiphyses and cuboidal bones, despite the lower material density of the new bone, which is deposited subperiosteally and on internal surfaces without prior osteoclastic resorption. With training of greater intensity, adaptive change is supervened by patho-anatomical change in the form of microdamage and frank lesions. In tendon, collagen fibril diameter distribution changes significantly during growth, but not after early training. The exact amount and type of protracted training that does cause reduction in mass average diameter (an early sign of progressive microdamage) have not been defined. Training is associated with an increase in the cross-sectional area of some tendons, possibly owing to slightly greater water content of non-collagenous or newly synthesized matrix. Early training may be associated with greater thickness of hyaline but not calcified articular cartilage, at least in some sites. The age at which adaptation of cartilage to biomechanical influences can occur may thus extend beyond very early life. However, cartilage appears to be the most susceptible of the three tissues to pathological alteration. The effect of training exercise on the anatomical or patho-anatomical features of connective tissue structures is affected by the timing, type and amount of natural or imposed exercise during growth and development which precedes the training. PMID:16637875

Nonsurgical treatment and early return to activity leads to improved Achilles tendon fatigue mechanics and functional outcomes during early healing in an animal model.

PubMed

Freedman, Benjamin R; Gordon, Joshua A; Bhatt, Pankti R; Pardes, Adam M; Thomas, Stephen J; Sarver, Joseph J; Riggin, Corinne N; Tucker, Jennica J; Williams, Alexis W; Zanes, Robert C; Hast, Michael W; Farber, Daniel C; Silbernagel, Karin G; Soslowsky, Louis J

2016-12-01

Achilles tendon ruptures are common and devastating injuries; however, an optimized treatment and rehabilitation protocol has yet to be defined. Therefore, the objective of this study was to investigate the effects of surgical repair and return to activity on joint function and Achilles tendon properties after 3 weeks of healing. Sprague-Dawley rats (N = 100) received unilateral blunt transection of their Achilles tendon. Animals were then randomized into repaired or non-repaired treatments, and further randomized into groups that returned to activity after 1 week (RTA1) or after 3 weeks (RTA3) of limb casting in plantarflexion. Limb function, passive joint mechanics, and tendon properties (mechanical, organizational using high frequency ultrasound, histological, and compositional) were evaluated. Results showed that both treatment and return to activity collectively affected limb function, passive joint mechanics, and tendon properties. Functionally, RTA1 animals had increased dorsiflexion ROM and weight bearing of the injured limb compared to RTA3 animals 3-weeks post-injury. Such functional improvements in RTA1 tendons were evidenced in their mechanical fatigue properties and increased cross sectional area compared to RTA3 tendons. When RTA1 was coupled with nonsurgical treatment, superior fatigue properties were achieved compared to repaired tendons. No differences in cell shape, cellularity, GAG, collagen type I, or TGF-β staining were identified between groups, but collagen type III was elevated in RTA3 repaired tendons. The larger tissue area and increased fatigue resistance created in RTA1 tendons may prove critical for optimized outcomes in early Achilles tendon healing following complete rupture. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:2172-2180, 2016. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Patella Tendon Injuries Secondary to Cement Spacers Used at First-Stage Revision of Infected Total Knee Replacement

PubMed Central

Wilson, Katherine; Kothwal, Rahul; Khan, Wasim S.; Williams, Rhodri; Morgan-Jones, Rhidian

2015-01-01

We describe a series of three patients who sustained patella tendon injuries in infected total knee arthroplasties following the use of a static cement spacer at first-stage knee revision. The patella tendon injuries resulted in significant compromise to wound healing and knee stability requiring multiple surgeries. The mid-term function was poor with an Oxford score at 24 months ranging from 12 to 20. Based on our experience, we advise caution in the use of static cement spacer blocks. If they are to be used, we recommend that they should be keyed in the bone to prevent patella tendon injuries. PMID:25905106

The Effects of Bio-Lubricating Molecules on Flexor Tendon Reconstruction in A Canine Allograft Model In Vivo

PubMed Central

Zhao, Chunfeng; Wei, Zhuang; Kirk, Ramona L.; Thoreson, Andrew R.; Jay, Gregory D.; Moran, Steven L.; An, Kai-Nan; Amadio, Peter C.

2014-01-01

Background Using allograft is an attractive alternative for flexor tendon reconstruction because of the lack of donor morbidity, and better matching to the intrasynovial environment. The purpose of this study was to use biolubricant molecules to modify the graft surface to decrease adhesions and improve digit function. Methods 28 flexor digitorum profundus (FDP) tendons from the 2nd and 5th digits of 14 dogs were first lacerated and repaired to create a model with repair failure and scar digit for tendon reconstruction. Six weeks after the initial surgery, the tendons were reconstructed with FDP allograft tendons obtained from canine cadavers. One graft tendon in each dog was treated with saline as a control and the other was treated with gelatin, carbodiimide derivatized, hyaluronic acid and lubricin (cd-HA-Lubricin). Six weeks postoperatively, digit function, graft mechanics, and biology were analyzed. Results Allograft tendons treated with cd-HA-Lubricin had decreased adhesions at the proximal tendon/graft repair and within flexor sheath, improved digit function, and increased graft gliding ability. The treatment also reduced the strength at the distal tendon to bone repair, but the distal attachment rupture rate was similar for both graft types. Histology showed that viable cells migrated to the allograft, but these were limited to the tendon surface. Conclusion cd-HA-Lubricin treatment of tendon allograft improves digit functional outcomes after flexor tendon reconstruction. However, delayed bone-tendon healing should be a caution. Furthermore, the cell infiltration into the allograft tendons substance should be a target for future studies, to shorten the allograft self-regeneration period. PMID:24445876

The role of bone marrow-derived cells during the bone healing process in the GFP mouse bone marrow transplantation model.

PubMed

Tsujigiwa, Hidetsugu; Hirata, Yasuhisa; Katase, Naoki; Buery, Rosario Rivera; Tamamura, Ryo; Ito, Satoshi; Takagi, Shin; Iida, Seiji; Nagatsuka, Hitoshi

2013-03-01

Bone healing is a complex and multistep process in which the origin of the cells participating in bone repair is still unknown. The involvement of bone marrow-derived cells in tissue repair has been the subject of recent studies. In the present study, bone marrow-derived cells in bone healing were traced using the GFP bone marrow transplantation model. Bone marrow cells from C57BL/6-Tg (CAG-EGFP) were transplanted into C57BL/6 J wild mice. After transplantation, bone injury was created using a 1.0-mm drill. Bone healing was histologically assessed at 3, 7, 14, and 28 postoperative days. Immunohistochemistry for GFP; double-fluorescent immunohistochemistry for GFP-F4/80, GFP-CD34, and GFP-osteocalcin; and double-staining for GFP and tartrate-resistant acid phosphatase were performed. Bone marrow transplantation successfully replaced the hematopoietic cells into GFP-positive donor cells. Immunohistochemical analyses revealed that osteoblasts or osteocytes in the repair stage were GFP-negative, whereas osteoclasts in the repair and remodeling stages and hematopoietic cells were GFP-positive. The results indicated that bone marrow-derived cells might not differentiate into osteoblasts. The role of bone marrow-derived cells might be limited to adjustment of the microenvironment by differentiating into inflammatory cells, osteoclasts, or endothelial cells in immature blood vessels.

Biomechanical monitoring of healing bone based on acoustic emission technology.

PubMed

Hirasawa, Yasusuke; Takai, Shinro; Kim, Wook-Cheol; Takenaka, Nobuyuki; Yoshino, Nobuyuki; Watanabe, Yoshinobu

2002-09-01

Acoustic emission testing is a well-established method for assessment of the mechanical integrity of general construction projects. The purpose of the current study was to investigate the usefulness of acoustic emission technology in monitoring the yield strength of healing callus during external fixation. Thirty-five patients with 39 long bones treated with external fixation were evaluated for fracture healing by monitoring load for the initiation of acoustic emission signal (yield strength) under axial loading. The major criteria for functional bone union based on acoustic emission testing were (1) no acoustic emission signal on full weightbearing, and (2) a higher estimated strength than body weight. The yield strength monitored by acoustic emission testing increased with the time of healing. The external fixator could be removed safely and successfully in 97% of the patients. Thus, the acoustic emission method has good potential as a reliable method for monitoring the mechanical status of healing bone.

Vitamin E and the Healing of Bone Fracture: The Current State of Evidence

PubMed Central

Borhanuddin, Boekhtiar; Mohd Fozi, Nur Farhana; Naina Mohamed, Isa

2012-01-01

Background. The effect of vitamin E on health-related conditions has been extensively researched, with varied results. However, to date, there was no published review of the effect of vitamin E on bone fracture healing. Purpose. This paper systematically audited past studies of the effect of vitamin E on bone fracture healing. Methods. Related articles were identified from Medline, CINAHL, and Scopus databases. Screenings were performed based on the criteria that the study must be an original study that investigated the independent effect of vitamin E on bone fracture healing. Data were extracted using standardised forms, followed by evaluation of quality of reporting using ARRIVE Guidelines, plus recalculation procedure for the effect size and statistical power of the results. Results. Six animal studies fulfilled the selection criteria. The study methods were heterogeneous with mediocre reporting quality and focused on the antioxidant-related mechanism of vitamin E. The metasynthesis showed α-tocopherol may have a significant effect on bone formation during the normal bone remodeling phase of secondary bone healing. Conclusion. In general, the effect of vitamin E on bone fracture healing remained inconclusive due to the small number of heterogeneous and mediocre studies included in this paper. PMID:23304211

Angiopoietin‐like 4 promotes angiogenesis in the tendon and is increased in cyclically loaded tendon fibroblasts

PubMed Central

Mousavizadeh, Rouhollah; Scott, Alex; Lu, Alex; Ardekani, Gholamreza S; Behzad, Hayedeh; Lundgreen, Kirsten; Ghaffari, Mazyar; McCormack, Robert G

2016-01-01

Key points Angiopoietin‐like 4 (ANGPTL4) modulates tendon neovascularization.Cyclic loading stimulates the activity of transforming growth factor‐β and hypoxia‐inducible factor 1α and thereby increases the expression and release of ANGPTL4 from human tendon cells.Targeting ANGPTL4 and its regulatory pathways is a potential avenue for regulating tendon vascularization to improve tendon healing or adaptation. Abstract The mechanisms that regulate angiogenic activity in injured or mechanically loaded tendons are poorly understood. The present study examined the potential role of angiopoietin‐like 4 (ANGPTL4) in the angiogenic response of tendons subjected to repetitive mechanical loading or injury. Cyclic stretching of human tendon fibroblasts stimulated the expression and release of ANGPTL4 protein via transforming growth factor‐β (TGF‐β) and hypoxia‐inducible factor 1α (HIF‐1α) signalling, and the released ANGPTL4 was pro‐angiogenic. Angiogenic activity was increased following ANGPTL4 injection into mouse patellar tendons, whereas the patellar tendons of ANGPTL4 knockout mice displayed reduced angiogenesis following injury. In human rotator cuff tendons, the expression of ANGPTL4 was correlated with the density of tendon endothelial cells. To our knowledge, this is the first study characterizing a role of ANGPTL4 in the tendon. ANGPTL4 may assist in the regulation of vascularity in the injured or mechanically loaded tendon. TGF‐β and HIF‐1α comprise two signalling pathways that modulate the expression of ANGPTL4 by mechanically stimulated tendon fibroblasts and, in the future, these could be manipulated to influence tendon healing or adaptation. PMID:26670924

Functional weight-bearing mobilization after Achilles tendon rupture enhances early healing response: a single-blinded randomized controlled trial.

PubMed

Valkering, Kars P; Aufwerber, Susanna; Ranuccio, Francesco; Lunini, Enricomaria; Edman, Gunnar; Ackermann, Paul W

2017-06-01

Functional weight-bearing mobilization may improve repair of Achilles tendon rupture (ATR), but the underlying mechanisms and outcome were unknown. We hypothesized that functional weight-bearing mobilization by means of increased metabolism could improve both early and long-term healing. In this prospective randomized controlled trial, patients with acute ATR were randomized to either direct post-operative functional weight-bearing mobilization (n = 27) in an orthosis or to non-weight-bearing (n = 29) plaster cast immobilization. During the first two post-operative weeks, 15°-30° of plantar flexion was allowed and encouraged in the functional weight-bearing mobilization group. At 2 weeks, patients in the non-weight-bearing cast immobilization group received a stiff orthosis, while the functional weight-bearing mobilization group continued with increased range of motion. At 6 weeks, all patients discontinued immobilization. At 2 weeks, healing metabolites and markers of procollagen type I (PINP) and III (PIIINP) were examined using microdialysis. At 6 and 12 months, functional outcome using heel-rise test was assessed. Healing tendons of both groups exhibited increased levels of metabolites glutamate, lactate, pyruvate, and of PIIINP (all p < 0.05). Patients in functional weight-bearing mobilization group demonstrated significantly higher concentrations of glutamate compared to the non-weight-bearing cast immobilization group (p = 0.045).The upregulated glutamate levels were significantly correlated with the concentrations of PINP (r = 0.5, p = 0.002) as well as with improved functional outcome at 6 months (r = 0.4; p = 0.014). Heel-rise tests at 6 and 12 months did not display any differences between the two groups. Functional weight-bearing mobilization enhanced the early healing response of ATR. In addition, early ankle range of motion was improved without the risk of Achilles tendon elongation and without altering long-term functional

The use of autologous blood-derived growth factors in bone regeneration

PubMed Central

Civinini, Roberto; Macera, Armando; Nistri, Lorenzo; Redl, Birgit; Innocenti, Massimo

2011-01-01

Platelet-rich plasma (PRP) is defined as a portion of the plasma fraction of autologous blood having platelet concentrations above baseline. When activated the platelets release growth factors that play an essential role in bone healing such as Platelet-derived Growth Factor, Transforming Growth Factor-β, Vascular Endothelial Growth Factor and others. Multiple basic science and in vivo animal studies agree that PRP has a role in the stimulation of the healing cascade in ligament, tendon, muscle cartilage and in bone regeneration in the last years PRP had a widespread diffusion in the treatment of soft tissue and bone healing. The purpose of this review is to describe the biological properties of platelets and its factors, the methods used for producing PRP, to provide a background on the underlying basic science and an overview of evidence based medicine on clinical application of PRP in bone healing. PMID:22461800

Clinical factors affecting pathological fracture and healing of unicameral bone cysts

PubMed Central

2014-01-01

Background Unicameral bone cyst (UBC) is the most common benign lytic bone lesion seen in children. The aim of this study is to investigate clinical factors affecting pathological fracture and healing of UBC. Methods We retrospectively reviewed 155 UBC patients who consulted Nagoya musculoskeletal oncology group hospitals in Japan. Sixty of the 155 patients had pathological fracture at presentation. Of 141 patients with follow-up periods exceeding 6 months, 77 were followed conservatively and 64 treated by surgery. Results The fracture risk was significantly higher in the humerus than other bones. In multivariate analysis, ballooning of bone, cyst in long bone, male sex, thin cortical thickness and multilocular cyst were significant adverse prognostic factors for pathological fractures at presentation. The healing rates were 30% and 83% with observation and surgery, respectively. Multivariate analysis revealed that fracture at presentation and history of biopsy were good prognostic factors for healing of UBC in patients under observation. Conclusion The present results suggest that mechanical disruption of UBC such as fracture and biopsy promotes healing, and thus watchful waiting is indicated in these patients, whereas patients with poor prognostic factors for fractures should be considered for surgery. PMID:24884661

Clinical factors affecting pathological fracture and healing of unicameral bone cysts.

PubMed

Urakawa, Hiroshi; Tsukushi, Satoshi; Hosono, Kozo; Sugiura, Hideshi; Yamada, Kenji; Yamada, Yoshihisa; Kozawa, Eiji; Arai, Eisuke; Futamura, Naohisa; Ishiguro, Naoki; Nishida, Yoshihiro

2014-05-17

Unicameral bone cyst (UBC) is the most common benign lytic bone lesion seen in children. The aim of this study is to investigate clinical factors affecting pathological fracture and healing of UBC. We retrospectively reviewed 155 UBC patients who consulted Nagoya musculoskeletal oncology group hospitals in Japan. Sixty of the 155 patients had pathological fracture at presentation. Of 141 patients with follow-up periods exceeding 6 months, 77 were followed conservatively and 64 treated by surgery. The fracture risk was significantly higher in the humerus than other bones. In multivariate analysis, ballooning of bone, cyst in long bone, male sex, thin cortical thickness and multilocular cyst were significant adverse prognostic factors for pathological fractures at presentation. The healing rates were 30% and 83% with observation and surgery, respectively. Multivariate analysis revealed that fracture at presentation and history of biopsy were good prognostic factors for healing of UBC in patients under observation. The present results suggest that mechanical disruption of UBC such as fracture and biopsy promotes healing, and thus watchful waiting is indicated in these patients, whereas patients with poor prognostic factors for fractures should be considered for surgery.

Alteration of blood clot structures by interleukin-1 beta in association with bone defects healing

PubMed Central

Wang, Xin; Friis, Thor E.; Masci, Paul P.; Crawford, Ross W.; Liao, Wenbo; Xiao, Yin

2016-01-01

The quality of hematomas are crucial for successful early bone defect healing, as the structure of fibrin clots can significantly influence the infiltration of cells, necessary for bone regeneration, from adjacent tissues into the fibrin network. This study investigated if there were structural differences between hematomas from normal and delayed healing bone defects and whether such differences were linked to changes in the expression of IL-1β. Using a bone defect model in rats, we found that the hematomas in the delayed healing model had thinner fibers and denser clot structures. Moreover, IL-1β protein levels were significantly higher in the delayed healing hematomas. The effects of IL-1β on the structural properties of human whole blood clots were evaluated by thrombelastograph (TEG), scanning electronic microscopy (SEM), compressive study, and thrombolytic assays. S-nitrosoglutathione (GSNO) was applied to modulate de novo hematoma structure and the impact on bone healing was evaluated in the delayed healing model. We found that GSNO produced more porous hematomas with thicker fibers and resulted in significantly enhanced bone healing. This study demonstrated that IL-1β and GSNO had opposing effects on clot architecture, the structure of which plays a pivotal role in early bone healing. PMID:27767056

Minimally invasive repair of the tibialis anterior tendon using a semitendinosus autograft.

PubMed

Michels, Frederick; Van Der Bauwhede, Jan; Oosterlinck, Dirk; Thomas, Sam; Guillo, Stéphane

2014-03-01

Ruptures of the tibialis anterior tendon are rare but can cause substantial functional deficiencies. The literature regarding the treatment of such injuries is very limited. Atraumatic ruptures often occur in the presence of an abnormal tendon structure, and retraction often makes end-to-end repair impossible. With traumatic lesions, the risk of developing both adhesions and scar tissue is high. This study assesses the results of a surgical reconstruction using the interposition of a semitendinosus tendon autograft in 12 patients. Three patients had a traumatic rupture, and 9 patients had an atraumatic rupture. In 8 patients, the procedure was carried out using a minimally invasive technique. The average postoperative American Orthopaedic Foot & Ankle Society (AOFAS) Ankle-Hindfoot score was 95.7 in the atraumatic group and 94.7 in the traumatic group. Active dorsiflexion was possible after 2 to 3 weeks. We believe that the interposition of a strong, healthy tendon facilitated healing and allowed early weight bearing. All patients had good recovery of dorsiflexion and gait. Repairing a ruptured tibialis anterior tendon using a semitendinosus autograft was a reliable technique and offered a good result. With the minimally invasive approach, there was no need to divide the extensor retinaculum, which we believe allowed faster recovery and reduced the risk of adhesions and wound healing problems. Level IV, retrospective case series.

Angiopoietin-like 4 promotes angiogenesis in the tendon and is increased in cyclically loaded tendon fibroblasts.

PubMed

Mousavizadeh, Rouhollah; Scott, Alex; Lu, Alex; Ardekani, Gholamreza S; Behzad, Hayedeh; Lundgreen, Kirsten; Ghaffari, Mazyar; McCormack, Robert G; Duronio, Vincent

2016-06-01

Angiopoietin-like 4 (ANGPTL4) modulates tendon neovascularization. Cyclic loading stimulates the activity of transforming growth factor-β and hypoxia-inducible factor 1α and thereby increases the expression and release of ANGPTL4 from human tendon cells. Targeting ANGPTL4 and its regulatory pathways is a potential avenue for regulating tendon vascularization to improve tendon healing or adaptation. The mechanisms that regulate angiogenic activity in injured or mechanically loaded tendons are poorly understood. The present study examined the potential role of angiopoietin-like 4 (ANGPTL4) in the angiogenic response of tendons subjected to repetitive mechanical loading or injury. Cyclic stretching of human tendon fibroblasts stimulated the expression and release of ANGPTL4 protein via transforming growth factor-β (TGF-β) and hypoxia-inducible factor 1α (HIF-1α) signalling, and the released ANGPTL4 was pro-angiogenic. Angiogenic activity was increased following ANGPTL4 injection into mouse patellar tendons, whereas the patellar tendons of ANGPTL4 knockout mice displayed reduced angiogenesis following injury. In human rotator cuff tendons, the expression of ANGPTL4 was correlated with the density of tendon endothelial cells. To our knowledge, this is the first study characterizing a role of ANGPTL4 in the tendon. ANGPTL4 may assist in the regulation of vascularity in the injured or mechanically loaded tendon. TGF-β and HIF-1α comprise two signalling pathways that modulate the expression of ANGPTL4 by mechanically stimulated tendon fibroblasts and, in the future, these could be manipulated to influence tendon healing or adaptation. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

Effect of Poloxamer 407 as a carrier vehicle on rotator cuff healing in a rat model.

PubMed

Kim, Soung-Yon; Chae, Soo-Won; Lee, Juneyoung

2014-03-01

In vivo studies showing the effects of biologic healing-promoting factors on tendon-to-bone healing after rotator cuff repair have focused only on biologic healing-promoting factors and have not taken into consideration the effect of the carrier vehicle. Moreover, most studies have evaluated the healing process using different carrier vehicles, each of which may have specific effects on tendon healing. This may explain the large variability seen in outcomes in research studies. In this study, we investigated the effects of Poloxamer 407 as a carrier vehicle on rotator cuff healing at the repair site and compared it with those of a collagen sponge, which is a commonly used carrier vehicle. Fifty-seven adult male Sprague-Dawley rats underwent detachment and immediate repair of the bilateral supraspinatus tendons. Rats were randomly assigned to three groups: repair only, repair with collagen sponge, and repair with Poloxamer 407. The repairs were evaluated at 1, 2, 4, and 8 weeks after surgery with histological analysis and biomechanical testing. At 4 weeks, more cellular organization, a greater number of collagen fibers, and increased maturity of collagen fibers were observed in the repair with Poloxamer 407 group than in the other groups. The repair with collagen sponge group had delayed development and collagen fiber maturation. Significant differences in the biomechanical properties were found between groups at 4 weeks. Stiffness in the case of the repair with Poloxamer 407 group was significantly higher than that in the repair with collagen sponge group. The modulus was significantly lower in the repair with collagen sponge group than in the repair only group. However, the use of Poloxamer 407 versus the collagen sponge did not significantly affect the biomechanical properties of the repaired tendons at 8 weeks. Carrier vehicles may have differing effects at the early stages of rotator cuff healing. The use of Poloxamer 407 as a carrier vehicle may be useful for

An interface finite element model can be used to predict healing outcome of bone fractures.

PubMed

Alierta, J A; Pérez, M A; García-Aznar, J M

2014-01-01

After fractures, bone can experience different potential outcomes: successful bone consolidation, non-union and bone failure. Although, there are a lot of factors that influence fracture healing, experimental studies have shown that the interfragmentary movement (IFM) is one of the main regulators for the course of bone healing. In this sense, computational models may help to improve the development of mechanical-based treatments for bone fracture healing. Hence, based on this fact, we propose a combined repair-failure mechanistic computational model to describe bone fracture healing. Despite being a simple model, it is able to correctly estimate the time course evolution of the IFM compared to in vivo measurements under different mechanical conditions. Therefore, this mathematical approach is especially suitable for modeling the healing response of bone to fractures treated with different mechanical fixators, simulating realistic clinical conditions. This model will be a useful tool to identify factors and define targets for patient specific therapeutics interventions. © 2013 Published by Elsevier Ltd.

Partial gravity unloading inhibits bone healing responses in a large animal model.

PubMed

Gadomski, Benjamin C; McGilvray, Kirk C; Easley, Jeremiah T; Palmer, Ross H; Santoni, Brandon G; Puttlitz, Christian M

2014-09-22

The reduction in mechanical loading associated with space travel results in dramatic decreases in the bone mineral density (BMD) and mechanical strength of skeletal tissue resulting in increased fracture risk during spaceflight missions. Previous rodent studies have highlighted distinct bone healing differences in animals in gravitational environments versus those during spaceflight. While these data have demonstrated that microgravity has deleterious effects on fracture healing, the direct translation of these results to human skeletal repair remains problematic due to substantial differences between rodent and human bone. Thus, the objective of this study was to investigate the effects of partial gravitational unloading on long-bone fracture healing in a previously-developed large animal Haversian bone model. In vivo measurements demonstrated significantly higher orthopedic plate strains (i.e. load burden) in the Partial Unloading (PU) Group as compared to the Full Loading (FL) Group following the 28-day healing period due to inhibited healing in the reduced loading environment. DEXA BMD in the metatarsus of the PU Group decreased 17.6% (p<0.01) at the time of the ostectomy surgery. Four-point bending stiffness of the PU Group was 4.4 times lower than that of the FL Group (p<0.01), while µCT and histomorphometry demonstrated reduced periosteal callus area (p<0.05), mineralizing surface (p<0.05), mineral apposition rate (p<0.001), bone formation rate (p<0.001), and periosteal/endosteal osteoblast numbers (p<0.001/p<0.01, respectively) as well as increased periosteal osteoclast number (p<0.05). These data provide strong evidence that the mechanical environment dramatically affects the fracture healing cascade, and likely has a negative impact on Haversian system healing during spaceflight. Copyright © 2014 Elsevier Ltd. All rights reserved.

Vitamin D and the immunomodulation of rotator cuff injury

PubMed Central

Dougherty, Kaitlin A; Dilisio, Matthew F; Agrawal, Devendra K

2016-01-01

Tendon-to-bone healing after rotator cuff repair surgery has a failure rate of 20%–94%. There has been a recent interest to determine the factors that act as determinants between successful and unsuccessful rotator cuff repair. Vitamin D level in patients is one of the factors that have been linked to bone and muscle proliferation and healing, and it may have an effect on tendon-to-bone healing. The purpose of this article is to critically review relevant published research that relates to the effect of vitamin D on rotator cuff tears and subsequent healing. A review of the literature was conducted to identify all studies that investigate the relationship between vitamin D and tendon healing, in addition to its mechanism of action. The data were then analyzed in order to summarize what is currently known about vitamin D, rotator cuff pathology, and tendon-to-bone healing. The activated metabolite of vitamin D, 1α,25-dihydroxyvitamin D3, affects osteoblast proliferation and differentiation. Likewise, vitamin D plays a significant role in the tendon-to-bone healing process by increasing the bone mineral density and strengthening the skeletal muscles. The 1α,25-dihydroxyvitamin D3 binds to vitamin D receptors on myocytes to stimulate growth and proliferation. The form of vitamin D produced by the liver, calcifediol, is a key initiator of the myocyte healing process by moving phosphate into myocytes, which improves function and metabolism. Investigation into the effect of vitamin D on tendons has been sparse, but limited studies have been promising. Matrix metalloproteinases play an active role in remodeling the extracellular matrix (ECM) of tendons, particularly deleterious remodeling of the collagen fibers. Also, the levels of transforming growth factor-β3 positively influence the success of the surgery for rotator cuff repair. In the tendon-to-bone healing process, vitamin D has been shown to successfully influence bone and muscle healing, but more research is

[Conservative functional treatment of Achilles tendon ruptures].

PubMed

Hüfner, T; Gaulke, R; Imrecke, J; Krettek, C; Stübig, T

2010-09-01

The conservative functional treatment of Achilles tendon ruptures has developed further over the last 20 years and is basically possible for 60-80% of patients. The treatment leads to success if the indications obtained by dynamic sonography are correctly interpreted (adaptation of the tendon ends up to 20 degrees plantar flexion), if the patient presents sufficient compliance and the physiotherapy is increasingly intensified depending on tendon healing. Modern ortheses allow an increased equinus position and therefore improved protection of the healing tendon. If these factors are present a relatively low re-rupture rate of only 7% can be achieved. The decisive advantage of conservative functional therapy is the avoidance of specific operative risks, such as infection and injury to the sural nerve. After removal of the orthesis the tendon should continue to be modeled using shoe insoles and raised heels.

Tendon injuries

PubMed Central

Wu, Fan; Nerlich, Michael; Docheva, Denitsa

2017-01-01

Tendons connect muscles to bones, ensuring joint movement. With advanced age, tendons become more prone to degeneration followed by injuries. Tendon repair often requires lengthy periods of rehabilitation, especially in elderly patients. Existing medical and surgical treatments often fail to regain full tendon function. The development of novel treatment methods has been hampered due to limited understanding of basic tendon biology. Recently, it was discovered that tendons, similar to other mesenchymal tissues, contain tendon stem/progenitor cells (TSPCs) which possess the common stem cell properties. The current strategies for enhancing tendon repair consist mainly of applying stem cells, growth factors, natural and artificial biomaterials alone or in combination. In this review, we summarise the basic biology of tendon tissues and provide an update on the latest repair proposals for tendon tears. Cite this article: EFORT Open Rev 2017;2:332-342. DOI: 10.1302/2058-5241.2.160075 PMID:28828182

Oxygen as a critical determinant of bone fracture healing-a multiscale model.

PubMed

Carlier, Aurélie; Geris, Liesbet; van Gastel, Nick; Carmeliet, Geert; Van Oosterwyck, Hans

2015-01-21

A timely restoration of the ruptured blood vessel network in order to deliver oxygen and nutrients to the fracture zone is crucial for successful bone healing. Indeed, oxygen plays a key role in the aerobic metabolism of cells, in the activity of a myriad of enzymes as well as in the regulation of several (angiogenic) genes. In this paper, a previously developed model of bone fracture healing is further improved with a detailed description of the influence of oxygen on various cellular processes that occur during bone fracture healing. Oxygen ranges of the cell-specific oxygen-dependent processes were established based on the state-of-the art experimental knowledge through a rigorous literature study. The newly developed oxygen model is compared with previously published experimental and in silico results. An extensive sensitivity analysis was also performed on the newly introduced oxygen thresholds, indicating the robustness of the oxygen model. Finally, the oxygen model was applied to the challenging clinical case of a critical sized defect (3mm) where it predicted the formation of a fracture non-union. Further model analyses showed that the harsh hypoxic conditions in the central region of the callus resulted in cell death and disrupted bone healing thereby indicating the importance of a timely vascularization for the successful healing of a large bone defect. In conclusion, this work demonstrates that the oxygen model is a powerful tool to further unravel the complex spatiotemporal interplay of oxygen delivery, diffusion and consumption with the several healing steps, each occurring at distinct, optimal oxygen tensions during the bone repair process. Copyright © 2014 Elsevier Ltd. All rights reserved.

Healing of the bone with anti-fracture drugs.

PubMed

Vannucci, Letizia; Brandi, Maria Luisa

2016-12-01

Fracture healing is a complex physiological process. As impaired fracture healing is more frequent in osteoporotic subjects, anti-osteoporotic drugs could have some impact on this process. Areas covered: We reviewed the current literature to evaluate the effects of these drugs on fracture healing and their potential role in supporting this process, especially when impaired. A PubMed/Medline search was undertaken combining the terms 'fracture healing', 'anti-resorptive drugs', 'anabolic agents', 'anti-osteoporotic drugs'. Expert opinion: As clinical evidence on the role of anti-osteoporotic drugs in the process of fracture healing consists mainly of case reports or studies with a relatively small number of patients, large randomized clinical trials are needed in order to extend to the human setting the promising results on these agents as inductors or co-adjuvants of bone healing derived from animal studies.

Distal Attachment of Flexor Tendon Allograft: A Biomechanical Study of Different Reconstruction Techniques in Human Cadaver Hands

PubMed Central

Wei, Zhuang; Thoreson, Andrew R.; Amadio, Peter C.; An, Kai-Nan; Zhao, Chunfeng

2014-01-01

We compared the mechanical force of tendon-to-bone repair techniques for flexor tendon reconstruction. Thirty-six flexor digitorum profundus (FDP) tendons were divided into three groups based upon the repair technique: (1) suture/button repair using FDP tendon (Pullout button group), (2) suture bony anchor using FDP tendon (Suture anchor group), and (3) suture/button repair using FDP tendon with its bony attachment preserved (Bony attachment group). The repair failure force and stiffness were measured. The mean load to failure and stiffness in the bony attachment group were significantly higher than that in the pullout button and suture anchor groups. No significant difference was found in failure force and stiffness between the pullout button and suture anchor groups. An intrasynovial flexor tendon graft with its bony attachment has significantly improved tensile properties at the distal repair site when compared with a typical tendon-to-bone attachment with a button or suture anchor. The improvement in the tensile properties at the repair site may facilitate postoperative rehabilitation and reduce the risk of graft rupture. PMID:23754507

Role of xenogenous bovine platelet gel embedded within collagen implant on tendon healing: an in vitro and in vivo study

PubMed Central

Oryan, Ahmad; Meimandi-Parizi, Abdolhamid; Maffulli, Nicola

2015-01-01

Surgical reconstruction of large Achilles tendon defects is demanding. Platelet concentrates may be useful to favor healing in such conditions. The characteristics of bovine platelet-gel embedded within a collagen-implant were determined in vitro, and its healing efficacy was examined in a large Achilles tendon defect in rabbits. Two cm of the left Achilles tendon of 60 rabbits were excised, and the animals were randomly assigned to control (no implant), collagen-implant, or bovine-platelet-gel-collagen-implant groups. The tendon edges were maintained aligned using a Kessler suture. No implant was inserted in the control group. In the two other groups, a collagen-implant or bovine-platelet-gel-collagen-implant was inserted in the defect. The bioelectricity and serum platelet-derived growth factor levels were measured weekly and at 60 days post injury, respectively. After euthanasia at 60 days post injury, the tendons were tested at macroscopic, microscopic, and ultrastructural levels, and their dry matter and biomechanical performances were also assessed. Another 60 rabbits were assigned to receive no implant, a collagen-implant, or a bovine-platelet-gel-collagen-implant, euthanized at 10, 20, 30, and 40 days post injury, and their tendons were evaluated grossly and histologically to determine host-graft interactions. Compared to the control and collagen-implant, treatment with bovine-platelet-gel-collagen-implant improved tissue bioelectricity and serum platelet-derived growth factor levels, and increased cell proliferation, differentiation, and maturation. It also increased number, diameter, and density of the collagen fibrils, alignment and maturation of the collagen fibrils and fibers, biomechanical properties and dry matter content of the injured tendons at 60 days post injury. The bovine-platelet-gel-collagen-implant also increased biodegradability, biocompatibility, and tissue incorporation behavior of the implant compared to the collagen-implant alone

Gene expression profiles of changes underlying different-sized human rotator cuff tendon tears.

PubMed

Chaudhury, Salma; Xia, Zhidao; Thakkar, Dipti; Hakimi, Osnat; Carr, Andrew J

2016-10-01

Progressive cellular and extracellular matrix (ECM) changes related to age and disease severity have been demonstrated in rotator cuff tendon tears. Larger rotator cuff tears demonstrate structural abnormalities that potentially adversely influence healing potential. This study aimed to gain greater insight into the relationship of pathologic changes to tear size by analyzing gene expression profiles from normal rotator cuff tendons, small rotator cuff tears, and large rotator cuff tears. We analyzed gene expression profiles of 28 human rotator cuff tendons using microarrays representing the entire genome; 11 large and 5 small torn rotator cuff tendon specimens were obtained intraoperatively from tear edges, which we compared with 12 age-matched normal controls. We performed real-time polymerase chain reaction and immunohistochemistry for validation. Torn rotator cuff tendons demonstrated upregulation of a number of key genes, such as matrix metalloproteinase 3, 10, 12, 13, 15, 21, and 25; a disintegrin and metalloproteinase (ADAM) 12, 15, and 22; and aggrecan. Amyloid was downregulated in all tears. Small tears displayed upregulation of bone morphogenetic protein 5. Chemokines and cytokines that may play a role in chemotaxis were altered; interleukins 3, 10, 13, and 15 were upregulated in tears, whereas interleukins 1, 8, 11, 18, and 27 were downregulated. The gene expression profiles of normal controls and small and large rotator cuff tear groups differ significantly. Extracellular matrix remodeling genes were found to contribute to rotator cuff tear pathogenesis. Rotator cuff tears displayed upregulation of a number of matrix metalloproteinase (3, 10, 12, 13, 15, 21, and 25), a disintegrin and metalloproteinase (ADAM 12, 15, and 22) genes, and downregulation of some interleukins (1, 8, and 27), which play important roles in chemotaxis. These gene products may potentially have a role as biomarkers of failure of healing or therapeutic targets to improve tendon

[Reconstruction of big rotator cuff ruptures. A new technique of tendon refixation with the corkscrew suture anchor system].

PubMed

Kessler, M A; Lichtenberg, S; Habermeyer, P

2003-10-01

Tendon retraction and fatty degeneration is a major problem in repair of massive rotator cuff tears. Especially in the transosseous refixation technique, a tension-free refixation cannot be obtained in all cases. The purpose of this prospective study was to evaluate the postoperative results using a new tension-free reinsertion technique with a Corkscrew suture anchor system. Thirty patients (25 males, 5 females) with complete one and two tendon tears underwent open rotator cuff repair (rupture of one tendon: n=14, 47%). The torn tendons were mobilized and reinserted medially to reduce tension. Medialization was achieved by inserting tendon near the osteochondral border in a bony trough. The number of implanted suture anchors ranged from 2 to 6 (mean: 3.56). The mean age was 56 years (39-68 years) with a follow-up of 24 months (17-33 months). In one patient physical and sonographic examination showed a complete and in two patients a partial rerupture. A temporarily frozen shoulder occurred in two cases. No infection or rejection response was seen. In no case was revision surgery necessary. No displacement or loosening of the Corkscrew anchors was noticed. The constant score improved from 45 points preoperatively to 85 points at the time of follow-up (mean). The Corkscrew suture anchor system in combination with the new suture technique offers the possibility of a stable reinsertion even in reduced calcified bone structure. This facilitates good conditions for stable fibroblastic healing. Our midterm results show good osseous union combined with a low rerupture rate.

Tendon Functional Extracellular Matrix

PubMed Central

Screen, H.R.C.; Birk, D.E.; Kadler, K.E.; Ramirez, F; Young, M.F.

2015-01-01

This article is one of a series, summarising views expressed at the Orthopaedic Research Society New Frontiers in Tendon Research Conference. This particular article reviews the three workshops held under the “Functional Extracellular Matrix” stream. The workshops focused on the roles of the tendon extracellular matrix, such as performing the mechanical functions of tendon, creating the local cell environment and providing cellular cues. Tendon is a complex network of matrix and cells, and its biological functions are influenced by widely-varying extrinsic and intrinsic factors such as age, nutrition, exercise levels and biomechanics. Consequently, tendon adapts dynamically during development, ageing and injury. The workshop discussions identified research directions associated with understanding cell-matrix interactions to be of prime importance for developing novel strategies to target tendon healing or repair. PMID:25640030

Simulation of peri-implant bone healing due to immediate loading in dental implant treatments.

PubMed

Chou, Hsuan-Yu; Müftü, Sinan

2013-03-15

The goal of this work was to investigate the role of immediate loading on the peri-implant bone healing in dental implant treatments. A mechano-regulatory tissue differentiation model that takes into account the stimuli through the solid and the fluid components of the healing tissue, and the diffusion of pluripotent stem cells into the healing callus was used. A two-dimensional axisymmetric model consisting of a dental implant, the healing callus tissue and the host bone tissue was constructed for the finite element analysis. Poroelastic material properties were assigned to the healing callus and the bone tissue. The effects of micro-motion, healing callus size, and implant thread design on the length of the bone-to-implant contact (BIC) and the bone volume (BV) formed in the healing callus were investigated. In general, the analysis predicted formation of a continuous layer of soft tissue along the faces of the implant which are parallel to the loading direction. This was predicted to be correlated with the high levels of distortional strain transferred through the solid component of the stimulus. It was also predicted that the external threads on the implant, redistribute the interfacial load, thus help reduce the high distortional stimulus and also help the cells to differentiate to bone tissue. In addition, the region underneath the implant apex was predicted to experience high fluid stimulus that results in the development of soft tissue. The relationship between the variables considered in this study and the outcome measures, BV and BIC, was found to be highly nonlinear. A three-way analysis of variance (ANOVA) of the results was conducted and it showed that micro-motion presents the largest hindrance to bone formation during healing. Copyright © 2013 Elsevier Ltd. All rights reserved.

[Polarized microscopic observation of the collagen change in bone healing during bone lengthening].

PubMed

Zou, Pei; Li, Junhui; Li, Zhuyi

2006-01-01

To investigate the feature and regularity of the collagen change in bone healing during bone lengthening. Bone lengthening model was made in the middle segment of the rabbit tibia. Five days after the model was established, the bone was lengthened 1.5 mm per day for 14 days. The rabbits were put to death after elongation, 7, 14, 21, 30, 40, 50, 60 and 70 days after elongation. The distracted area of the bone was imbedded with paraffin. After being stained by the picric acid-sirius red staining, the slice was observed under polarized microscope. The features of the collagen change in the distracted bone were as follows: (1) In the fibrous tissue of the distracted area during lengthening period and the early stage after lengthening, there was not only collagen III but also much collagen I. (2) Collagen I , II and III were observed in the cartilage. (3) Collagen I, II and III were also observed in the pseudo-growth plate. (4) Collagen I took the dominance during lengthening period and the late stage after lengthening. New bone formation in bone lengthening is under the distracted force, so the collagen changes have different features compared with that in fracture healing. Collagen I, II and III can be identified by picric acid-sirius red staining and polarized microscope, so a new method for studying the collagen typing in bone repairing is provided.

Time-Dependent Alterations of MMPs, TIMPs and Tendon Structure in Human Achilles Tendons after Acute Rupture

PubMed Central

Minkwitz, Susann; Schmock, Aysha; Kurtoglu, Alper; Tsitsilonis, Serafeim; Manegold, Sebastian; Klatte-Schulz, Franka

2017-01-01

A balance between matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) is required to maintain tendon homeostasis. Variation in this balance over time might impact on the success of tendon healing. This study aimed to analyze structural changes and the expression profile of MMPs and TIMPs in human Achilles tendons at different time-points after rupture. Biopsies from 37 patients with acute Achilles tendon rupture were taken at surgery and grouped according to time after rupture: early (2–4 days), middle (5–6 days), and late (≥7 days), and intact Achilles tendons served as control. The histological score increased from the early to the late time-point after rupture, indicating the progression towards a more degenerative status. In comparison to intact tendons, qRT-PCR analysis revealed a significantly increased expression of MMP-1, -2, -13, TIMP-1, COL1A1, and COL3A1 in ruptured tendons, whereas TIMP-3 decreased. Comparing the changes over time post rupture, the expression of MMP-9, -13, and COL1A1 significantly increased, whereas MMP-3 and -10 expression decreased. TIMP expression was not significantly altered over time. MMP staining by immunohistochemistry was positive in the ruptured tendons exemplarily analyzed from early and late time-points. The study demonstrates a pivotal contribution of all investigated MMPs and TIMP-1, but a minor role of TIMP-2, -3, and -4, in the early human tendon healing process. PMID:29053586

Healing of rabbit calvarial critical-sized defects using autogenous bone grafts and fibrin glue.

PubMed

Lappalainen, Olli-Pekka; Korpi, Riikka; Haapea, Marianne; Korpi, Jarkko; Ylikontiola, Leena P; Kallio-Pulkkinen, Soili; Serlo, Willy S; Lehenkari, Petri; Sándor, George K

2015-04-01

This study aimed to evaluate ossification of cranial bone defects comparing the healing of a single piece of autogenous calvarial bone representing a bone flap as in cranioplasty compared to particulated bone slurry with and without fibrin glue to represent bone collected during cranioplasty. These defect-filling materials were then compared to empty control cranial defects. Ten White New Zealand adult male rabbits had bilateral critical-sized calvarial defects which were left either unfilled as control defects or filled with a single full-thickness piece of autogenous bone, particulated bone, or particulated bone combined with fibrin glue. The defects were left to heal for 6 weeks postoperatively before termination. CT scans of the calvarial specimens were performed. Histomorphometric assessment of hematoxylin-eosin- and Masson trichrome-stained specimens was used to analyze the proportion of new bone and fibrous tissue in the calvarial defects. There was a statistically significant difference in both bone and soft tissue present in all the autogenous bone-grafted defect sites compared to the empty negative control defects. These findings were supported by CT scan findings. While fibrin glue combined with the particulated bone seemed to delay ossification, the healing was more complete compared to empty control non-grafted defects. Autogenous bone grafts in various forms such as solid bone flaps or particulated bone treated with fibrin glue were associated with bone healing which was superior to the empty control defects.

The roles of cellular and molecular components of a hematoma at early stage of bone healing.

PubMed

Shiu, Hoi Ting; Leung, Ping Chung; Ko, Chun Hay

2018-04-01

Bone healing is a complex repair process that commences with the formation of a blood clot at the injured bone, termed hematoma. It has evidenced that a lack of a stable hematoma causes delayed bone healing or non-union. The hematoma at the injured bone constitutes the early healing microenvironment. It appears to dictate healing pathways that ends in a regenerative bone. However, the hematoma is often clinically removed from the damaged site. Conversely, blood-derived products have been used in bone tissue engineering for treating critical sized defects, including fibrin gels and platelet-rich plasma. A second generation of platelet concentrate that is based on leukocyte and fibrin content has also been developed and introduced in market. Conflicting effect of these products in bone repair are reported. We propose that the bone healing response becomes dysregulated if the blood response and subsequent formation and properties of a hematoma are altered. This review focuses on the central structural, cellular, and molecular components of a fracture hematoma, with a major emphasis on their roles in regulating bone healing mechanism, and their interactions with mesenchymal stem cells. New angles towards a better understanding of these factors and relevant mechanisms involved at the beginning of bone healing may help to clarify limited or adverse effects of blood-derived products on bone repair. We emphasize that the recreation of an early hematoma niche with critical compositions might emerge as a viable therapeutic strategy for enhanced skeletal tissue engineering. Copyright © 2017 John Wiley & Sons, Ltd.

An electrospun polydioxanone patch for the localisation of biological therapies during tendon repair.

PubMed

Hakimi, O; Murphy, R; Stachewicz, U; Hislop, S; Carr, A J

2012-10-23

Rotator cuff tendon pathology is thought to account for 30-70 % of all shoulder pain. For cases that have failed conservative treatment, surgical re-attachment of the tendon to the bone with a non-absorbable suture is a common option. However, the failure rate of these repairs is high, estimated at up to 75 %. Studies have shown that in late disease stages the tendon itself is extremely degenerate, with reduced cell numbers and poor matrix organisation. Thus, it has been suggested that adding biological factors such as platelet rich plasma (PRP) and mesenchymal stem cells could improve healing. However, the articular capsule of the glenohumeral joint and the subacromial bursa are large spaces, and injecting beneficial factors into these sites does not ensure localisation to the area of tendon damage. Thus, the aim of this study was to develop a biocompatible patch for improving the healing rates of rotator cuff repairs. The patch will create a confinement around the repair area and will be used to guide injections to the vicinity of the surgical repair. Here, we characterised and tested a preliminary prototype of the patch utilising in vitro tools and primary tendon-derived cells, showing exceptional biocompatibility despite rapid degradation, improved cell attachment and that cells could migrate across the patch towards a chemo-attractant. Finally, we showed the feasibility of detecting the patch using ultrasound and injecting liquid into the confinement ex vivo. There is a potential for using this scaffold in the surgical repair of interfaces such as the tendon insertion in the rotator cuff, in conjunction with beneficial factors.

Analysis of fracture healing in osteopenic bone caused by disuse: experimental study.

PubMed

Paiva, A G; Yanagihara, G R; Macedo, A P; Ramos, J; Issa, J P M; Shimano, A C

2016-03-01

Osteoporosis has become a serious global public health issue. Hence, osteoporotic fracture healing has been investigated in several previous studies because there is still controversy over the effect osteoporosis has on the healing process. The current study aimed to analyze two different periods of bone healing in normal and osteopenic rats. Sixty, 7-week-old female Wistar rats were randomly divided into four groups: unrestricted and immobilized for 2 weeks after osteotomy (OU2), suspended and immobilized for 2 weeks after osteotomy (OS2), unrestricted and immobilized for 6 weeks after osteotomy (OU6), and suspended and immobilized for 6 weeks after osteotomy (OS6). Osteotomy was performed in the middle third of the right tibia 21 days after tail suspension, when the osteopenic condition was already set. The fractured limb was then immobilized by orthosis. Tibias were collected 2 and 6 weeks after osteotomy, and were analyzed by bone densitometry, mechanical testing, and histomorphometry. Bone mineral density values from bony calluses were significantly lower in the 2-week post-osteotomy groups compared with the 6-week post-osteotomy groups (multivariate general linear model analysis, P<0.000). Similarly, the mechanical properties showed that animals had stronger bones 6 weeks after osteotomy compared with 2 weeks after osteotomy (multivariate general linear model analysis, P<0.000). Histomorphometry indicated gradual bone healing. Results showed that osteopenia did not influence the bone healing process, and that time was an independent determinant factor regardless of whether the fracture was osteopenic. This suggests that the body is able to compensate for the negative effects of suspension.

Rabbit Achilles tendon full transection model – wound healing, adhesion formation and biomechanics at 3, 6 and 12 weeks post-surgery

PubMed Central

Meier Bürgisser, Gabriella; Calcagni, Maurizio; Bachmann, Elias; Fessel, Gion; Snedeker, Jess G.; Giovanoli, Pietro

2016-01-01

ABSTRACT After tendon rupture repair, two main problems may occur: re-rupture and adhesion formation. Suitable non-murine animal models are needed to study the healing tendon in terms of biomechanical properties and extent of adhesion formation. In this study 24 New Zealand White rabbits received a full transection of the Achilles tendon 2 cm above the calcaneus, sutured with a 4-strand Becker suture. Post-surgical analysis was performed at 3, 6 and 12 weeks. In the 6-week group, animals received a cast either in a 180 deg stretched position during 6 weeks (adhesion provoking immobilization), or were re-casted with a 150 deg position after 3 weeks (adhesion inhibiting immobilization), while in the other groups (3 and 12 weeks) a 180 deg position cast was applied for 3 weeks. Adhesion extent was analyzed by histology and ultrasound. Histopathological scoring was performed according to a method by Stoll et al. (2011), and the main biomechanical properties were assessed. Histopathological scores increased as a function of time, but did not reach values of healthy tendons after 12 weeks (only around 15 out of 20 points). Adhesion provoking immobilization led to an adhesion extent of 82.7±9.7%, while adhesion inhibiting immobilization led to 31.9±9.8% after 6 weeks. Biomechanical properties increased over time, however, they did not reach full strength nor elastic modulus at 12 weeks post-operation. Furthermore, the rabbit Achilles tendon model can be modulated in terms of adhesion formation to the surrounding tissue. It clearly shows the different healing stages in terms of histopathology and offers a suitable model regarding biomechanics because it exhibits similar biomechanics as the human flexor tendons of the hand. PMID:27635037

The Effect of Cyclooxygenase Inhibition on Tendon-Bone Healing in an In Vitro Coculture Model

PubMed Central

Schwarting, Tim; Pretzsch, Sebastian; Debus, Florian; Ruchholtz, Steffen; Lechler, Philipp

2015-01-01

The effects of cyclooxygenase (COX) inhibition following the reconstruction of the anterior cruciate ligament remain unclear. We examined the effects of selective COX-2 and nonselective COX inhibition on bone-tendon integration in an in vitro model. We measured the dose-dependent effects of ibuprofen and parecoxib on the viability of lipopolysaccharide- (LPS-) stimulated and unstimulated mouse MC3T3-E1 and 3T3 cells, the influence on gene expression at the osteoblast, interface, and fibroblast regions measured by quantitative PCR, and cellular outgrowth assessed on histological sections. Ibuprofen led to a dose-dependent suppression of MC3T3 cell viability, while parecoxib reduced the viability of 3T3 cultures. Exposure to ibuprofen significantly suppressed expression of Alpl (P < 0.01), Bglap (P < 0.001), and Runx2 (P < 0.01), and although parecoxib reduced expression of Alpl (P < 0.001), Fmod (P < 0.001), and Runx2 (P < 0.01), the expression of Bglap was increased (P < 0.01). Microscopic analysis showed a reduction in cellular outgrowth in LPS-stimulated cultures following exposure to ibuprofen and parecoxib. Nonselective COX inhibition and the specific inhibition of COX-2 led to region-specific reductions in markers of calcification and cell viability. We suggest further in vitro and in vivo studies examining the biologic and biomechanical effects of selective and nonselective COX inhibition. PMID:26063979

Bone-to-bone Fixation Enhances Functional Healing of the Porcine Anterior Cruciate Ligament Using a Collagen-Platelet Composite

PubMed Central

Murray, Martha M.; Magarian, Elise; Zurakowski, David; Fleming, Braden C.

2010-01-01

Purpose The purpose of this study was to determine if providing bony stabilization between the tibia and femur would improve the structural properties of an “enhanced” ACL repair using a collagen-platelet composite when compared to the traditional (Marshall) suture technique. Methods Twelve pigs underwent unilateral ACL transection and were treated with sutures connecting the bony femoral ACL attachment site to the distal ACL stump (LIGAMENT group), or to the tibia via a bone tunnel (TIBIA group). A collagen-platelet composite was placed around the sutures to enhance the biologic repair in both groups. Anteroposterior (AP) knee laxity and the graft structural properties were measured after 15 weeks of healing in both the ACL-repaired and contralateral ACL-intact joints. Results Enhanced ACL repair with bone-to-bone fixation significantly improved yield load and linear stiffness of the ACL repairs (p<0.05) after 15 weeks of healing. However, laxity values of the knees were similar in both groups of repaired knees (p>0.10). Conclusions Using an enhanced ACL suture repair technique that includes bone-to-bone fixation to protect the repair in the initial healing stages resulted in an ACL with improved structural properties after 15 weeks in the porcine model. Clinical Relevance The healing response of an ACL suture repair using a collagen-platelet composite can be enhanced by providing bony stabilization between the tibia and femur to protect the graft during the initial healing process in a translational model. PMID:20810092

Correlation of bone defect dimensions with healing outcome one year after apical surgery.

PubMed

von Arx, Thomas; Hänni, Stefan; Jensen, Simon Storgård

2007-09-01

This clinical study prospectively evaluated the healing outcome 1 year after apical surgery in relation to bony crypt dimensions measured intraoperatively. The study cohort included 183 teeth in an equal number of patients. For statistical analysis, results were dichotomized (healed versus non-healed cases). The overall success rate was 83% (healed cases). Healing outcome was not significantly related to the level and height of the facial bone plate. In contrast, a significant difference was found for the mean size of the bony crypt when healed cases (395 mm(3)) were compared with non-healed cases (554 mm(3)). In addition, healed cases had a significantly shorter mean distance (4.30 mm) from the facial bone surface to the root canal (horizontal access) compared with non-healed cases (5.13 mm). With logistic regression, however, the only parameter found to be significantly related to healing outcome was the length of the access window to the bony crypt.

Arthroscopic single-bundle anterior cruciate ligament reconstruction with six-strand hamstring tendon allograft versus bone-patellar tendon-bone allograft.

PubMed

Dai, Chengliang; Wang, Fei; Wang, Xiaomeng; Wang, Ruipeng; Wang, Shengjie; Tang, Shiyu

2016-09-01

The aim of this study was to compare the clinical outcomes of arthroscopic single-bundle anterior cruciate ligament (ACL) reconstruction with six-strand hamstring tendon (HT) allograft versus bone-patellar tendon-bone (BPTB) allograft. The prospective randomized controlled trial was included 129 patients. Sixty-nine patients received reconstruction with six-strand HT allografts (HT group), whereas 60 patients with BPTB allografts (BPTB group). Outcome assessment included re-rupture findings, International Knee Documentation Committee (IKDC) scores, Lysholm scores, KT-1000 arthrometer, Lachman test, pivot-shift test, range of motion (ROM) and single-leg hop test. At a mean follow-up of 52 months, 113 patients (HT group, 61 patients; BPTB group, 52 patients) completed a minimum 4-year follow-up. Four patients in HT group and six in BPTB group experienced ACL re-rupture (6.2 vs. 10.3 %) and received revision surgery. Significant between-group differences were observed in KT-1000 outcomes and pivot-shift test 1 (1.2 ± 1.5 vs. 1.8 ± 1.3, p = 0.025; positive rate 6.5 vs. 18.9 %, p = 0.036), 2 (1.1 ± 1.4 vs. 1.6 ± 1.2, p = 0.044; 8.1 vs. 20.7 %, p = 0.039), 4 (1.1 ± 1.5 vs. 1.7 ± 1.4, p = 0.031; 9.7 vs. 25 %, p = 0.012) years postoperatively. The outcomes between the two groups were comparable in terms of IKDC scores, Lysholm scores, Lachman test, ROM and single-leg hop test. Six-strand HT allograft achieved superior anteroposterior and rotational stability after single-bundle ACL reconstruction. It is a reasonable graft substitute for ACL reconstruction. II.

Effect of microthreads on coronal bone healing of narrow-diameter implants with reverse-tapered design in beagle dogs.

PubMed

Chang, Yun-Young; Kim, Su-Hwan; Park, Keun-Oh; Yun, Jeong-Ho

2017-12-01

The objective of this study was to investigate the effect of microthreads on the coronal bone healing of narrow-diameter implants with reverse-tapered design. A total of 52 implants were classified into two groups according to presence or absence of coronal microthreads, the reverse-tapered narrow-diameter implant (RTN) group, and the reverse-tapered narrow-diameter implant with microthreads (RTNM) group. The implants were installed in split-mouth design in the edentulous mandible of six dogs. Three animals were sacrificed at 4 weeks and three at 8 weeks. Resonance frequency analysis, bone measurement using microcomputed tomography (micro-CT), removal torque test, and histometric analysis were performed. No significant differences in implant stability quotient value were observed between the groups at baseline, 4 weeks, or 8 weeks. Bone measurement using micro-CT showed that bone-implant contact volume (BICV) and bone-implant contact volume ratio (BICVR) in the coronal part of RTNM were statistically higher than those in RTN at 4 and 8 weeks. Histometric analysis showed statistically higher bone-implant contact length (BICL) in the coronal part of RTNM than in RTN at 4 weeks; however, bone-implant contact ratio (BICR) was not significantly different between the groups. At 8 weeks, the BICL and BICR did not differ significantly between the groups. Removal torque test showed no significant differences between the groups at 4 and 8 weeks. The microthreads might facilitate more coronal bone-implant contact due to increased surface areas at an early healing phase; however, they did not significantly affect coronal bone healing at 8 weeks. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Fetal Bovine Dermal Repair Scaffold Used for the Treatment of Difficult-to- Heal Complex Wounds.

PubMed

Strauss, Neil H; Brietstein, Richard J

2012-11-01

 Introduction. Treating difficult-to-heal wounds with complexities, including those with exposed tendon/bone or infection, is a challenge that regularly confronts practitioners in a variety of clinical environments. The purpose of this study was to review the effectiveness of an acellular fetal bovine dermal repair scaffold (PriMatrix Dermal Repair Scaffold, TEI Biosciences, Inc, Boston, MA) used to treat complex difficult-to-heal wounds presenting in the authors' practice. A retrospective chart review was conducted of a single practice with multiple practicing physicians between 2008 and 2010. Over this time period, 70 patients with 83 wounds were treated with the acellular fetal bovine dermis following surgical debridement of the wound. Forty-nine patients (58 wounds) met established inclusion/exclusioncriteria and were critically evaluated. Wounds treated with the acellular fetal bovine dermis included chronic diabetic wounds, venous wounds, and pressure ulcers, as well as wounds caused by trauma and surgery. Additionally, the patients treated had comorbidities commonly associated with recalcitrant wounds. Of the wounds evaluated in this study, 75.9% successfully healed; 63.8% reepithelialized, and 12.1% were closed with a skin graft subsequent to treatment. Notably, the majority (58.6%) of the wounds reepithelialized by 12 weeks following a single application of the dermal repair scaffold. In the subset of challenging wounds with exposed tendon/bone, 80.8% of the wounds were treated successfully (61.5% reepithelialized, and 19.3% were skin grafted), indicating the successful regeneration and reepithelialization of new vascularized tissue by fetal dermal collagen in relatively avascular wound defects. The acellular fetal bovine dermal repair scaffold can be used as part of an effective treatment regimen to heal complex wounds with exposed tendon/bone caused by varying etiologies. The product actively participates in the generation of a new

Healing of extraction sockets filled with BoneCeramic® prior to implant placement: preliminary histological findings.

PubMed

De Coster, Peter; Browaeys, Hilde; De Bruyn, Hugo

2011-03-01

Various grafting materials have been designed to minimize edentulous ridge volume loss following tooth extraction by encouraging new bone formation in healing sockets. BoneCeramic® is a composite of hydroxyapatite and bèta-tricalcium phosphate with pores of 100-500 microns. The aim of this study was to evaluate bone regeneration in healing sockets substituted with BoneCeramic® prior to implant procedures. Fifteen extraction sockets were substituted with BoneCeramic® and 14 sockets were left to heal naturally in 10 patients (mean age 59.6 years). Biopsies were collected only from the implant recipient sites during surgery after healing periods ranging from 6-74 weeks (mean 22). In total, 24 biopsies were available; 10 from substituted and 14 from naturally healed sites. In one site, the implant was not placed intentionally and, in four substituted sites, implant placement had to be postponed due to inappropriate healing, hence from five sites biopsies were not available. Histological sections were examined by transmitted light microscope. At the time of implant surgery, bone at substituted sites was softer than in controls, compromising initial implant stability. New bone formation at substituted sites was consistently poorer than in controls, presenting predominantly loose connective tissue and less woven bone. The use of BoneCeramic® as a grafting material in fresh extraction sockets appears to interfere with normal healing processes of the alveolar bone. On the basis of the present preliminary findings, its indication as a material for bone augmentation, when implant placement is considered within 6-38 weeks after extraction, should be revised. © 2009, Copyright the Authors. Journal Compilation © 2011, Wiley Periodicals, Inc.

Serum leptin, bone mineral density and the healing of long bone fractures in men with spinal cord injury.

PubMed

Wang, Lei; Liu, Linjuan; Pan, Zhanpeng; Zeng, Yanjun

2015-11-16

Previously reported fracture rates in patients with spinal cord injury range from 1% to 20%. However, the exact role of spinal cord injury in bone metabolism has not yet been clarified. In order to investigate the effects of serum leptin and bone mineral density on the healing of long bone fractures in men with spinal cord injury, 15 male SCI patients and 15 matched controls were involved in our study. The outcome indicated that at 4 and 8 weeks after bone fracture, callus production in patients with spinal cord injury was lower than that in controls. Besides, bone mineral density was significantly reduced at 2, 4 and 8 weeks. In addition, it was found that at each time point, patients with spinal cord injury had significantly higher serum leptin levels than controls and no association was found between serum leptin level and bone mineral density of lumbar vertebrae. Moreover, bone mineral density was positively correlated with bone formation in both of the groups. These findings suggest that in early phases i.e. week 4 and 8, fracture healing was impaired in patients with spinal cord injury and that various factors participated in the complicated healing process, such as hormonal and mechanical factors.

Scaffolds in Tendon Tissue Engineering

PubMed Central

Longo, Umile Giuseppe; Lamberti, Alfredo; Petrillo, Stefano; Maffulli, Nicola; Denaro, Vincenzo

2012-01-01

Tissue engineering techniques using novel scaffold materials offer potential alternatives for managing tendon disorders. Tissue engineering strategies to improve tendon repair healing include the use of scaffolds, growth factors, cell seeding, or a combination of these approaches. Scaffolds have been the most common strategy investigated to date. Available scaffolds for tendon repair include both biological scaffolds, obtained from mammalian tissues, and synthetic scaffolds, manufactured from chemical compounds. Preliminary studies support the idea that scaffolds can provide an alternative for tendon augmentation with an enormous therapeutic potential. However, available data are lacking to allow definitive conclusion on the use of scaffolds for tendon augmentation. We review the current basic science and clinical understanding in the field of scaffolds and tissue engineering for tendon repair. PMID:22190961

Rapid and reliable healing of critical size bone defects with genetically modified sheep muscle.

PubMed

Liu, F; Ferreira, E; Porter, R M; Glatt, V; Schinhan, M; Shen, Z; Randolph, M A; Kirker-Head, C A; Wehling, C; Vrahas, M S; Evans, C H; Wells, J W

2015-09-21

Large segmental defects in bone fail to heal and remain a clinical problem. Muscle is highly osteogenic, and preliminary data suggest that autologous muscle tissue expressing bone morphogenetic protein-2 (BMP-2) efficiently heals critical size defects in rats. Translation into possible human clinical trials requires, inter alia, demonstration of efficacy in a large animal, such as the sheep. Scale-up is fraught with numerous biological, anatomical, mechanical and structural variables, which cannot be addressed systematically because of cost and other practical issues. For this reason, we developed a translational model enabling us to isolate the biological question of whether sheep muscle, transduced with adenovirus expressing BMP-2, could heal critical size defects in vivo. Initial experiments in athymic rats noted strong healing in only about one-third of animals because of unexpected immune responses to sheep antigens. For this reason, subsequent experiments were performed with Fischer rats under transient immunosuppression. Such experiments confirmed remarkably rapid and reliable healing of the defects in all rats, with bridging by 2 weeks and remodelling as early as 3-4 weeks, despite BMP-2 production only in nanogram quantities and persisting for only 1-3 weeks. By 8 weeks the healed defects contained well-organised new bone with advanced neo-cortication and abundant marrow. Bone mineral content and mechanical strength were close to normal values. These data demonstrate the utility of this model when adapting this technology for bone healing in sheep, as a prelude to human clinical trials.

Mechanical and structural properties of bone in non-critical and critical healing in rat.

PubMed

Hoerth, Rebecca M; Seidt, Britta M; Shah, Miheer; Schwarz, Carolin; Willie, Bettina M; Duda, Georg N; Fratzl, Peter; Wagermaier, Wolfgang

2014-09-01

A fracture in bone results in a dramatic change of mechanical loading conditions at the site of injury. Usually, bone injuries heal normally but with increasing fracture gaps, healing is retarded, eventually leading to non-unions. The clinical situation of these two processes with different outcomes is well described. However, the exact relation between the mechanical environment and characteristics of the tissues at all levels of structural hierarchy remains unclear. Here we studied the differences in material formation of non-critical (1mm) and critical (5mm gap) healing. We employed a rat osteotomy model to explore bone material structure depending upon the different mechanical conditions. In both cases, primary bone formation was followed by secondary bone deposition with mineral particle sizes changing from on average short and thick to long and thin particles. Bony bridging occurred at first in the endosteal callus and the nanostructure and microstructure developed towards cortical ordered material organization. In contrast, in critical healing, instead of bridging, a marrow cavity closure was formed endosteal, exhibiting tissue structure oriented along the curvature and a periosteal callus with less mature material structure. The two healing processes separated between 4 and 6 weeks post-osteotomy. The outcome of healing was determined by the varied geometrical conditions in critical and non-critical healing, inducing completely different mechanical situations. Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Postinjury biomechanics of Achilles tendon vary by sex and hormone status

PubMed Central

Fryhofer, George W.; Freedman, Benjamin R.; Hillin, Cody D.; Salka, Nabeel S.; Pardes, Adam M.; Weiss, Stephanie N.; Farber, Daniel C.

2016-01-01

Achilles tendon ruptures are common injuries. Sex differences are present in mechanical properties of uninjured Achilles tendon, but it remains unknown if these differences extend to tendon healing. We hypothesized that ovariectomized females (OVX) and males would exhibit inferior postinjury tendon properties compared with females. Male, female, and OVX Sprague-Dawley rats (n = 32/group) underwent acclimation and treadmill training before blunt transection of the Achilles tendon midsubstance. Injured hindlimbs were immobilized for 1 wk, followed by gradual return to activity and assessment of active and passive hindlimb function. Animals were euthanized at 3 or 6 wk postinjury to assess tendon structure, mechanics, and composition. Passive ankle stiffness and range of motion were superior in females at 3 wk; however, by 6 wk, passive and active function were similar in males and females but remained inferior in OVX. At 6 wk, female tendons had greater normalized secant modulus, viscoelastic behavior, and laxity compared with males. Normalized secant modulus, cross-sectional area and tendon glycosaminoglycan composition were inferior in OVX compared with females at 6 wk. Total fatigue cycles until tendon failure were similar among groups. Postinjury muscle fiber size was better preserved in females compared with males, and females had greater collagen III at the tendon injury site compared with males at 6 wk. Despite male and female Achilles tendons withstanding similar durations of fatigue loading, early passive hindlimb function and tendon mechanical properties, including secant modulus, suggest superior healing in females. Ovarian hormone loss was associated with inferior Achilles tendon healing. PMID:27633741

Endoscopy-assisted percutaneous repair of acute Achilles tendon tears.

PubMed

Chiu, Chih-Hao; Yeh, Wen-Lin; Tsai, Min-Chien; Chang, Shih-Sheng; Hsu, Kuo-Yao; Chan, Yi-Sheng

2013-08-01

We developed a technique for endoscopy-assisted percutaneous repair of acute Achilles tendon tears. Nineteen patients with acute Achilles tendon tears were prospectively recruited into the study. All patients (18 male, 1 female) had sports-related injuries. Preoperative diagnosis was made from patient history, physical examination, and sonography. The average patient age was 38.7 years, and follow-up averaged 24 months. All patients received endoscopy-assisted percutaneous Achilles tendon repair with modified Bunnell sutures passed by bird beak and No. 5 Ethibond under direct visualization using 4.0-mm arthroscopy. Results were evaluated by physical examination, sonography, and magnetic resonance imaging (MRI). All 19 patients achieved tendon healing. All patients were evaluated by sonography, and the tendons of 16 patients were imaged using MRI to evaluate the extent of healing. Final dorsiflexion was 16 degrees and plantar flexion 26 degrees, and 95% of the patients (18/19) returned to their previous level of sporting activity. One patient developed a superficial infection, and 2 patients had postoperative sural nerve injury with numbness for 1 month. There were no other major complications. Endoscopy-assisted percutaneous repair of the Achilles tendon allowed good tendon healing and return to sports at 6 months. Sural nerve injury during surgery was a potential complication of this procedure. Level IV, retrospective case series.

Effect of Poloxamer 407 as a carrier vehicle on rotator cuff healing in a rat model

PubMed Central

2014-01-01

Background In vivo studies showing the effects of biologic healing-promoting factors on tendon-to-bone healing after rotator cuff repair have focused only on biologic healing-promoting factors and have not taken into consideration the effect of the carrier vehicle. Moreover, most studies have evaluated the healing process using different carrier vehicles, each of which may have specific effects on tendon healing. This may explain the large variability seen in outcomes in research studies. In this study, we investigated the effects of Poloxamer 407 as a carrier vehicle on rotator cuff healing at the repair site and compared it with those of a collagen sponge, which is a commonly used carrier vehicle. Methods Fifty-seven adult male Sprague–Dawley rats underwent detachment and immediate repair of the bilateral supraspinatus tendons. Rats were randomly assigned to three groups: repair only, repair with collagen sponge, and repair with Poloxamer 407. The repairs were evaluated at 1, 2, 4, and 8 weeks after surgery with histological analysis and biomechanical testing. Results At 4 weeks, more cellular organization, a greater number of collagen fibers, and increased maturity of collagen fibers were observed in the repair with Poloxamer 407 group than in the other groups. The repair with collagen sponge group had delayed development and collagen fiber maturation. Significant differences in the biomechanical properties were found between groups at 4 weeks. Stiffness in the case of the repair with Poloxamer 407 group was significantly higher than that in the repair with collagen sponge group. The modulus was significantly lower in the repair with collagen sponge group than in the repair only group. However, the use of Poloxamer 407 versus the collagen sponge did not significantly affect the biomechanical properties of the repaired tendons at 8 weeks. Conclusions Carrier vehicles may have differing effects at the early stages of rotator cuff healing. The use of

Mechanical induction of critically delayed bone healing in sheep: radiological and biomechanical results.

PubMed

Schell, Hanna; Thompson, Mark S; Bail, Hermann J; Hoffmann, Jan-Erik; Schill, Alexander; Duda, Georg N; Lienau, Jasmin

2008-10-20

This study aimed to mechanically produce a standardized ovine model for a critically delayed bone union. A tibial osteotomy was stabilized with either a rigid (group I) or mechanically critical (group II) external fixator in sheep. Interfragmentary movements and ground reaction forces were monitored throughout the healing period of 9 weeks. After sacrifice at 6 weeks, 9 weeks and 6 months, radiographs were taken and the tibiae were examined mechanically. Interfragmentary movements were considerably larger in group II throughout the healing period. Unlike group I, the operated limb in group II did not return to full weight bearing during the treatment period. Radiographic and mechanical observations showed significantly inferior bone healing in group II at 6 and 9 weeks compared to group I. After 6 months, five sheep treated with the critical fixator showed radiological bridging of the osteotomy, but the biomechanical strength of the repair was still inferior to group I at 9 weeks. The remaining three animals had even developed a hypertrophic non-union. In this study, mechanical instability was employed to induce a critically delayed healing model in sheep. In some cases, this approach even led to the development of a hypertrophic non-union. The mechanical induction of critical bone healing using an external fixation device is a reasonable attempt to investigate the patho-physiological healing cascade without suffering from any biological intervention. Therefore, the presented ovine model provides the basis for a comparative evaluation of mechanisms controlling delayed and standard bone healing.

Fracture bone healing and biodegradation of AZ31 implant in rats.

PubMed

Iglesias, C; Bodelón, O G; Montoya, R; Clemente, C; Garcia-Alonso, M C; Rubio, J C; Escudero, M L

2015-04-17

The ideal temporary implant should offer enough mechanical support to allow healing of the fracture and then biodegrade and be resorbed by metabolic mechanisms without causing any toxic effect. The aim of this research has been to simultaneously study in situ bone healing and the biodegradation of AZ31 Mg alloy as an osteosynthesis material. The in vivo study was carried out in AZ31 implants with and without Mg-fluoride coating inserted in un-fractured and fractured femurs of Wistar rats for long experimentation time, from 1 to 13 months, by means of computed tomography, histological and histomorphometric analysis. Tomography analysis showed the bone healing and biodegradation of AZ31 implants. The fracture is healed in 100% of the animals, and AZ31 maintains its mechanical integrity throughout the healing process. Biodegradation was monitored, quantifying the evolution of gas over time by 3D composition of tomography images. In all the studied groups, gas pockets disappear with time as a result of the diffusion process through soft tissues. Histomorphometric studies reveal that after 13 months the 46.32% of AZ31 alloy has been resorbed. The resorption of the coated and uncoated AZ31 implants inserted in fractured femurs after 1, 9 and 13 months does not have statistically significant differences. There is a balance between the biodegradation of AZ31 and bone healing which allows the use of AZ31 to be proposed as an osteosynthesis material.

Evaluation of bone healing in femurs lengthened via the gradual distraction method.

PubMed

Jochymek, Jiri; Gal, Petr

2007-06-01

Treatment of leg length inequality via lengthening of the shorter extremity is an infrequent orthopedic procedure due to the requirement of special distraction devices and possible serious complications. Essential qualitative changes in operative technique development are associated with the name of G. A. Ilizarov, who paved the way for the autoregenerate gradual distraction method in the 1950s. In the years 1990 through 2006 a total of 57 patients underwent femur lengthening via gradual distraction using various types of external fixators at the Department of Pediatric Surgery, Orthopedics, and Traumatology, Faculty Hospital in Brno. The quality of bone healing was monitored and a number of parameters followed and statistically evaluated using regularly scheduled X-ray examinations. In 11 cases we had to remove the external fixator following the distraction phase, perform an osteosynthesis via a splint and fill the distraction gap via spongioplasty. The bone healing was satisfactory in the remaining 46 patients and the lengthened bone required no other fixation method. The analysis showed statistically significant deceleration in bone healing following distraction in female patients over 12 years of age, and in boys over 14 years of age. Lack of periosteal callus five weeks after surgery always signified serious problems in further healing. Severe complications were recorded in 11 cases during the distraction phase, and in 9 cases after the removal of the distraction apparatus. The aim of this report was to present the results of our study of distraction gap bone healing using the gradual lengthening approach.

Smoking and Bone Healing - A Risky Surgical Combination

MedlinePlus

... Risky Surgical Combination A A A | Print | Share Smoking and Bone Healing – A Risky Surgical Combination Imagine ... saying that they'd prefer patients to quit smoking. There hasn't been a great deal of ...

Present status and future potential of enhancing bone healing using nanotechnology.

PubMed

Stylios, George; Wan, Taoyu; Giannoudis, Peter

2007-03-01

An overview of the current state of tissue engineering material systems used in bone healing is presented. A variety of fabrication processes have been developed that have resulted in porous implant substrates that can address unresolved clinical problems. The merits of these biomaterial systems are evaluated in the context of the mechanical properties and biomedical performances most suitable for bone healing. An optimal scaffold for bone tissue engineering applications should be biocompatible and act as a 3D template for in vitro and in vivo bone growth; in addition, its degradation products should be non-toxic and easily excreted by the body. To achieve these features, scaffolds must consist of an interconnected porous network of micro- and nanoscale to allow extensive body fluid transport through the pores, which will trigger bone ingrowth, cell migration, tissue ingrowth, and eventually vascularization.

[Bone fracture and the healing mechanisms. The role of BMP signaling in fracture healing].

PubMed

Imai, Yuuki; Takaoka, Kunio

2009-05-01

When bone tissue, which plays a central role in locomotive organs, is broken by trauma and decreased in its own function of support, it is lead to be remarkable decline in the activity of daily life (ADL). Recently, in a clinical situation, various treatments have been tried for prophylaxis of fractures, and these treatments have been rewarded with good results. However, fractures would be occurred in a certain amount and there would be serious problems in ADL if the treatment fails to repair fractures. Furthermore, fractures could spontaneously heal in several weeks, it can be achieved in early rehabilitation and improvement of ADL, if we can accelerate fracture healing. Bone morphogenetic proteins, which were advocated by Dr. Urist, would be expected to be a key to establish much better society especially for the old.

The interfascicular matrix enables fascicle sliding and recovery in tendon, and behaves more elastically in energy storing tendons

PubMed Central

Thorpe, Chavaunne T.; Godinho, Marta S.C.; Riley, Graham P.; Birch, Helen L.; Clegg, Peter D.; Screen, Hazel R.C.

2015-01-01

While the predominant function of all tendons is to transfer force from muscle to bone and position the limbs, some tendons additionally function as energy stores, reducing the cost of locomotion. Energy storing tendons experience extremely high strains and need to be able to recoil efficiently for maximum energy storage and return. In the equine forelimb, the energy storing superficial digital flexor tendon (SDFT) has much higher failure strains than the positional common digital extensor tendon (CDET). However, we have previously shown that this is not due to differences in the properties of the SDFT and CDET fascicles (the largest tendon subunits). Instead, there is a greater capacity for interfascicular sliding in the SDFT which facilitates the greater extensions in this particular tendon (Thorpe et al., 2012). In the current study, we exposed fascicles and interfascicular matrix (IFM) from the SDFT and CDET to cyclic loading followed by a test to failure. The results show that IFM mechanical behaviour is not a result of irreversible deformation, but the IFM is able to withstand cyclic loading, and is more elastic in the SDFT than in the CDET. We also assessed the effect of ageing on IFM properties, demonstrating that the IFM is less able to resist repetitive loading as it ages, becoming stiffer with increasing age in the SDFT. These results provide further indications that the IFM is important for efficient function in energy storing tendons, and age-related alterations to the IFM may compromise function and predispose older tendons to injury. PMID:25958330

The interfascicular matrix enables fascicle sliding and recovery in tendon, and behaves more elastically in energy storing tendons.

PubMed

Thorpe, Chavaunne T; Godinho, Marta S C; Riley, Graham P; Birch, Helen L; Clegg, Peter D; Screen, Hazel R C

2015-12-01

While the predominant function of all tendons is to transfer force from muscle to bone and position the limbs, some tendons additionally function as energy stores, reducing the cost of locomotion. Energy storing tendons experience extremely high strains and need to be able to recoil efficiently for maximum energy storage and return. In the equine forelimb, the energy storing superficial digital flexor tendon (SDFT) has much higher failure strains than the positional common digital extensor tendon (CDET). However, we have previously shown that this is not due to differences in the properties of the SDFT and CDET fascicles (the largest tendon subunits). Instead, there is a greater capacity for interfascicular sliding in the SDFT which facilitates the greater extensions in this particular tendon (Thorpe et al., 2012). In the current study, we exposed fascicles and interfascicular matrix (IFM) from the SDFT and CDET to cyclic loading followed by a test to failure. The results show that IFM mechanical behaviour is not a result of irreversible deformation, but the IFM is able to withstand cyclic loading, and is more elastic in the SDFT than in the CDET. We also assessed the effect of ageing on IFM properties, demonstrating that the IFM is less able to resist repetitive loading as it ages, becoming stiffer with increasing age in the SDFT. These results provide further indications that the IFM is important for efficient function in energy storing tendons, and age-related alterations to the IFM may compromise function and predispose older tendons to injury. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

A Concert between Biology and Biomechanics: The Influence of the Mechanical Environment on Bone Healing

PubMed Central

Glatt, Vaida; Evans, Christopher H.; Tetsworth, Kevin

2017-01-01

In order to achieve consistent and predictable fracture healing, a broad spectrum of growth factors are required to interact with one another in a highly organized response. Critically important, the mechanical environment around the fracture site will significantly influence the way bone heals, or if it heals at all. The role of the various biological factors, the timing, and spatial relationship of their introduction, and how the mechanical environment orchestrates this activity, are all crucial aspects to consider. This review will synthesize decades of work and the acquired knowledge that has been used to develop new treatments and technologies for the regeneration and healing of bone. Moreover, it will discuss the current state of the art in experimental and clinical studies concerning the application of these mechano-biological principles to enhance bone healing, by controlling the mechanical environment under which bone regeneration takes place. This includes everything from the basic principles of fracture healing, to the influence of mechanical forces on bone regeneration, and how this knowledge has influenced current clinical practice. Finally, it will examine the efforts now being made for the integration of this research together with the findings of complementary studies in biology, tissue engineering, and regenerative medicine. By bringing together these diverse disciplines in a cohesive manner, the potential exists to enhance fracture healing and ultimately improve clinical outcomes. PMID:28174539

Basic concepts regarding fracture healing and the current options and future directions in managing bone fractures.

PubMed

Bigham-Sadegh, Amin; Oryan, Ahmad

2015-06-01

Fracture healing is a complex physiological process, which involves a well-orchestrated series of biological events. Repair of large bone defects resulting from trauma, tumours, osteitis, delayed unions, non-unions, osteotomies, arthrodesis and multifragmentary fractures is a current challenge of surgeons and investigators. Different therapeutic modalities have been developed to enhance the healing response and fill the bone defects. Different types of growth factors, stem cells, natural grafts (autografts, allografts or xenografts) and biologic- and synthetic-based tissue-engineered scaffolds are some of the examples. Nevertheless, these organic and synthetic materials and therapeutic agents have some significant limitations, and there are still no well-approved treatment modalities to meet all the expected requirements. Bone tissue engineering is a newer option than the traditional grafts and may overcome many limitations of the bone graft. To select an appropriate treatment strategy in achieving a successful and secure healing, more information concerning injuries of bones, their healing process and knowledge of the factors involved are required. The main goals of this work are to present different treatment modalities of the fractured bones and to explain how fractures normally heal and what factors interfere with fracture healing. This study provides an overview of the processes of fracture healing and discusses the current therapeutic strategies that have been claimed to be effective in accelerating fracture healing. © 2014 The Authors. International Wound Journal © 2014 Medicalhelplines.com Inc and John Wiley & Sons Ltd.

Tenogenesis of bone marrow-, adipose-, and tendon-derived stem cells in a dynamic bioreactor.

PubMed

Youngstrom, Daniel W; LaDow, Jade E; Barrett, Jennifer G

2016-11-01

Tendons are frequently damaged and fail to regenerate, leading to pain, loss of function, and reduced quality of life. Mesenchymal stem cells (MSCs) possess clinically useful tissue-regenerative properties and have been exploited for use in tendon tissue engineering and cell therapy. However, MSCs exhibit phenotypic heterogeneity based on the donor tissue used, and the efficacy of cell-based treatment modalities may be improved by optimizing cell source based on relative differentiation capacity. Equine MSCs were isolated from bone marrow (BM), adipose (AD), and tendon (TN), expanded in monolayer prior to seeding on decellularized tendon scaffolds (DTS), and cell-laden constructs were placed in a bioreactor designed to mimic the biophysical environment of the tendon. It was hypothesized that TN MSCs would differentiate toward a tendon cell phenotype better than BM and AD MSCs in response to a conditioning period involving cyclic mechanical stimulation for 1 hour per day at 3% strain and 0.33 Hz. All cell types integrated into DTS adopted an elongated morphology similar to tenocytes, expressed tendon marker genes, and improved tissue mechanical properties after 11 days. TN MSCs expressed the greatest levels of scleraxis, collagen type-I, and cartilage oligomeric matrix protein. Major histocompatibility class-II protein mRNA expression was not detected in any of the MSC types, suggesting low immunogenicity for allogeneic transplantation. The results suggest that TN MSCs are the ideal cell type for regenerative medicine therapies for tendinopathies, exhibiting the most mature tendon-like phenotype in vitro. When TN MSCs are unavailable, BM or AD MSCs may serve as robust alternatives.

Low dose PTH improves metaphyseal bone healing more when muscles are paralyzed.

PubMed

Sandberg, Olof; Macias, Brandon R; Aspenberg, Per

2014-06-01

Stimulation of bone formation by PTH is related to mechanosensitivity. The response to PTH treatment in intact bone could therefore be blunted by unloading. We studied the effects of mechanical loading on the response to PTH treatment in bone healing. Most fractures occur in the metaphyses, therefor we used a model for metaphyseal bone injury. One hind leg of 20 male SD rats was unloaded via intramuscular botulinum toxin injections. Two weeks later, the proximal unloaded tibia had lost 78% of its trabecular contents. At this time-point, the rats received bilateral proximal tibiae screw implants. Ten of the 20 rats were given daily injections of 5 μg/kg PTH (1-34). After two weeks of healing, screw fixation was measured by pull-out, and microCT of the distal femur cancellous compartment was performed. Pull-out force provided an estimate for cancellous bone formation after trauma. PTH more than doubled the pull-out force in the unloaded limbs (from 14 to 30 N), but increased it by less than half in the loaded ones (from 30 to 44 N). In relative terms, PTH had a stronger effect on pull-out force in unloaded bone than in loaded bone (p=0.03). The results suggest that PTH treatment for stimulation of bone healing does not require simultaneous mechanical stimulation. Copyright © 2014 Elsevier Inc. All rights reserved.

Decellularized Tendon Extracellular Matrix—A Valuable Approach for Tendon Reconstruction?

PubMed Central

Schulze-Tanzil, Gundula; Al-Sadi, Onays; Ertel, Wolfgang; Lohan, Anke

2012-01-01

Tendon healing is generally a time-consuming process and often leads to a functionally altered reparative tissue. Using degradable scaffolds for tendon reconstruction still remains a compromise in view of the required high mechanical strength of tendons. Regenerative approaches based on natural decellularized allo- or xenogenic tendon extracellular matrix (ECM) have recently started to attract interest. This ECM combines the advantages of its intrinsic mechanical competence with that of providing tenogenic stimuli for immigrating cells mediated, for example, by the growth factors and other mediators entrapped within the natural ECM. A major restriction for their therapeutic application is the mainly cell-associated immunogenicity of xenogenic or allogenic tissues and, in the case of allogenic tissues, also the risk of disease transmission. A survey of approaches for tendon reconstruction using cell-free tendon ECM is presented here, whereby the problems associated with the decellularization procedures, the success of various recellularization strategies, and the applicable cell types will be thoroughly discussed. Encouraging in vivo results using cell-free ECM, as, for instance, in rabbit models, have already been reported. However, in comparison to native tendon, cells remain mostly inhomogeneously distributed in the reseeded ECM and do not align. Hence, future work should focus on the optimization of tendon ECM decellularization and recolonization strategies to restore tendon functionality. PMID:24710540

Black bone disease in a healing fracture.

PubMed

Thiam, Desmond; Teo, Tse Yean; Malhotra, Rishi; Tan, Kong Bing; Chee, Yu Han

2016-01-28

Black bone disease refers to the hyperpigmentation of bone secondary to prolonged usage of minocycline. We present a report of a 34-year-old man who underwent femoral shaft fracture fixation complicated by deep infection requiring debridement. The implants were removed 10 months later after long-term treatment with minocycline and fracture union. A refracture of the femoral shaft occurred 2 days after implant removal and repeat fixation was required. Intraoperatively, abundant heavily pigmented and dark brown bone callus was noted over the old fracture site. There was no evidence of other bony pathology and the appearance was consistent with minocycline-associated pigmentation. As far as we are aware, this is the first case of black bone disease affecting callus within the interval period of bone healing. We also discuss the relevant literature on black bone disease to bring light on this rare entity that is an unwelcomed surprise to operating orthopaedic surgeons. 2016 BMJ Publishing Group Ltd.

Injectable Reactive Biocomposites For Bone Healing In Critical-Size Rabbit Calvarial Defects

DTIC Science & Technology

2012-03-29

defects (i.e. be conformable), provide temporary protection to the brain until the bone heals, and enhance tissue regeneration with the delivery of...temporary protection to the brain until the bone heals, and enhance tissue regeneration with the delivery of biologics. In this study, we evaluated the...complex defects (i.e. be conformable), harden to provide temporary protection until tissue remodels (i.e. be settable), and enhance tissue regeneration

In Vivo Hypobaric Hypoxia Performed During the Remodeling Process Accelerates Bone Healing in Mice

PubMed Central

Durand, Marjorie; Collombet, Jean-Marc; Frasca, Sophie; Begot, Laurent; Lataillade, Jean-Jacques; Le Bousse-Kerdilès, Marie-Caroline

2014-01-01

We investigated the effects of respiratory hypobaric hypoxia on femoral bone-defect repair in mice because hypoxia is believed to influence both mesenchymal stromal cell (MSC) and hematopoietic stem cell mobilization, a process involved in the bone-healing mechanism. To mimic conditions of non-weight-bearing limb immobilization in patients suffering from bone trauma, our hypoxic mouse model was further subjected to hind-limb unloading. A hole was drilled in the right femur of adult male C57/BL6J mice. Four days after surgery, mice were subjected to hind-limb unloading for 1 week. Seven days after surgery, mice were either housed for 4 days in a hypobaric room (FiO2 at 10%) or kept under normoxic conditions. Unsuspended control mice were housed in either hypobaric or normoxic conditions. Animals were sacrificed on postsurgery day 11 to allow for collection of both contralateral and lesioned femurs, blood, and spleen. As assessed by microtomography, delayed hypoxia enhanced bone-healing efficiency by increasing the closing of the cortical defect and the newly synthesized bone volume in the cavity by +55% and +35%, respectively. Proteome analysis and histomorphometric data suggested that bone-repair improvement likely results from the acceleration of the natural bone-healing process rather than from extended mobilization of MSC-derived osteoprogenitors. Hind-limb unloading had hardly any effect beyond delayed hypoxia-enhanced bone-healing efficiency. PMID:24944208

Comparison of bone healing and outcomes between allogenous bone chip and hydroxyapatite chip grafts in open wedge high tibial osteotomy.

PubMed

Lee, O-Sung; Lee, Kyung Jae; Lee, Yong Seuk

2017-11-03

Allogenous bone chips and hydroxyapatite (HA) chips have been known as good options for filling an inevitable void after open wedge high tibial osteotomy (OWHTO). However, there are concerns regarding bone healing after the use of these grafts. The purpose of this study was to compare the bone healing represented by the osteoconductivity and absorbability between allogenous bone chips and HA chips in OWHTO. The outcomes of bone healing of 53 patients who received an allogenous bone chip graft and 41 patients who received an HA chip graft were retrospectively evaluated, and the results were compared between the two groups. Osteoconductivity and absorbability were serially evaluated for the assessment of bone healing at 6 weeks, 3 months, 6 months, and 1 year postoperatively. The osteoconductivity of the allogenous bone chips was greater than that of the HA chips at 6 weeks postoperatively (p < 0.05). However, there were no statistically significant differences from 3 months to 1 year postoperatively. The absorbability showed no statistically significant differences 6 weeks and 3 months after OWHTO; however, the allogenous bone chip group showed a greater absorbability at 6 months and 1 year postoperatively (42.8 ± 14.2 vs. 34.6 ± 13.8, p = 0.006 at 6 months postoperatively; 54.6 ± 14.4 vs. 43.0 ± 14.0, p < 0.001 at 1 year postoperatively). However, the two graft materials showed similar results of HKA angle, WBL ratio, posterior tibial slope.

High energy focused shock wave therapy accelerates bone healing. A blinded, prospective, randomized canine clinical trial.

PubMed

Kieves, N R; MacKay, C S; Adducci, K; Rao, S; Goh, C; Palmer, R H; Duerr, F M

2015-01-01

To evaluate the influence of shock wave therapy (SWT) on radiographic evidence of bone healing after tibial plateau leveling osteotomy (TPLO). Healthy dogs between two to nine years of age that underwent TPLO were randomly assigned to receive either electro-hydraulic SWT (1,000 shocks) or sham treatment (SHAM). Treatment or SHAM was administered to the osteotomy site immediately postoperatively and two weeks postoperatively. Three blinded radiologists evaluated orthogonal radiographs performed eight weeks postoperatively with both a 5-point and a 10-point bone healing scale. Linear regression analysis was used to compare median healing scores between groups. Forty-two dogs (50 stifles) were included in the statistical analysis. No major complications were observed and all osteotomies healed uneventfully. The median healing scores were significantly higher at eight weeks postoperatively for the SWT group compared to the SHAM group for the 10-point (p <0.0002) and 5-point scoring systems (p <0.0001). Shock wave therapy applied immediately and two weeks postoperatively led to more advanced bone healing at the eight week time point in this study population. The results of this study support the use of electro-hydraulic SWT as a means of accelerating acute bone healing of canine osteotomies. Additional studies are needed to evaluate its use for acceleration of bone healing following fracture, or with delayed union.

Nonsteroidal Anti-Inflammatory Drugs and Bone-Healing: A Systematic Review of Research Quality.

PubMed

Marquez-Lara, Alejandro; Hutchinson, Ian D; Nuñez, Fiesky; Smith, Thomas L; Miller, Anna N

2016-03-15

Nonsteroidal anti-inflammatory drugs (NSAIDs) are often avoided by orthopaedic surgeons because of their possible influence on bone-healing. This belief stems from multiple studies, in particular animal studies, that show delayed bone-healing or nonunions associated with NSAID exposure. The purpose of this review was to critically analyze the quality of published literature that evaluates the impact of NSAIDs on clinical bone-healing. A MEDLINE and Embase search was conducted to identify all articles relating to bone and fracture-healing and the utilization of NSAIDs. All human studies, including review articles, were identified for further analysis. Non-English-language manuscripts and in vitro and animal studies were excluded. A total of twelve clinical articles and twenty-four literature reviews were selected for analysis. The quality of the clinical studies was assessed with a modified Coleman Methodology Score with emphasis on the NSAID utilization. Review articles were analyzed with regard to variability in the cited literature and final conclusions. The mean modified Coleman Methodology Score (and standard deviation) was significantly lower (p = 0.032) in clinical studies that demonstrated a negative effect of NSAIDs on bone-healing (40.0 ± 14.3 points) compared with those that concluded that NSAIDs were safe (58.8 ± 10.3 points). Review articles also demonstrated substantial variability in the number of cited clinical studies and overall conclusions. There were only two meta-analyses and twenty-two narrative reviews. The mean number (and standard deviation) of clinical studies cited was significantly greater (p = 0.008) for reviews that concluded that NSAIDs were safe (8.0 ± 4.8) compared with those that recommended avoiding them (2.1 ± 2.1). Unanimously, all reviews admitted to the need for prospective randomized controlled trials to help clarify the effects of NSAIDs on bone-healing. This systematic literature review highlights the great variability

The Improvement of Bone-Tendon Fixation by Porous Titanium Interference Screw: A Rabbit Animal Model.

PubMed

Tsai, Pei-I; Chen, Chih-Yu; Huang, Shu-Wei; Yang, Kuo-Yi; Lin, Tzu-Hung; Chen, San-Yuan; Sun, Jui-Sheng

2018-05-04

The interference screw is a widely used fixation device in the anterior cruciate ligament (ACL) reconstruction surgeries. Despite the generally satisfactory results, problems of using interference screws were reported. By using additive manufacturing (AM) technology, we developed an innovative titanium alloy (Ti 6 Al 4 V) interference screw with rough surface and inter-connected porous structure designs to improve the bone-tendon fixation. An innovative Ti 6 Al 4 V interference screws were manufactured by AM technology. In vitro mechanical tests were performed to validate its mechanical properties. Twenty-seven New Zealand white rabbits were randomly divided into control and AM screw groups for biomechanical analyses and histological analysis at 4, 8 and 12 weeks postoperatively; while micro-CT analysis was performed at 12 weeks postoperatively. The biomechanical tests showed that the ultimate failure load in the AM interference screw group was significantly higher than that in the control group at all tested periods. These results were also compatible with the findings of micro-CT and histological analyses. In micro-CT analysis, the bone-screw gap was larger in the control group; while for the additive manufactured screw, the screw and bone growth was in close contact. In histological study, the bone-screw gaps were wider in the control group and were almost invisible in the AM screw group. The innovative AM interference screws with surface roughness and inter-connected porous architectures demonstrated better bone-tendon-implant integration, and resulted in stronger biomechanical characteristics when compared to traditional screws. These advantages can be transferred to future interference screw designs to improve their clinical performance. The AM interference screw could improve graft fixation and eventually result in better biomechanical performance of the bone-tendon-screw construct. The innovative AM interference screws can be transferred to future

Bone grafts, bone substitutes and orthobiologics

PubMed Central

Roberts, Timothy T.; Rosenbaum, Andrew J.

2012-01-01

The biology of fracture healing is better understood than ever before, with advancements such as the locking screw leading to more predictable and less eventful osseous healing. However, at times one’s intrinsic biological response, and even concurrent surgical stabilization, is inadequate. In hopes of facilitating osseous union, bone grafts, bone substitutes and orthobiologics are being relied on more than ever before. The osteoinductive, osteoconductive and osteogenic properties of these substrates have been elucidated in the basic science literature and validated in clinical orthopaedic practice. Furthermore, an industry built around these items is more successful and in demand than ever before. This review provides a comprehensive overview of the basic science, clinical utility and economics of bone grafts, bone substitutes and orthobiologics. PMID:23247591

Influence of preoperative musculotendinous junction position on rotator cuff healing using single-row technique.

PubMed

Tashjian, Robert Z; Hung, Man; Burks, Robert T; Greis, Patrick E

2013-11-01

The purpose of this study was to evaluate the correlation of rotator cuff musculotendinous junction (MTJ) retraction with healing after rotator cuff repair and with preoperative sagittal tear size. We reviewed preoperative and postoperative magnetic resonance imaging (MRI) studies of 51 patients undergoing arthroscopic single-row rotator cuff repair between March 1, 2005, and February 20, 2010. Preoperative MRI studies were evaluated for anteroposterior tear size, tendon retraction, tendon length, muscle quality, and MTJ position with respect to the glenoid. The position of the MTJ was referenced off the glenoid face as either lateral or medial. Postoperative MRI studies obtained at a minimum of 1 year postoperatively (mean, 25 ± 13.9 months) were evaluated for healing, tendon length, and MTJ position. We found that 39 of 51 tears (76%) healed, with 26 of 30 small/medium tears (87%) and 13 of 21 large/massive tears (62%) healing. Greater tendon retraction, worse preoperative muscle quality, and a more medialized MTJ were all associated with worse tendon healing (P < .05). Of tears that had a preoperative MTJ lateral to the face of the glenoid, 93% healed, whereas only 55% of tears that had a preoperative MTJ medial to the face of the glenoid healed (P < .05). Healed repairs that had limited tendon lengthening (<1 cm) and limited MTJ position change (<1 cm) from preoperative were found to be smaller, had less preoperative tendon retraction, had less preoperative MTJ medialization, and had less preoperative rotator cuff fatty infiltration (P < .05). Preoperative MTJ medialization, tendon retraction, and muscle quality are all predictive of tendon healing postoperatively when using a single-row rotator cuff repair technique. The position of the MTJ with respect to the glenoid face can be predictive of healing, with over 90% healing if lateral and 50% if medial to the face. Lengthening of the tendon accounts for a significant percentage of the musculotendinous unit

Tendon entheses of the human masticatory muscles.

PubMed

Hems, T; Tillmann, B

2000-09-01

Tendons attach to the limb skeleton via chondral-apophysary or periosteal-diaphysary entheses. It was the aim of the present study to investigate the tendon entheses of the temporal, the masseter, as well as the medial and lateral pterygoid muscles, considering the biomechanics and the mode of osteogenesis at the attachment sites. The origin and insertion zones of the four masticatory muscles were studied histologically and by polarization light microscopy in six halves of human heads. Contrary to the limb skeleton no causal relationship between the histological structure of the tendon entheses and the osteogenic mode of the bone areas involved was observed in the masticatory muscles that were studied. Based on the histological findings, a purely structural classification of the tendon attachments irrespective of the osteogenesis is therefore proposed that is applicable to the entire skeleton. It is possible to distinguish between tendon entheses inserting into periosteum, into bone or into fibrocartilage. Tendon attachments with periosteal insertion are found at the temporal plane, the retromolar triangle, zygomatic arch, lateral pterygoid plate, in the caudal zone of the pterygoid fovea of the neck of mandible as well as major portions of the ramus and angle of the mandible. The attachment zones in which collagen fibrils of tendons insert into the bone via the periosteum correspond in their structure to plane periosteal-diaphysary insertions into the diaphyses of long bones. Attachment zones to the bone are present at the inferior temporal line, the base of the coronoid process, the caudal surface of the zygomatic arch, the cranial zones of the pterygoid fovea of the neck of the mandible as well as at circumscribed areas of the ramus and angle of the mandible. In these zones the collagen fibers of the tendon insert immediately into the bone without any mediation of other tissues. The entheses resemble those of circumscribed periosteal-diaphysary attachments to

Bone Healing in Extraction Sockets Covered With Collagen Membrane Alone or Associated With Porcine-Derived Bone Graft: a Comparative Histological and Histomorphometric Analysis.

PubMed

Guarnieri, Renzo; Testarelli, Luca; Stefanelli, Luigi; De Angelis, Francesca; Mencio, Francesca; Pompa, Giorgio; Di Carlo, Stefano

2017-01-01

The present paper reports data of a randomized study aimed to analyse and compare the histologic and histomorphometric aspects of bone healing in extraction sites covered with collagen membrane alone or associated with porcine-derived bone graft. Thirty patients, with single extraction sockets without severe bone wall defects in the premolar/molar region, were included. Ten extraction sockets were grafted with porcine-derived bone and covered with collagen membrane (group 1), 10 sites were covered with collagen membrane alone (group 2), and 10 sites healed spontaneously (group 3). After 4 months of healing, 26 (8 in group 1, 9 in group 2, and 9 in group 3) bone core specimens were harvested for histologic evaluation, then dental implants were placed. Sites in the group 1 and in the group 2 showed similar histologic and histomorphometric results without significantly differences in the percentage of vital bone (57.43% [SD 4.8] vs. 60.01% [SD 3.2]), and non-mineralized connective tissue 22.99% (SD 5.3) vs. 18.53% (SD 6.2). In group 1 a 16.57% (SD 3.8) of residual material was found. Results showed that the use of collagen membrane alone or associated to porcine-derived bone improves the healing bone process compared to that of extraction sites spontaneously healed. Moreover, histomorphometric data related to bone quality, indicated that extraction sites without severe walls defects and with a vestibular bone thickness > 1.5 mm, treated with a low resorbtion rate collagen membrane alone, do not need more than 4 months for dental implant insertion.

Contribution of methylglyoxal to delayed healing of bone injury in diabetes.

PubMed

Aikawa, Takao; Matsubara, Hidenori; Ugaji, Shuhei; Shirakawa, Junichi; Nagai, Ryoji; Munesue, Seiichi; Harashima, Ai; Yamamoto, Yasuhiko; Tsuchiya, Hiroyuki

2017-07-01

Patients with diabetes are vulnerable to delayed bone fracture healing or pseudoarthrosis. Chronic sustained hyperglycemia, reactive intermediate derivatives of glucose metabolism, such as methylglyoxal (MGO), and advanced glycation end‑products (AGEs) are implicated in diabetic complications. In the present study, it was examined whether MGO is able to cause disturbed bone healing in diabetes. Diabetes was induced in male mice by injection of streptozotocin (50 mg/kg) for 5 days. A bone defect (1.0‑mm diameter) was created in the left distal femur, and bone repair was assessed from an examination of computed tomography scans. ST2 cells were exposed to MGO (0‑400 µM) to investigate osteoblastic differentiation, cell viability, and damage. Consequently, blood glucose and hemoglobin A1c levels in diabetic mice were determined to be 493±14.1 mg/dl and 8.0±0.05%, respectively. Compared with non‑diabetic control mice, diabetic mice exhibited markedly delayed bone healing, with increased levels of the MGO‑derived AGEs, Nε‑(carboxymethyl)‑lysine and Nδ‑(5‑hydro‑5‑methyl‑4‑imidazolone‑2‑yl)‑ornithine, in the sera and femurs. MGO inhibited the osteoblastic differentiation of ST2 cells in a dose‑dependent manner, and markedly decreased cell proliferation through cytotoxicity. In conclusion, MGO has been demonstrated to cause impaired osteoblastic differentiation and delayed bone repair in diabetes. Therefore, detoxification of MGO may be a potentially useful strategy against bone problems in patients with diabetes.

Biologic augmentation of rotator cuff repair with mesenchymal stem cells during arthroscopy improves healing and prevents further tears: a case-controlled study.

PubMed

Hernigou, Philippe; Flouzat Lachaniette, Charles Henri; Delambre, Jerome; Zilber, Sebastien; Duffiet, Pascal; Chevallier, Nathalie; Rouard, Helene

2014-09-01

The purpose of this study was to evaluate the efficiency of biologic augmentation of rotator cuff repair with iliac crest bone marrow-derived mesenchymal stem cells (MSCs). The prevalence of healing and prevention of re-tears were correlated with the number of MSCs received at the tendon-to-bone interface. Forty-five patients in the study group received concentrated bone marrow-derived MSCs as an adjunct to single-row rotator cuff repair at the time of arthroscopy. The average number of MSCs returned to the patient was 51,000 ± 25,000. Outcomes of patients receiving MSCs during their repair were compared to those of a matched control group of 45 patients who did not receive MSCs. All patients underwent imaging studies of the shoulder with iterative ultrasound performed every month from the first postoperative month to the 24th month. The rotator cuff healing or re-tear was confirmed with MRI postoperatively at three and six months, one and two years and at the most recent follow up MRI (minimum ten-year follow-up). Bone marrow-derived MSC injection as an adjunctive therapy during rotator cuff repair enhanced the healing rate and improved the quality of the repaired surface as determined by ultrasound and MRI. Forty-five (100 %) of the 45 repairs with MSC augmentation had healed by six months, versus 30 (67 %) of the 45 repairs without MSC treatment by six months. Bone marrow concentrate (BMC) injection also prevented further ruptures during the next ten years. At the most recent follow-up of ten years, intact rotator cuffs were found in 39 (87 %) of the 45 patients in the MSC-treated group, but just 20 (44 %) of the 45 patients in the control group. The number of transplanted MSCs was determined to be the most relevant to the outcome in the study group, since patients with a loss of tendon integrity at any time up to the ten-year follow-up milestone received fewer MSCs as compared with those who had maintained a successful repair during the same interval. This

Efficacy of bone marrow-stimulating technique in rotator cuff repair.

PubMed

Bilsel, Kerem; Yildiz, Fatih; Kapicioglu, Mehmet; Uzer, Gokcer; Elmadag, Mehmet; Pulatkan, Anil; Esrefoglu, Mukaddes; Bozdag, Ergun; Milano, Giuseppe

2017-08-01

This study used a chronic rotator cuff (RC) tear model to investigate the effect of microfracture as a bone marrow-stimulating (BMS) technique for RC healing. A chronic retracted RC tendon tear model was created bilaterally in the subscapularis tendons of 20 New Zealand rabbits. The tendons were repaired after 8 weeks using a single-row configuration. Tendons in the right shoulder were repaired in standard fashion (control group). Microfractures were performed in the left shoulders before repair (microfracture group). The animals were euthanized 8 and 16 weeks after repair. The repaired tendons were tested biomechanically for their ultimate failure load, linear stiffness, and elongation at failure. Gross and histologic evaluations of the tendon-to-bone healing were evaluated. Macroscopically, subscapularis tendons were attached on the lesser tuberosity. In the microfracture group, collagen fibers were organized in relatively thicker bundles. The mean ultimate failure load of the microfracture group was significantly greater at 8 weeks (148.4 ± 31 N vs. 101.4 ± 26 N, respectively; P = .011) and 16 weeks (155 ± 30 N vs. 114.9 ± 25 N, respectively; P = .017) after repair. There were no significant differences between the groups for linear stiffness at 8 weeks (15.9 ± 2.7 N/mm vs. 15.8 ± 1.3 N/mm, respectively; P = .798) and 16 weeks (16.9 ± 4.3 N/mm vs. 17.1 ± 3.6 N/mm, respectively, P = .848) and elongation at failure at 8 weeks (4.7 ± 1.1 mm vs. 4.7 ± 1.3 mm, respectively; P = .848) and 16 weels (4.8 ± 1.5 mm vs. 4.9 ± 0.9 mm, respectively; P = .749). The microfracture on the tuberosity of the repaired chronic rotator cuff tear promoted dynamic tendon healing with significantly increased ultimate force to failure and with thicker collagen bundles and more fibrocartilage histologically at 8 weeks. Copyright © 2017 Journal of Shoulder and Elbow Surgery Board of

In vitro investigation of a tissue-engineered cell-tendon complex mimicking the transitional architecture at the ligament-bone interface.

PubMed

Wang, Zhibing; Zhang, Yuan; Zhu, Jie; Dong, Shiwu; Jiang, Tao; Zhou, Yue; Zhang, Xia

2015-03-01

Restoration of the transitional ligament-bone interface is critical for graft-bone integration. We postulated that an allogenic scaffold mimicking the fibrogenic, chondrogenic, and osteogenic transition gradients could physiologically promote ligament-bone incorporation. The aim of this study was to construct and characterize a composite tendon scaffold with a continuous and heterogeneous transition region mimicking a native ligament insertion site. Genetically modified heterogeneous cell populations were seeded within specific regions of decellularized rabbit Achilles tendons to fabricate a stratified scaffold containing three biofunctional regions supporting fibrogenesis, chondrogenesis, and osteogenesis. The observed morphology, architecture, cytocompatibility, and biomechanics of the scaffolds demonstrated their improved bio-physico-chemical properties. The formation of the transitional regions was augmented via enhanced delivery of two transcription factors, sex determining region Y-box 9 and runt-related transcription factor 2, which also triggered early up-regulated expression of cartilage- and bone-relevant markers, according to quantitative PCR and immunoblot analyses. Gradient tissue-specific matrix formation was also confirmed within the predesignated regions via histological staining and immunofluorescence assays. These results suggest that a transitional interface could be replicated on an engineered tendon through stratified tissue integration. The scaffold offers the advantages of a multitissue transition involving controlled cellular interactions and matrix heterogeneity, which can be applied for the regeneration of the ligament-bone interface. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Inflamed shoulder tendons (image)

MedlinePlus

Tearing and inflammation of the tendons of the shoulder muscles can occur in sports which require the ... pitching, swimming, and lifting weights. Most often the shoulder will heal if a break is taken from ...

Stem cell-mediated accelerated bone healing observed with in vivo molecular and small animal imaging technologies in a model of skeletal injury.

PubMed

Lee, Sheen-Woo; Padmanabhan, Parasuraman; Ray, Pritha; Gambhir, Sanjiv Sam; Doyle, Timothy; Contag, Christopher; Goodman, Stuart B; Biswal, Sandip

2009-03-01

Adult stem cells are promising therapeutic reagents for skeletal regeneration. We hope to validate by molecular imaging technologies the in vivo life cycle of adipose-derived multipotent cells (ADMCs) in an animal model of skeletal injury. Primary ADMCs were lentivirally transfected with a fusion reporter gene and injected intravenously into mice with bone injury or sham operation. Bioluminescence imaging (BLI), [(18)F]FHBG (9-(fluoro-hydroxy-methyl-butyl-guanine)-micro-PET, [(18)F]Fluoride ion micro-PET and micro-CT were performed to monitor stem cells and their effect. Bioluminescence microscopy and immunohistochemistry were done for histological confirmation. BLI showed ADMC's traffic from the lungs then to the injury site. BLI microscopy and immunohistochemistry confirmed the ADMCs in the bone defect. Micro-CT measurements showed increased bone healing in the cell-injected group compared to the noninjected group at postoperative day 7 (p < 0.05). Systemically administered ADMC's traffic to the site of skeletal injury and facilitate bone healing, as demonstrated by molecular and small animal imaging. Molecular imaging technologies can validate the usage of adult adipose tissue-derived multipotent cells to promote fracture healing. Imaging can in the future help establish therapeutic strategies including dosage and administration route. (c) 2008 Orthopaedic Research Society.

Effect of Electromagnetic Wave on Bone Healing in Fixed and Unfixed Conditions.

PubMed

Onger, Mehmet Emin; Göçer, Hasan; Çirakli, Alper; Büyükceran, Ismail; Kiliç, Mesut; Kaplan, Süleyman

2016-09-01

Mobile phones have come into daily life and are now one of the most frequently used devices for communication. The aim of this study was to evaluate possible effect of electromagnetic wave (EMW) with and without fixation material on bone healing.Forty male rats were exposed to fracture on tibia bone and were randomly divided into 4 groups as E(+)K(+), E(+)K(-), E(-)K(+), and E(-)K(-) where E(+) means EMW exposure and K(+) means Kirschner wire fixation. At the end of study tibia samples were taken from all the groups for the quantitative evaluation of regeneration.Significant difference was found between Group E(+)K(+) and E(-)K(+) in terms of both new bone and capillary volume.Electromagnetic wave may be harmful for bone healing with fixation whereas it has no same effect on bone regeneration without fixation.

Vancomycin-bearing synthetic bone graft delivers rhBMP-2 and promotes healing of critical rat femoral segmental defects.

PubMed

Skelly, Jordan D; Lange, Jeffrey; Filion, Tera M; Li, Xinning; Ayers, David C; Song, Jie

2014-12-01

Bone grafts simultaneously delivering therapeutic proteins and antibiotics may be valuable in orthopaedic trauma care. Previously, we developed a poly(2-hydroxyethyl methacrylate)-nanocrystalline hydroxyapatite (pHEMA-nHA) synthetic bone graft that, when preabsorbed with 400-ng rhBMP-2/7, facilitated the functional repair of critical-size rat femoral defects. Recently, we showed that pHEMA-nHA effectively retains/releases vancomycin and rhBMP-2 in vitro. The success of such a strategy requires that the incorporation of vancomycin does not compromise the structural integrity of the graft nor its ability to promote bone healing. (1) To evaluate the ability of pHEMA-nHA-vancomycin composites in combination with 3-µg rhBMP-2 to repair 5 mm rat femoral segmental defects, and (2) To determine if the encapsulated vancomycin impairs the graft/rhBMP-2-assisted bone repair. pHEMA-nHA-vancomycin, pHEMA-nHA, or collagen sponge control with/without 3-µg rhBMP-2 were press-fit in 5 mm femoral defects in SASCO-SD male rats (289-300 g). Histology, microcomputed tomography, and torsion testing were performed on 8- and 12-week explants to evaluate the extent and quality of repair. The effect of vancomycin on the temporal absorption of endogenous BMP-2 and stromal cell-derived factor-1 was evaluated by immunohistochemistry. These factors are important for bone healing initiation and stem cell recruitment, respectively. Partial bridging of the defect with bony callus by 12 weeks was observed with pHEMA-nHA-vancomycin without rhBMP-2 while full bridging with substantially mineralized callus and partial restoration of torsional strength was achieved with 3-µg rhBMP-2. The presence of vancomycin changed the absorption patterns of endogenous proteins on the grafts, but did not appear to substantially compromise graft healing. The composite pHEMA-nHA-vancomycin preabsorbed with 3-µg rhBMP-2 promoted repair of 5 mm rat femoral segmental defects. With the sample sizes applied

Stability of double-row rotator cuff repair is not adversely affected by scaffold interposition between tendon and bone.

PubMed

Beitzel, Knut; Chowaniec, David M; McCarthy, Mary Beth; Cote, Mark P; Russell, Ryan P; Obopilwe, Elifho; Imhoff, Andreas B; Arciero, Robert A; Mazzocca, Augustus D

2012-05-01

Rotator cuff reconstructions may be improved by adding growth factors, cells, or other biologic factors into the repair zone. This usually requires a biological carrier (scaffold) to be integrated into the construct and placed in the area of tendon-to-bone healing. This needs to be done without affecting the constructs mechanics. Hypothesis/ The hypothesis was that scaffold placement, as an interposition, has no adverse effects on biomechanical properties of double-row rotator cuff repair. The purpose of this study was to examine the effect of scaffold interposition on the initial strength of rotator cuff repairs. Controlled laboratory study. Twenty-five fresh-frozen shoulders (mean age: 65.5 ± 8.9 years) were randomly assigned to 5 groups. Groups were chosen to represent a broad spectrum of commonly used scaffold types: (1) double-row repair without augmentation, (2) double-row repair with interposition of a fibrin clot (Viscogel), (3) double-row repair with interposition of a collagen scaffold (Mucograft) between tendon and bone, (4) double-row repair with interposition of human dermis patch (ArthroFlex) between tendon and bone, and (5) double-row repair with human dermis patch (ArthroFlex) placed on top of the repair. Cyclic loading to measure displacement was performed to 3000 cycles at 1 Hz with an applied 10- to 100-N load. The ultimate load to failure was determined at a rate of 31 mm/min. There were no significant differences in mean displacement under cyclic loading, slope, or energy absorbed to failure between all groups (P = .128, P = .981, P = .105). Ultimate load to failure of repairs that used the collagen patch as an interposition (573.3 ± 75.6 N) and a dermis patch on top of the reconstruction (575.8 ± 22.6 N) was higher compared with the repair without a scaffold (348.9 ± 98.8 N; P = .018 and P = .025). No significant differences were found for repairs with the fibrin clot as an interposition (426.9 ± 103.6 N) and the decellularized dermis

Antibiotic-loaded bone void filler accelerates healing in a femoral condylar rat model.

PubMed

Shiels, S M; Cobb, R R; Bedigrew, K M; Ritter, G; Kirk, J F; Kimbler, A; Finger Baker, I; Wenke, J C

2016-08-01

Demineralised bone matrix (DBM) is rarely used for the local delivery of prophylactic antibiotics. Our aim, in this study, was to show that a graft with a bioactive glass and DBM combination, which is currently available for clinical use, can be loaded with tobramycin and release levels of antibiotic greater than the minimum inhibitory concentration for Staphylococcus aureus without interfering with the bone healing properties of the graft, thus protecting the graft and surrounding tissues from infection. Antibiotic was loaded into a graft and subsequently evaluated for drug elution kinetics and the inhibition of bacterial growth. A rat femoral condylar plug model was used to determine the effect of the graft, loaded with antibiotic, on bone healing. We found that tobramycin loaded into a graft composed of bioglass and DBM eluted antibiotic above the minimum inhibitory concentration for three days in vitro. It was also found that the antibiotic loaded into the graft produced no adverse effects on the bone healing properties of the DBM at a lower level of antibiotic. This antibiotic-loaded bone void filler may represent a promising option for the delivery of local antibiotics in orthopaedic surgery. Cite this article: Bone Joint J 2016;98-B:1126-31. ©2016 The British Editorial Society of Bone & Joint Surgery.

Quadriceps tendon autograft for arthroscopic knee ligament reconstruction: use it now, use it often.

PubMed

Sheean, Andrew J; Musahl, Volker; Slone, Harris S; Xerogeanes, John W; Milinkovic, Danko; Fink, Christian; Hoser, Christian

2018-04-28

Traditional bone-patellar tendon-bone and hamstring tendon ACL grafts are not without limitations. A growing body of anatomic, biomechanical and clinical data has demonstrated the utility of quadriceps tendon autograft in arthroscopic knee ligament reconstruction. The quadriceps tendon autograft provides a robust volume of tissue that can be reliably harvested, mitigating the likelihood of variably sized grafts and obviating the necessity of allograft augmentation. Modern, minimally invasive harvest techniques offer the advantages of low rates of donor site morbidity and residual extensor mechanism strength deficits. New data suggest that quadriceps tendon autograft may possess superior biomechanical characteristics when compared with bone-patella tendon-bone (BPTB) autograft. However, there have been very few direct, prospective comparisons between the clinical outcomes associated with quadriceps tendon autograft and other autograft options (eg, hamstring tendon and bone-patellar tendon-bone). Nevertheless, quadriceps tendon autograft should be one of the primary options in any knee surgeon's armamentarium. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Low level laser therapy in healing tendon

NASA Astrophysics Data System (ADS)

Carvalho, P. T. C.; Batista, Cheila O. C.; Fabíola, C.

2005-11-01

This study aims to verify the effects of AsGa Laser in the scarring of tendon lesion in rats with low nourishment condition and to analyze the ideal light density by means of histopathologic findings highlighted by light microscopy. After the proposed nutritional condition was verified the animals were divided into 3 groups denominated as follows: GI control group, GII laser 1 J/sq.cm. and GIII laser 4 J/sq.cm. The lesions were induced by means of routine surgical process for tendon exposure: There was a crushing process with Allis pincers followed by saturated incision. The data obtained in relation to the amount of macrophage, leukocyte, fibroblast, vessel neoformation, fibrosis and collagen were submitted to parametric statistic procedures of variance analysis and "Tukey" Test and the result obtained was p < 0,05. According to the obtained results it can be concluded that low power laser therapy proved to be efficient in tendon repairing even though the animals suffered from malnutrition as well as the 1 J energy density proved to be more efficient in this case.

In silico Mechano-Chemical Model of Bone Healing for the Regeneration of Critical Defects: The Effect of BMP-2

PubMed Central

2015-01-01

The healing of bone defects is a challenge for both tissue engineering and modern orthopaedics. This problem has been addressed through the study of scaffold constructs combined with mechanoregulatory theories, disregarding the influence of chemical factors and their respective delivery devices. Of the chemical factors involved in the bone healing process, bone morphogenetic protein-2 (BMP-2) has been identified as one of the most powerful osteoinductive proteins. The aim of this work is to develop and validate a mechano-chemical regulatory model to study the effect of BMP-2 on the healing of large bone defects in silico. We first collected a range of quantitative experimental data from the literature concerning the effects of BMP-2 on cellular activity, specifically proliferation, migration, differentiation, maturation and extracellular matrix production. These data were then used to define a model governed by mechano-chemical stimuli to simulate the healing of large bone defects under the following conditions: natural healing, an empty hydrogel implanted in the defect and a hydrogel soaked with BMP-2 implanted in the defect. For the latter condition, successful defect healing was predicted, in agreement with previous in vivo experiments. Further in vivo comparisons showed the potential of the model, which accurately predicted bone tissue formation during healing, bone tissue distribution across the defect and the quantity of bone inside the defect. The proposed mechano-chemical model also estimated the effect of BMP-2 on cells and the evolution of healing in large bone defects. This novel in silico tool provides valuable insight for bone tissue regeneration strategies. PMID:26043112

Healing improvement after rotator cuff repair using gelatin-grafted poly(L-lactide) electrospun fibrous membranes.

PubMed

Zhao, Song; Xie, Xiaoxing; Pan, Guoqing; Shen, Peng; Zhao, Jinzhong; Cui, Wenguo

2015-01-01

Rotator cuff tears (RCTs) are a common cause of shoulder pain and disability in middle and older age. Despite improvements in the understanding of this disease process and advances in surgical treatment, rotator cuff (RC) repair failure rates remain high. Insufficient healing capacity is likely the main factor for failure of reconstruction. We fabricated implantable biodegradable gelatin-grafted poly(L-lactide) (PLLA) fibrous membranes using electrospinning technology and evaluated them using in vitro cell proliferation assays. Then, we established chronic rat RCT models and randomly assigned rats into one of three groups. In group 1 (n = 48), the detached supraspinatus tendon was repaired to its anatomic footprint (transosseous repair). In groups 2 and 3, the rats underwent transosseous repair and were implanted with either pure PLLA membranes (n = 48) or gelatin-PLLA membranes (n = 48) to augment the repairs. The animals were killed at 2, 4, and 8 wk postoperatively, which was followed by histomorphometric and biomechanical evaluation. Histologic observations revealed that gelatin-PLLA membranes have excellent biocompatibility and biodegradability. At 2, 4, and 8 wk postoperatively, the gelatin-PLLA membranes significantly increased the area of glycosaminoglycan staining at the tendon-bone interface compared with the control group (P < 0.05) and significantly improved collagen organization, as measured by birefringence under polarized light at the healing enthesis compared with the control and PLLA groups (P < 0.05). Biomechanical testing revealed that the gelatin-PLLA group had a greater ultimate load to failure and stiffness than the control group at 4 and 8 wk (P < 0.05). The gelatin-PLLA membranes had the highest stress of the healing enthesis. Local application of gelatin-PLLA fibrous membranes to the healing tendon-bone interface after RC repair in a rat chronic RCT model was found to strengthen the healing enthesis, increase the area of

A comparative study of the effects of bromelain and fresh pineapple juice on the early phase of healing in acute crush achilles tendon injury.

PubMed

Aiyegbusi, Ayoola I; Olabiyi, Olaleye O; Duru, Francis I O; Noronha, Cressie C; Okanlawon, Abayomi O

2011-04-01

Bromelain, an enzyme extracted from the stem of the pineapple plant, has been reported to reduce pain and swelling in acute soft tissue injuries, but no study has been done to compare its effect with that of fresh pineapple juice on the healing of acute tendon injuries. This study compared the effects of commercial bromelain and fresh pineapple juice on tenocyte proliferation and the malondialdehyde (MDA) level in the early stage of healing in a crush injury to the Achilles tendon of Sprague-Dawley rats. Twenty-four male rats were divided randomly into three groups of eight rats each; all the rats had induced crush injury to the Achilles tendon: Group 1 (control), no treatment; Group 2, oral bromelain treatment at a dosage of 7 mg/kg of body weight daily; and Group 3, fresh diluted pineapple juice at a dosage of 30 mg/kg of body weight. Treatment was given over the first 14 days post-injury. On day 15 post-injury, the animals were sacrificed, and the tendons were excised and processed for histological study and MDA assay. Results show a significant difference in the tenocyte population between the bromelain group and the control (P < .05), whereas pineapple juice also increased the tenocyte population, although not significantly (P = .36). Pineapple juice, however, significantly lowered the MDA level compared with both the control and bromelain-treated groups. Based on this study, 600 GDU bromelain given at a dosage of 7 mg/kg had a better effect on tenocyte proliferation than fresh pineapple juice given once daily in acute tendon injury.

The structure of the insertions of the tendons of biceps brachii, triceps and brachialis in elderly dissecting room cadavers.

PubMed Central

Benjamin, M; Newell, R L; Evans, E J; Ralphs, J R; Pemberton, D J

1992-01-01

The terminal portions of the tendon of brachialis, and the distal tendons of biceps brachii and triceps, were compared by routine histology. All tendons came from elderly dissecting room cadavers. There were pronounced quantitative differences between the 3 tendons in (1) the thickness of the attachment-zone fibrocartilage, (2) the thickness of cortical calcified tissue, and (3) the percentage of bone to marrow. There was significantly more uncalcified fibrocartilage at the attachment of biceps than at the other sites, reflecting greater range of movement of the tendon at this site. The thickness of cortical calcified tissue and the percentage of bone to marrow were significantly greater at the attachment of brachialis than either biceps or triceps. The large quantities of bone at the attachment of brachialis may be related more to the importance of the coronoid process in buttressing the elbow joint than to any special requirement for large amounts of calcified tissue at the tendon attachment. Near its attachment zone, the biceps tendon splits into superficial and deep laminae that are distinct from the macroscopic subdivision of this tendon. It is suggested that the lamination may facilitate the movements of pronation and supination. In support of this, the deep portion of the superficial lamina contained fibrocartilage where it rubbed against the attachment-zone of the deep lamina. In one body, the fibrocartilage of the biceps attachment-zone was subject to degenerative changes, including cell clumping and matrix fissuring. Images Fig. 2 Fig. 3 PMID:1506288

[Rupture of the Achilles tendon].

PubMed

Ulmar, B; Simon, S; Eschler, A; Mittlmeier, T

2014-10-01

The rupture of the Achilles tendon is the most frequent tendon rupture in humans and it is associated with increasing incidence. The main risk factor is intrinsic degeneration of the tendon. During the rupture the person feels a whiplash or dagger thrust-like pain, followed by restricted walking ability and decreased plantar flexion of the ankle. The positive Simmond/Thompson test and a palpable dent above the tendon rupture are pathognomical. Diagnostically, ultrasound of the tendon and lateral x-ray of the calcaneus (bony pull-out of the tendon insertion) are necessary. Regarding correct indication and treatment modalities, most established conservative and surgical therapies realize optimal functional results. Surgical treatment promises better primary stability and slightly earlier better functional results, but there is the potential for surgical complications. Conservative therapy is associated with higher rates of re-rupture and healing of the tendon under elongation. Therefore, therapy planning in Achilles tendon rupture should be determined based on each patient. We recommend surgical treatment in patients with higher sporting demands and in younger patients (< 50 years).

Nanomedicine for safe healing of bone trauma: Opportunities and challenges

PubMed Central

Behzadi, Shahed; Luther, Gaurav A.; Harris, Mitchel B.; Farokhzad, Omid C.; Mahmoudi, Morteza

2017-01-01

Historically, high-energy extremity injuries resulting in significant soft-tissue trauma and bone loss were often deemed unsalvageable and treated with primary amputation. With improved soft-tissue coverage and nerve repair techniques, these injuries now present new challenges in limb-salvage surgery. High-energy extremity trauma is pre-disposed to delayed or unpredictable bony healing and high rates of infection, depending on the integrity of the soft-tissue envelope. Furthermore, orthopedic trauma surgeons are often faced with the challenge of stabilizing and repairing large bony defects while promoting an optimal environment to prevent infection and aid bony healing. During the last decade, nanomedicine has demonstrated substantial potential in addressing the two major issues intrinsic to orthopedic traumas (i.e., high infection risk and low bony reconstruction) through combatting bacterial infection and accelerating/increasing the effectiveness of the bone-healing process. This review presents an overview and discusses recent challenges and opportunities to address major orthopedic trauma through nanomedical approaches. PMID:28918266

Muscle-bone Interactions During Fracture Healing

DTIC Science & Technology

2015-03-01

stem cells (MSCs). The in- flammatory cells release cytokines such as TNF-α, IL-1, IL- 6, IL-11, and IL-18 to induce osteogenic differentiation of MSCs...Bone, Fracture, Mesenchymal Stem Cells , Paracrine Review Article Hylonome The authors have no conflict of interest. Corresponding author: Melissa...1992;(275):280-6. 16. Mills SJ, Cowin AJ, Kaur P. Pericytes, mesenchymal stem cells and the wound healing process. Cells 2013;2:621-34. 17. Kumar A

Rehabilitation of flexor and extensor tendon injuries in the hand: current updates.

PubMed

Howell, Julianne W; Peck, Fiona

2013-03-01

In recent years, a significant amount of research in the field of tendon injury in the hand has contributed to advances in both surgical and rehabilitation techniques. The introduction of early motion has improved tendon healing, reduced complications, and enhanced final outcomes. There is overwhelming evidence to show that carefully devised rehabilitation programs are critical to achieving favourable outcomes. Whatever the type, or level, of flexor or extensor injury, the ultimate goal of both the surgeon and therapist is to protect the repair, modify peritendinous adhesions, promote optimal tendon excursion and preserve joint motion. Early tendon motion regimens are initiated at surgery or within 5 days post repair. Intra-operative information from the surgeon to the therapist is vital to the choice of splint protected position to reduce repair rupture/gap forces, and to commencement of active, or splint controlled, motion for tendon excursion. Decisions should align with the phases of healing, the clinician's observations, frequent range of motion measurements and patient input. Clinical concepts pertinent to early motion rehabilitation decisions are presented by zone of injury for both flexor and extensor tendons during the early phases of healing. Copyright © 2013. Published by Elsevier Ltd.

Structural and functional assessment of intense therapeutic ultrasound effects on partial Achilles tendon transection

NASA Astrophysics Data System (ADS)

Barton, Jennifer K.; Rice, Photini S.; Howard, Caitlin C.; Koevary, Jen W.; Danford, Forest; Gonzales, David A.; Vande Geest, Jon; Latt, L. Daniel; Szivek, John A.; Amodei, Richard; Slayton, Michael

2018-02-01

Tendinopathies and tendon tears heal slowly because tendons have a limited blood supply. Intense therapeutic ultrasound (ITU) is a treatment modality that creates very small, focal coagula in tissue, which can stimulate a healing response. This pilot study investigated the effects of ITU on rabbit and rat models of partial Achilles tendon rupture. The right Achilles tendons of 20 New Zealand White rabbits and 118 rats were partially transected. Twenty-four hours after surgery, ITU coagula were placed in the tendon and surrounding tissue, alternating right and left legs. At various time points, the following data were collected: ultrasound imaging, optical coherence tomography (OCT) imaging, mechanical testing, gene expression analysis, histology, and multiphoton microscopy (MPM) of sectioned tissue. Ultrasound visualized cuts and treatment lesions. OCT showed the effect of the interventions on birefringence banding caused by collagen organization. MPM showed inflammatory infiltrate, collagen synthesis and organization. By day 14- 28, all tendons had a smooth appearance and histology, MPM and OCT still could still visualize residual healing processes. Few significant results in gene expression were seen, but trends were that ITU treatment caused an initial decrease in growth and collagen gene expression followed by an increase. No difference in failure loads was found between control, cut, and ITU treatment groups, suggesting that sufficient healing had occurred by 14 days to restore all test tissue to control mechanical properties. These results suggest that ITU does not cause harm to tendon tissue. Upregulation of some genes suggests that ITU may increase healing response.

The effect of granulocyte-colony stimulating factor on rotator cuff healing after injury and repair.

PubMed

Ross, David; Maerz, Tristan; Kurdziel, Michael; Hein, Joel; Doshi, Shashin; Bedi, Asheesh; Anderson, Kyle; Baker, Kevin

2015-05-01

The failure rate of tendon-bone healing after repair of rotator cuff tears remains high. A variety of biologic- and cell-based therapies aimed at improving rotator cuff healing have been investigated, and stem cell-based techniques have become increasingly more common. However, most studies have focused on the implantation of exogenous cells, which introduces higher risk and cost. We aimed to improve rotator cuff healing by inducing endogenous stem cell mobilization with systemic administration of granulocyte-colony stimulating factor (G-CSF). We asked: (1) Does G-CSF administration increase local cellularity after acute rotator cuff repair? (2) Is there histologic evidence that G-CSF improved organization at the healing enthesis? (3) Does G-CSF administration improve biomechanical properties of the healing supraspinatus tendon-bone complex? (4) Are there micro-MRI-based observations indicating G-CSF-augmented tendon-bone healing? After creation of full-thickness supraspinatus tendon defects with immediate repair, 52 rats were randomized to control or G-CSF-treated groups. G-CSF was administered for 5 days after repair and rats were euthanized at 12 or 19 postoperative days. Shoulders were subjected to micro-MR imaging, stress relaxation, and load-to-failure as well as blinded histologic and histomorphometric analyses. G-CSF-treated animals had significantly higher cellularity composite scores at 12 and 19 days compared with both control (12 days: 7.40 ± 1.14 [confidence interval {CI}, 5.98-8.81] versus 4.50 ± 0.57 [CI, 3.58-5.41], p = 0.038; 19 days: 8.00 ± 1.00 [CI, 6.75-9.24] versus 5.40 ± 0.89 [CI, 4.28-6.51], p = 0.023) and normal animals (12 days: p = 0.029; 19 days: p = 0.019). There was no significant difference between G-CSF-treated animals or control animals in ultimate stress (MPa) and strain, modulus (MPa), or yield stress (MPa) and strain at either 12 days (p = 1.000, p = 0.104, p = 1.000, p = 0.909, and p = 0.483, respectively) or 19 days (p = 0

Collagen V haploinsufficiency in a murine model of classic Ehlers-Danlos syndrome is associated with deficient structural and mechanical healing in tendons.

PubMed

Johnston, Jessica M; Connizzo, Brianne K; Shetye, Snehal S; Robinson, Kelsey A; Huegel, Julianne; Rodriguez, Ashley B; Sun, Mei; Adams, Sheila M; Birk, David E; Soslowsky, Louis J

2017-12-01

Classic Ehlers-Danlos syndrome (EDS) patients suffer from connective tissue hyperelasticity, joint instability, skin hyperextensibility, tissue fragility, and poor wound healing due to heterozygous mutations in COL5a1 or COL5a2 genes. This study investigated the roles of collagen V in establishing structure and function in uninjured patellar tendons as well as in the injury response using a Col5a1 +/- mouse, a model for classic EDS. These analyses were done comparing tendons from a classic EDS model (Col5a1 +/- ) with wild-type controls. Tendons were subjected to mechanical testing, histological, and fibril analysis before injury as well as 3 and 6 weeks after injury. We found that Col5a1 +/- tendons demonstrated diminished recovery of mechanical competency after injury as compared to normal wild-type tendons, which recovered their pre-injury values by 6 weeks post injury. Additionally, the Col5a1 +/- tendons demonstrated altered fibril morphology and diameter distributions compared to the wild-type tendons. This study indicates that collagen V plays an important role in regulating collagen fibrillogenesis and the associated recovery of mechanical integrity in tendons after injury. In addition, the dysregulation with decreased collagen V expression in EDS is associated with a diminished injury response. The results presented herein have the potential to direct future targeted therapeutics for classic EDS patients. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2707-2715, 2017. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Forces associated with launch into space do not impact bone fracture healing

NASA Astrophysics Data System (ADS)

Childress, Paul; Brinker, Alexander; Gong, Cynthia-May S.; Harris, Jonathan; Olivos, David J.; Rytlewski, Jeffrey D.; Scofield, David C.; Choi, Sungshin Y.; Shirazi-Fard, Yasaman; McKinley, Todd O.; Chu, Tien-Min G.; Conley, Carolynn L.; Chakraborty, Nabarun; Hammamieh, Rasha; Kacena, Melissa A.

2018-02-01

Segmental bone defects (SBDs) secondary to trauma invariably result in a prolonged recovery with an extended period of limited weight bearing on the affected limb. Soldiers sustaining blast injuries and civilians sustaining high energy trauma typify such a clinical scenario. These patients frequently sustain composite injuries with SBDs in concert with extensive soft tissue damage. For soft tissue injury resolution and skeletal reconstruction a patient may experience limited weight bearing for upwards of 6 months. Many small animal investigations have evaluated interventions for SBDs. While providing foundational information regarding the treatment of bone defects, these models do not simulate limited weight bearing conditions after injury. For example, mice ambulate immediately following anesthetic recovery, and in most cases are normally ambulating within 1-3 days post-surgery. Thus, investigations that combine disuse with bone healing may better test novel bone healing strategies. To remove weight bearing, we have designed a SBD rodent healing study in microgravity (μG) on the International Space Station (ISS) for the Rodent Research-4 (RR-4) Mission, which launched February 19, 2017 on SpaceX CRS-10 (Commercial Resupply Services). In preparation for this mission, we conducted an end-to-end mission simulation consisting of surgical infliction of SBD followed by launch simulation and hindlimb unloading (HLU) studies. In brief, a 2 mm defect was created in the femur of 10 week-old C57BL6/J male mice (n = 9-10/group). Three days after surgery, 6 groups of mice were treated as follows: 1) Vivarium Control (maintained continuously in standard cages); 2) Launch Negative Control (placed in the same spaceflight-like hardware as the Launch Positive Control group but were not subjected to launch simulation conditions); 3) Launch Positive Control (placed in spaceflight-like hardware and also subjected to vibration followed by centrifugation); 4) Launch Positive

Forces associated with launch into space do not impact bone fracture healing.

PubMed

Childress, Paul; Brinker, Alexander; Gong, Cynthia-May S; Harris, Jonathan; Olivos, David J; Rytlewski, Jeffrey D; Scofield, David C; Choi, Sungshin Y; Shirazi-Fard, Yasaman; McKinley, Todd O; Chu, Tien-Min G; Conley, Carolynn L; Chakraborty, Nabarun; Hammamieh, Rasha; Kacena, Melissa A

2018-02-01

Segmental bone defects (SBDs) secondary to trauma invariably result in a prolonged recovery with an extended period of limited weight bearing on the affected limb. Soldiers sustaining blast injuries and civilians sustaining high energy trauma typify such a clinical scenario. These patients frequently sustain composite injuries with SBDs in concert with extensive soft tissue damage. For soft tissue injury resolution and skeletal reconstruction a patient may experience limited weight bearing for upwards of 6 months. Many small animal investigations have evaluated interventions for SBDs. While providing foundational information regarding the treatment of bone defects, these models do not simulate limited weight bearing conditions after injury. For example, mice ambulate immediately following anesthetic recovery, and in most cases are normally ambulating within 1-3 days post-surgery. Thus, investigations that combine disuse with bone healing may better test novel bone healing strategies. To remove weight bearing, we have designed a SBD rodent healing study in microgravity (µG) on the International Space Station (ISS) for the Rodent Research-4 (RR-4) Mission, which launched February 19, 2017 on SpaceX CRS-10 (Commercial Resupply Services). In preparation for this mission, we conducted an end-to-end mission simulation consisting of surgical infliction of SBD followed by launch simulation and hindlimb unloading (HLU) studies. In brief, a 2 mm defect was created in the femur of 10 week-old C57BL6/J male mice (n = 9-10/group). Three days after surgery, 6 groups of mice were treated as follows: 1) Vivarium Control (maintained continuously in standard cages); 2) Launch Negative Control (placed in the same spaceflight-like hardware as the Launch Positive Control group but were not subjected to launch simulation conditions); 3) Launch Positive Control (placed in spaceflight-like hardware and also subjected to vibration followed by centrifugation); 4) Launch Positive

Osteogenic effect of a gastric pentadecapeptide, BPC-157, on the healing of segmental bone defect in rabbits: a comparison with bone marrow and autologous cortical bone implantation.

PubMed

Sebecić, B; Nikolić, V; Sikirić, P; Seiwerth, S; Sosa, T; Patrlj, L; Grabarević, Z; Rucman, R; Petek, M; Konjevoda, P; Jadrijević, S; Perović, D; Slaj, M

1999-03-01

Gastrectomy often results in increased likelihood of osteoporosis, metabolic aberration, and risk of fracture, and there is a need for a gastric peptide with osteogenic activity. A novel stomach pentadecapeptide, BPC-157, improves wound and fracture healing in rats in addition to having an angiogenic effect. Therefore, in the present study, using a segmental osteoperiosteal bone defect (0.8 cm, in the middle of the left radius) that remained incompletely healed in all control rabbits for 6 weeks (assessed in 2 week intervals), pentadecapeptide BPC-157 was further studied (either percutaneously given locally [10 microg/kg body weight] into the bone defect, or applied intramuscularly [intermittently, at postoperative days 7, 9, 14, and 16 at 10 microg/kg body weight] or continuously [once per day, postoperative days 7-21 at 10 microg or 10 ng/kg body weight]). For comparison, rabbits percutaneously received locally autologous bone marrow (2 mL, postoperative day 7). As standard treatment, immediately after its formation, the bone defect was filled with an autologous cortical graft. Saline-treated (2 mL intramuscularly [i.m.] and 2 mL locally into the bone defect), injured animals were used as controls. Pentadecapeptide BPC-157 significantly improved the healing of segmental bone defects. For instance, upon radiographic assessment, the callus surface, microphotodensitometry, quantitative histomorphometry (10 microg/kg body weight i.m. for 14 days), or quantitative histomorphometry (10 ng/kg body weight i.m. for 14 days) the effect of pentadecapeptide BPC-157 was shown to correspond to improvement after local application of bone marrow or autologous cortical graft. Moreover, a comparison of the number of animals with unhealed defects (all controls) or healed defects (complete bony continuity across the defect site) showed that besides pentadecapeptide intramuscular application for 14 days (i.e., local application of bone marrow or autologous cortical graft), also

Effect of Adipose-Derived Stromal Cells and BMP12 on Intrasynovial Tendon Repair: A Biomechanical, Biochemical, and Proteomics Study

PubMed Central

Gelberman, Richard H.; Shen, Hua; Kormpakis, Ioannis; Rothrauff, Benjamin; Yang, Guang; Tuan, Rocky S.; Xia, Younan; Sakiyama-Elbert, Shelly; Silva, Matthew J.; Thomopoulos, Stavros

2016-01-01

The outcomes of flexor tendon repair are highly variable. As recent efforts to improve healing have demonstrated promise for growth factor- and cell-based therapies, the objective of the current study was to enhance repair via application of autologous adipose derived stromal cells (ASCs) and the tenogenic growth factor bone morphogenetic protein (BMP) 12. Controlled delivery of cells and growth factor was achieved in a clinically relevant canine model using a nanofiber/fibrin-based scaffold. Control groups consisted of repair-only (no scaffold) and acellular scaffold. Repairs were evaluated after 28 days of healing using biomechanical, biochemical, and proteomics analyses. Range of motion was reduced in the groups that received scaffolds compared to normal. There was no effect of ASC+BMP12 treatment for range of motion or tensile properties outcomes versus repair-only. Biochemical assays demonstrated increased DNA, glycosaminoglycans, and crosslink concentration in all repair groups compared to normal, but no effect of ASC+BMP12. Total collagen was significantly decreased in the acellular scaffold group compared to normal and significantly increased in the ASC+BMP12 group compared to the acellular scaffold group. Proteomics analysis comparing healing tendons to uninjured tendons revealed significant increases in proteins associated with inflammation, stress response, and matrix degradation. Treatment with ASC+BMP12 amplified these unfavorable changes. In summary, the treatment approach used in this study induced a negative inflammatory reaction at the repair site leading to poor healing. Future approaches should consider cell and growth factor delivery methods that do not incite negative local reactions. PMID:26445383

PREVALENCE OF HEALED LONG-BONE FRACTURES IN WILD CARNIVORES FROM THE NORTHEASTERN UNITED STATES.

PubMed

Argyros, George C; Roth, Aaron J

2016-09-01

Museum specimens representing 12 species of terrestrial carnivores from the northeastern United States were inspected for evidence of healed long-bone fractures. Of 413 individuals, 18 (4.4%) exhibited healed fractures. Thirteen (72.2%) occurred in hind limbs; five (27.8%) occurred in forelimbs. Mustelids had the highest prevalence of healed long-bone fractures (38.8%) of all observed fractures. Within family, 5.6% of Canidae and 2.8% of Mustelidae exhibited healed fractures. Bobcats had the highest taxon prevalence of fractures, 18%. Observational data to assess use of and behavior near roads could provide insight to causes of fracture. Capture in combination with noninvasive examination techniques could be employed to determine incidence of healed fractures in wild populations. Individuals with healed fractures could then be tracked via radio telemetry to determine if these animals behave differently than uninjured conspecifics, and assess long-term survivability and fitness.

Osteoimmune Mechanisms of Segmental Bone Fracture Healing and Therapy

DTIC Science & Technology

2016-09-01

to civilians. Despite efforts involving allografts , surgery and fixators, intramedullary nailing and invasive plate fixing to heal segmental...efforts are focused on: tissue engineering approaches aimed at developing osteoconductive scaffolds, better quality synthetic bone grafts, and use of

Experimental study of the effects of helium-neon laser radiation on repair of injured tendon

NASA Astrophysics Data System (ADS)

Xu, Yong-Qing; Li, Zhu-Yi; Weng, Long-Jiang; An, Mei; Li, Kai-Yun; Chen, Shao-Rong; Wang, Jian-Xin; Lu, Yu

1993-03-01

Despite extensive research into the biology of tendon healing, predictably restoring normal function to a digit after a flexor tendon laceration remains one of the most difficult problems facing the hand surgeon. The challenge of simultaneously achieving tendon healing while minimizing the peritendinous scar formation, which limits tendon gliding, has captured the attention of investigators for many years. It has been said that low-power density helium-neon laser radiation had effects on anti-inflammation, detumescence, progressive wound healing, and reducing intestinal adhesions. This experimental study aims at whether helium-neon laser can reduce injured tendon adhesions and improve functional recovery of the injured tendon. Fifty white Leghorn hens were used. Ten were randomly assigned as a normal control group, the other forty were used in the operation. After anesthetizing them with Amytal, a half of the profundus tendons of the second and third foretoes on both sides of the feet were cut. Postoperatively, the hens moved freely in the cages. One side of the toes operated on were randomly chosen as a treatment group, the other side served as an untreated control group. The injured tendon toes in the treatment group were irradiated for twenty minutes daily with a fiber light needle of helium-neon laser therapeutic apparatus (wavelength, 6328 angstroms) at a constant power density of 12.74 mW/cm2, the first exposure taking place 24 hours after the operation. The longest course of treatment was 3 weeks. The control group was not irradiated. At 3 days, 1, 2, 3, and 5 weeks after surgery, 8 hens were sacrificed and their tendons were examined. The experimental results: (1) active, passive flexion and tendon gliding functional recovery were significantly better in the treatment group (p < 0.01); (2) width and thickness of the tendon at the cut site were significantly smaller in the treatment group (p < 0.01); (3) degrees of tendon adhesions were significantly lighter

Effect of platelet-rich plasma and porcine dermal collagen graft augmentation for rotator cuff healing in a rabbit model.

PubMed

Chung, Seok Won; Song, Byung Wook; Kim, Yeun Ho; Park, Kyoung Un; Oh, Joo Han

2013-12-01

The rate of healing failure after surgical repair of chronic rotator cuff tears is considerably high. To verify the effect of platelet-rich plasma (PRP) with and without porcine dermal collagen graft augmentation on tendon-to-bone healing, using the rabbit supraspinatus tendon. Controlled laboratory study. A total of 80 rabbits were randomly allocated into 4 groups (20 rabbits per group: 12 for histological and 8 for mechanical testing): repair (R), repair + patch augmentation (RPa), repair + PRP (RPr), and repair + patch + PRP (RPaPr). The right shoulder was used for experimental interventions, and the left served as a control. Six weeks after the detachment of the supraspinatus, the torn tendon was repaired in a transosseous manner, simulating double-row repair in all groups. Platelet-rich plasma was prepared and applied onto the repair site in the RPr and RPaPr groups, and the patch was used to augment the repair in the RPa and RPaPr groups. The mechanical tensile strength test was performed at 8 weeks after repair and the histological evaluation at 4 and 8 weeks. At 4 weeks, the collagen fibers were poorly organized, and fiber continuity was not established in all groups. However, vascularity and cellularity were higher with granulation tissue formation in the PRP-treated groups (RPr and RPaPr) than the nontreated groups (R and RPa). At 8 weeks, tendon-to-bone integration was much improved with more collagen fibers, and longitudinally oriented collagen fibers were visible in all groups. The PRP-treated groups showed better collagen fiber continuity and orientation than the nontreated groups; however, no distinctive difference was found between the patch-augmented groups (RPa and RPaPr) and nonaugmented groups (R and RPr). The mean load-to-failure results were 61.57 ± 29.99 N, 76.84 ± 16.08 N, 105.35 ± 33.82 N, and 117.93 ± 12.60 N for the R, RPa, RPr, and RPaPr groups, respectively, and they were significantly different between the R and RPr (P = .018), R

Biological enhancement of graft-tunnel healing in anterior cruciate ligament reconstruction

PubMed Central

SACCOMANNO, MARISTELLA F.; CAPASSO, LUIGI; FRESTA, LUCA; MILANO, GIUSEPPE

2016-01-01

The sites where graft healing occurs within the bone tunnel and where the intra-articular ligamentization process takes place are the two most important sites of biological incorporation after anterior cruciate ligament (ACL) reconstruction, since they help to determine the mechanical behavior of the femur-ACL graft-tibia complex. Graft-tunnel healing is a complex process influenced by several factors, such as type of graft, preservation of remnants, bone quality, tunnel length and placement, fixation techniques and mechanical stress. In recent years, numerous experimental and clinical studies have been carried out to evaluate potential strategies designed to enhance and optimize the biological environment of the graft-tunnel interface. Modulation of inflammation, tissue engineering and gene transfer techniques have been applied in order to obtain a direct-type fibrocartilaginous insertion of the ACL graft, similar to that of native ligament, and to accelerate the healing process of tendon grafts within the bone tunnel. Although animal studies have given encouraging results, clinical studies are lacking and their results do not really support the use of the various strategies in clinical practice. Further investigations are therefore needed to optimize delivery techniques, therapeutic concentrations, maintenance of therapeutic effects over time, and to reduce the risk of undesirable effects in clinical practice. PMID:27900311

Delayed Expression of Circulating TGF-β1 and BMP-2 Levels in Human Nonunion Long Bone Fracture Healing.

PubMed

Hara, Yoshiaki; Ghazizadeh, Mohammad; Shimizu, Hajime; Matsumoto, Hisashi; Saito, Nobuyuki; Yagi, Takanori; Mashiko, Kazuki; Mashiko, Kunihiro; Kawai, Makoto; Yokota, Hiroyuki

2017-01-01

The healing process of bone fracture requires a well-controlled multistage and sequential order beginning immediately after the injury. However, complications leading to nonunion exist, creating serious problems and costs for patients. Transforming growth factor-beta 1 (TGF-β1) and bone morphogenic protein 2 (BMP-2) are two major growth factors involved in human bone fracture healing by promoting various stages of bone ossification. In this study, we aimed to determine the role of these factors during the fracture healing of human long bones and assess their impacts on nonunion condition. We performed a comprehensive analysis of plasma TGF-β1 and BMP-2 levels in blood samples from 10 patients with proved nonunion and 10 matched patients with normal union following a predetermined time schedule. The concentrations of TGF-β1 and BMP-2 were measured at each time point using a solid-phase ELISA. TGF-β1 and BMP-2 levels were detectable in all patients. For all patients, a maximal peak for TGF-β1 was found at 3-week. In normal union group, TGF-β1 showed a maximal peak at 2-week while nonunion group had a delayed maximal peak at 3-week. Plasma levels of BMP-2 for all patients and for normal union group reached a maximal peak at 1-week, but nonunion group showed a delayed maximal peak at 2-week. In general, plasma TGF-β1 or BMP-2 level was not significantly different between normal union and nonunion groups. The expression levels of TGF-β1 and BMP-2 appeared to be delayed in nonunion patients which could play an important role in developing an early marker of fracture union condition and facilitate improved patient's management.

SECEC Research Grant 2008 II: Use of platelet- and leucocyte-rich fibrin (L-PRF) does not affect late rotator cuff tendon healing: a prospective randomized controlled study.

PubMed

Zumstein, Matthias A; Rumian, Adam; Thélu, Charles Édouard; Lesbats, Virginie; O'Shea, Kieran; Schaer, Michael; Boileau, Pascal

2016-01-01

Because the retear rate after rotator cuff repairs remains high, methods to improve healing are very much needed. Platelet-rich concentrates have been shown to enhance tenocyte proliferation and promote extracellular matrix synthesis in vitro; however, their clinical benefit remains unclear. We hypothesized that arthroscopic rotator cuff repair with leucocyte- and platelet-rich fibrin (L-PRF) results in better clinical and radiographic outcome at 12 months of follow-up than without L-PRF. Thirty-five patients were randomized to receive arthroscopic rotator cuff repair with L-PRF locally applied to the repair site (L-PRF+ group, n = 17) or without L-PRF (L-PRF- group, n = 18). Preoperative and postoperative clinical evaluation included the Subjective Shoulder Value, visual analog score for pain, Simple Shoulder Test, and Constant-Murley score. The anatomic watertight healing, tendon thickness, and tendon quality was evaluated using magnetic resonance arthrography at 12 months of follow-up. No complications were reported in either group. The mean Subjective Shoulder Value, Simple Shoulder Test, and Constant-Murley scores increased from preoperatively to postoperatively, showing no significant differences between the groups. Complete anatomic watertight healing was found in 11 of 17 in the L-PRF+ group and in 11 of 18 in the L-PRP- group (P = .73). The mean postoperative defect size (214 ± 130 mm(2) in the L-PRF+ group vs 161 ± 149 mm(2) in the L-PRF- group; P = .391) and the mean postoperative tendon quality according to Sugaya (L-PRF+ group: 3.0 ± 1.4, L-PRF- group: 3.0 ± 0.9) were similar in both groups at 12 months of follow-up. Arthroscopic rotator cuff repair with application of L-PRF yields no beneficial effect in clinical outcome, anatomic healing rate, mean postoperative defect size, and tendon quality at 12 months of follow-up. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Arthroscopic repair of the rotator cuff: prospective study of tendon healing after 70 years of age in 145 patients.

PubMed

Flurin, P-H; Hardy, P; Abadie, P; Boileau, P; Collin, P; Deranlot, J; Desmoineaux, P; Duport, M; Essig, J; Godenèche, A; Joudet, T; Kany, J; Sommaire, C; Thelu, C-E; Valenti, P

2013-12-01

The level of activity of patients older than 70 years is tending to increase, as are their expectations in terms of joint function recuperation. It has not been proven that rotator cuff repair healing is satisfactory in the elderly. The main hypothesis of this study was: repair of supraspinous lesions in patients older than 70 years is reliable in terms of both clinical results and healing. The secondary hypothesis was: tendon healing is significantly correlated with the Constant, ASES, and SST scores as well as with age, tendon retraction, and fatty infiltration. Multicenter prospective study on 145 patients older than 70 years, with 135 patients reviewed at 1 year (93%). The mean age was 73.9 years. Full-thickness tears of the supraspinatus extended at most to the upper third of the infraspinatus and retraction limited to Patte stages 1 and 2 were included. Clinical assessment was carried out in accordance with the Constant, ASES, and SST scores. Healing was evaluated with ultrasound. A significant improvement was noted in the Constant (44/76)+31.5 (P<0.0001), ASES (35/90)+54.4 (P<0.0001), and SST (3.5/10)+6.6 (P>0.0001) scores at 1 year of follow-up. The healing rate was 89% with 15 re-tears, nine of which were stage 1 and six stage 2. The clinical result was not correlated with patient age (Constant, P=0.24; ASES, P=0.38; SST, P=0.83) nor with the retraction stage (Constant, P=0.71; ASES, P=0.35; SST, P=0.69) or the stage of fatty infiltration (P>0.7). Healing was correlated with the quality of the clinical result (Constant, P=0.02; ASES, P=0.03) and age (P=0.01) but was not correlated with retraction or the fatty infiltration stage (P>0.3). Arthroscopic repair significantly improves the clinical results, even in patients older than 70 years. The clinical results are not correlated with age (but deterioration of the result was not noted after 75 years) or frontal retraction (but the study only included retractions limited to stages 1 and 2). The healing rate is

Fracture healing using degradable magnesium fixation plates and screws.

PubMed

Chaya, Amy; Yoshizawa, Sayuri; Verdelis, Kostas; Noorani, Sabrina; Costello, Bernard J; Sfeir, Charles

2015-02-01

Internal bone fixation devices made with permanent metals are associated with numerous long-term complications and may require removal. We hypothesized that fixation devices made with degradable magnesium alloys could provide an ideal combination of strength and degradation, facilitating fracture fixation and healing while eliminating the need for implant removal surgery. Fixation plates and screws were machined from 99.9% pure magnesium and compared with titanium devices in a rabbit ulnar fracture model. Magnesium device degradation and the effect on fracture healing and bone formation were assessed after 4 weeks. Fracture healing with magnesium device fixation was compared with that of titanium devices using qualitative histologic analysis and quantitative histomorphometry. Micro-computed tomography showed device degradation after 4 weeks in vivo. In addition, 2-dimensional micro-computed tomography slices and histologic staining showed that magnesium degradation did not inhibit fracture healing or bone formation. Histomorphology showed no difference in bone-bridging fractures fixed with magnesium and titanium devices. Interestingly, abundant new bone was formed around magnesium devices, suggesting a connection between magnesium degradation and bone formation. Our results show potential for magnesium fixation devices in a loaded fracture environment. Furthermore, these results suggest that magnesium fixation devices may enhance fracture healing by encouraging localized new bone formation. Copyright © 2015 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

Uniformly-dispersed nanohydroxapatite-reinforced poly(ε-caprolactone) composite films for tendon tissue engineering application.

PubMed

Tong, Shi Yun; Wang, Zuyong; Lim, Poon Nian; Wang, Wilson; Thian, Eng San

2017-01-01

Regeneration of injuries at tendon-to-bone interface (TBI) remains a challenging issue due to the complex tissue composition involving both soft tendon tissues and relatively hard bone tissues. Tissue engineering using polymeric/ceramic composites has been of great interest to generate scaffolds for tissue's healing at TBI. Herein, we presented a novel method to blend polymers and bioceramics for tendon tissue engineering application. A homogeneous composite comprising of nanohydroxyapatite (nHA) particles in poly(ε-caprolactone) (PCL) matrix was obtained using a combination of solvent and mechanical blending process. X-ray diffraction analysis showed that the as-fabricated PCL/nHA composite film retained phase-pure apatite and semi-crystalline properties of PCL. Infrared spectroscopy spectra confirmed that the PCL/nHA composite film exhibited the characteristics functional groups of PCL and nHA, without alteration to the chemical properties of the composite. The incorporation of nHA resulted in PCL/nHA composite film with improved mechanical properties such as Young's Modulus and ultimate tensile stress, which were comparable to that of the native human rotator tendon. Seeding with human tenocytes, cells attached on the PCL/nHA composite film, and after 14days of culturing, these cells could acquire elongated morphology without induced cytotoxicity. PCL/nHA composite film could also result in increased cell metabolism with prolonged culturing, which was comparable to that of the PCL group and higher than that of the nHA group. All these results demonstrated that the developed technique of combining solvent and mechanical blending could be applied to fabricate composite films with potential for tendon tissue engineering applications. Copyright © 2016 Elsevier B.V. All rights reserved.

Fracture induced mobilization and incorporation of bone marrow-derived endothelial progenitor cells for bone healing.

PubMed

Matsumoto, Tomoyuki; Mifune, Yutaka; Kawamoto, Atsuhiko; Kuroda, Ryosuke; Shoji, Taro; Iwasaki, Hiroto; Suzuki, Takahiro; Oyamada, Akira; Horii, Miki; Yokoyama, Ayumi; Nishimura, Hiromi; Lee, Sang Yang; Miwa, Masahiko; Doita, Minoru; Kurosaka, Masahiro; Asahara, Takayuki

2008-04-01

We recently reported that systemic administration of peripheral blood (PB) CD34+ cells, an endothelial progenitor cell (EPC)-enriched population, contributed to fracture healing via vasculogenesis/angiogenesis. However, pathophysiological role of EPCs in fracture healing process has not been fully clarified. Therefore, we investigated the hypothesis whether mobilization and incorporation of bone marrow (BM)-derived EPCs may play a pivotal role in appropriate fracture healing. Serial examinations of Laser doppler perfusion imaging and histological capillary density revealed that neovascularization activity at the fracture site peaked at day 7 post-fracture, the early phase of endochondral ossifification. Fluorescence-activated cell sorting (FACS) analysis demonstrated that the frequency of BM cKit+Sca1+Lineage- (Lin-) cells and PB Sca1+Lin- cells, which are EPC-enriched fractions, significantly increased post-fracture. The Sca1+ EPC-derived vasuculogenesis at the fracture site was confirmed by double immunohistochemistry for CD31 and Sca1. BM transplantation from transgenic donors expressing LacZ transcriptionally regulated by endothelial cell-specific Tie-2 promoter into wild type also provided direct evidence that EPCs contributing to enhanced neovascularization at the fracture site were specifically derived from BM. Animal model of systemic administration of PB Sca1+Lin- Green Fluorescent Protein (GFP)+ cells further confirmed incorporation of the mobilized EPCs into the fracture site for fracture healing. These findings indicate that fracture may induce mobilization of EPCs from BM to PB and recruitment of the mobilized EPCs into fracture sites, thereby augment neovascularization during the process of bone healing. EPCs may play an essential role in fracture healing by promoting a favorable environment through neovascularization in damaged skeletal tissue. (c) 2008 Wiley-Liss, Inc.

Distinct frequency dependent effects of whole-body vibration on non-fractured bone and fracture healing in mice.

PubMed

Wehrle, Esther; Wehner, Tim; Heilmann, Aline; Bindl, Ronny; Claes, Lutz; Jakob, Franz; Amling, Michael; Ignatius, Anita

2014-08-01

Low-magnitude high-frequency vibration (LMHFV) provokes anabolic effects in non-fractured bone; however, in fracture healing, inconsistent results were reported and optimum vibration conditions remain unidentified. Here, we investigated frequency dependent effects of LMHFV on fracture healing. Twelve-week-old, female C57BL/6 mice received a femur osteotomy stabilized using an external fixator. The mice received whole-body vibrations (20 min/day) with 0.3g peak-to-peak acceleration and a frequency of either 35 or 45 Hz. After 10 and 21 days, the osteotomized femurs and intact bones (contra-lateral femurs, lumbar spine) were evaluated using bending-testing, µ-computed tomography, and histomorphometry. In non-fractured trabecular bone, vibration with 35 Hz significantly increased the relative amount of bone (+28%) and the trabecular number (+29%), whereas cortical bone was not influenced. LMHFV with 45 Hz failed to provoke anabolic effects in trabecular or cortical bone. Fracture healing was not significantly influenced by whole-body vibration with 35 Hz, whereas 45 Hz significantly reduced bone formation (-64%) and flexural rigidity (-34%) of the callus. Although the exact mechanisms remain open, our results suggest that small vibration setting changes could considerably influence LMHFV effects on bone formation in remodeling and repair, and even disrupt fracture healing, implicating caution when treating patients with impaired fracture healing. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Medicarpin, a Natural Pterocarpan, Heals Cortical Bone Defect by Activation of Notch and Wnt Canonical Signaling Pathways

PubMed Central

Gupta, Chandra Prakash; Kureel, Jyoti; Mansoori, Mohd Nizam; Shukla, Priyanka; John, Aijaz A.; Singh, Kavita; Purohit, Dipak; Awasthi, Pallavi; Singh, Divya; Goel, Atul

2015-01-01

We evaluated the bone regeneration and healing effect of Medicarpin (med) in cortical bone defect model that heals by intramembranous ossification. For the study, female Sprague–Dawley rats were ovariectomized and rendered osteopenic. A drill hole injury was generated in mid femoral bones of all the animals. Med treatment was commenced the day after and continued for 15 days. PTH was taken as a reference standard. Fifteen days post-treatment, animals were sacrificed. Bones were collected for histomorphometry studies at the injury site by micro-computed tomography (μCT) and confocal microscopy. RNA and protein was harvested from newly generated bone. For immunohistochemistry, 5μm sections of decalcified femur bone adjoining the drill hole site were cut. By μCT analysis and calcein labeling of newly generated bone it was found that med promotes bone healing and new bone formation at the injury site and was comparable to PTH in many aspects. Med treatment led to increase in the Runx-2 and osteocalcin signals indicating expansion of osteoprogenitors at the injury site as evaluated by qPCR and immunohistochemical localization. It was observed that med promoted bone regeneration by activating canonical Wnt and notch signaling pathway. This was evident by increased transcript and protein levels of Wnt and notch signaling components in the defect region. Finally, we confirmed that med treatment leads to elevated bone healing in pre-osteoblasts by co localization of beta catenin with osteoblast marker alkaline phosphatase. In conclusion, med treatment promotes new bone regeneration and healing at the injury site by activating Wnt/canonical and notch signaling pathways. This study also forms a strong case for evaluation of med in delayed union and non-union fracture cases. PMID:26657206

Medicarpin, a Natural Pterocarpan, Heals Cortical Bone Defect by Activation of Notch and Wnt Canonical Signaling Pathways.

PubMed

Dixit, Manisha; Raghuvanshi, Ashutosh; Gupta, Chandra Prakash; Kureel, Jyoti; Mansoori, Mohd Nizam; Shukla, Priyanka; John, Aijaz A; Singh, Kavita; Purohit, Dipak; Awasthi, Pallavi; Singh, Divya; Goel, Atul

2015-01-01

We evaluated the bone regeneration and healing effect of Medicarpin (med) in cortical bone defect model that heals by intramembranous ossification. For the study, female Sprague-Dawley rats were ovariectomized and rendered osteopenic. A drill hole injury was generated in mid femoral bones of all the animals. Med treatment was commenced the day after and continued for 15 days. PTH was taken as a reference standard. Fifteen days post-treatment, animals were sacrificed. Bones were collected for histomorphometry studies at the injury site by micro-computed tomography (μCT) and confocal microscopy. RNA and protein was harvested from newly generated bone. For immunohistochemistry, 5μm sections of decalcified femur bone adjoining the drill hole site were cut. By μCT analysis and calcein labeling of newly generated bone it was found that med promotes bone healing and new bone formation at the injury site and was comparable to PTH in many aspects. Med treatment led to increase in the Runx-2 and osteocalcin signals indicating expansion of osteoprogenitors at the injury site as evaluated by qPCR and immunohistochemical localization. It was observed that med promoted bone regeneration by activating canonical Wnt and notch signaling pathway. This was evident by increased transcript and protein levels of Wnt and notch signaling components in the defect region. Finally, we confirmed that med treatment leads to elevated bone healing in pre-osteoblasts by co localization of beta catenin with osteoblast marker alkaline phosphatase. In conclusion, med treatment promotes new bone regeneration and healing at the injury site by activating Wnt/canonical and notch signaling pathways. This study also forms a strong case for evaluation of med in delayed union and non-union fracture cases.