Flexor Tendon Healing Research Articles

Gene expression of Postn and FGF7 in canine chordae tendineae and their effects on flexor tenocyte biology.

Chordae tendineae, referred to as heart tendinous cords, act as tendons connecting the papillary muscles to the valves in the heart. Their role is analogous to tendons in the musculoskeletal system. Despite being exposed to millions of cyclic tensile stretches over a human's lifetime, chordae tendineae rarely suffer from overuse injuries. On the other hand, musculoskeletal tendinopathy is very common and remains challenging in clinical treatment. The objective of this study was to investigate the mechanism behind the remarkable durability and resistance to overuse injuries of chordae tendineae, as well as to explore their effects on flexor tenocyte biology. The messenger RNAexpression profiles of chordae tendineae were analyzed using RNA sequencing and verified by quantitative reverse transcription polymerase chain reaction and immunohistochemistry. Interestingly, we found that periostin (Postn) and fibroblast growth factor 7 (FGF7) were expressed at significantly higher levels in chordae tendineae, compared to flexor tendons. We further treated flexor tenocytes in vitro with periostin and FGF7 to examine their effects on the proliferation, migration, apoptosis, and tendon-related gene expression of flexor tenocytes. The results displayed enhanced cell proliferation ability at an early stage and an antiapoptotic effect on tenocytes, while treated with periostin and/or FGF7 proteins. Furthermore, there was a trend of promoted tenocyte migration capability. These findings indicated that Postn and FGF7 may represent novel cytokines to target flexor tendon healing. Clinical significance: The preliminary discovery leads to a novel idea for treating tendinopathy in the musculoskeletal system using specific molecules identified from chordae tendineae.

The effects of NF-κB suppression on the early healing response following intrasynovial tendon repair in a canine model.

The highly variable clinical outcomes noted after intrasynovial tendon repair have been associated with an early inflammatory response leading to the development of fibrovascular adhesions. Prior efforts to broadly suppress this inflammatory response have been largely unsuccessful. Recent studies have shown that selective inhibition ofIkappaB kinase beta(IKK-β), an upstream activator ofnuclear factor kappa-light chain enhancer of activated B cells(NF-κB) signaling, mitigates the early inflammatory response and leads to improved tendon healing outcomes. In the current study, we test the hypothesis that oral treatment with the IKK-β inhibitor ACHP (2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-piperidin-4-yl nicotinenitrile an inhibitor) will modulate the postoperative inflammatory response and improve intrasynovial flexor tendon healing. To test this hypothesis, the flexor digitorum profundus tendon of 21 canines was transected and repaired within the intrasynovial region and assessed after 3 and 14 days. Histomorphometry, gene expression analyses, immunohistochemistry, and quantitative polarized light imagingwere used to examine ACHP-mediated changes. ACHP led to reduction in phosphorylated p-65, indicating that NF-κB activity was suppressed. ACHP enhanced expression of inflammation-related genes at 3 days and suppressed expression of these genes at 14 days. Histomorphometry revealed enhanced cellular proliferation and neovascularization in ACHP-treated tendons compared with time-matched controls. These findings demonstrate that ACHP effectively suppressed NF-κB signaling and modulated early inflammation, leading to increased cellular proliferation and neovascularization without stimulating the formation of fibrovascular adhesions. Together, these data suggest that ACHP treatment accelerated the inflammatory and proliferative phases of tendon healing following intrasynovial flexor tendon repair. Clinical Significance: Using a clinically relevant large-animal model, this study revealed that targeted inhibition of nuclear factor kappa-light chain enhancer of activated B cellssignaling with ACHP provides a new therapeutic strategy for enhancing the repair of sutured intrasynovial tendons.

Rebalancing SMAD7/SMAD3 Signaling Reduces Adhesion Formation during Flexor Tendon Healing.

Transforming growth factor-β is a key factor in regulating adhesion formation during tendon healing. We investigated the effectiveness of SMAD family members, SMAD7 and SMAD3, in the TGF-β/Smad signaling during flexor tendon repair. Mouse flexor toe deep tendon rupture anastomosis models were made. On days 3, 7, 14, 21, and 28, the expressions of smad7 and smad3 in flexor tendon tissues were detected by RT-qPCR and western blot. Furthermore, postoperative intraperitoneal injections of SMAD7 agonists or SMAD3 antagonists were given. The degree of tendon healing was evaluated by adhesion testing and biomechanical experiments. Hematoxylin and eosin (HE) staining was used to observe the pathological changes. Immunohistochemistry was used to evaluate the expressions of collagen III, SMAD3, and SMAD7. The mRNA levels of matrix metalloproteinases, Mmp2 and Mmp9, and scleraxis (SCX) in flexor tendon tissue were detected by RT-qPCR. Smad3 expression increased and Smad7 expression decreased in flexor tendon tissue after injury. In addition, the SMAD7 agonist blocked SMAD3 phosphorylation. SMAD7 agonist and SMAD3 antagonist both improved adhesion formation during flexor tendon healing, and decreased the expressions of collagen III, Mmp9, and SCX, while increasing Mmp2 expression. This study provides a possible theoretical basis for the SMAD7-SMAD3 signal cascade during flexor tendon adhesion healing.

The influence of a nanoparticle gel loaded with siRNA-cyclooxygenase on flexor tendon healing: an in vivo animal study.

We investigated the influence of cyclooxygenase (COX)-1 and COX-2 siRNAs delivered through a nanoparticle-gel system on the strength of flexor tendon repairs. Sixteen flexor digitorum profundus (FDP) tendons of chicken toes were transected, repaired and wrapped with gels to evaluate gel adherence. We found that the gel adhered to the tendon surface firmly. Next, 56 tendons were used in a first set of in vivo experiments to compare the therapeutic effects of different doses of COX siRNAs. Another 15 tendons were added in a second set to further assess the effects of a dosage of 12 μg. After 4 weeks, the mean strength of the repaired tendons increased most notably in the toes treated with 12 μg COX siRNAs, and the number of samples with low strength (<35 N) was significantly smaller than in the group without molecular treatment. We conclude that COX-1 and COX-2 siRNAs delivered through a nanoparticle-gel system increased the healing strength of the repaired tendons.

Characterization of scar tissue biomechanics during adult murine flexor tendon healing

Tendon injuries are very common and result in significant impairments in mobility and quality of life. During healing, tendons produce a scar at the injury site, characterized by abundant and disorganized extracellular matrix and by permanent deficits in mechanical integrity compared to healthy tendon. Although a significant amount of work has been done to understand the healing process of tendons and to develop potential therapeutics for tendon regeneration, there is still a significant gap in terms of assessing the direct effects of therapeutics on the functional and material quality specifically of the scar tissue, and thus, on the overall tendon healing process. In this study, we focused on characterizing the mechanical properties of only the scar tissue in flexor digitorum longus (FDL) tendons during the proliferative and early remodeling healing phases and comparing these properties with the mechanical properties of the composite healing tissue. Our method was sensitive enough to identify significant differences in structural and material properties between the scar and tendon-scar composite tissues. To account for possible inaccuracies due to the small aspect ratio of scar tissue, we also applied inverse finite element analysis (iFEA) to compute mechanical properties based on simulated tests with accurate specimen geometries and boundary conditions. We found that the scar tissue linear tangent moduli calculated from iFEA were not significantly different from those calculated experimentally at all healing timepoints, validating our experimental findings, and suggesting the assumptions in our experimental calculations were accurate. Taken together, this study first demonstrates that due to the presence of uninjured stubs, testing composite healing tendons without isolating the scar tissue overestimates the material properties of the scar itself. Second, our scar isolation method promises to enable more direct assessment of how different treatment regimens (e.g., cellular ablation, biomechanical and/or biochemical stimuli, tissue engineered scaffolds) affect scar tissue function and material quality in multiple different types of tendons.

The use of connective tissue growth factor mimics for flexor tendon repair.

Intrasynovial flexor tendon lacerations of the hand are clinically problematic, typically requiring operative repair and extensive rehabilitation. The small-molecule connective tissue growth factor (CTGF) mimics, oxotremorine M (Oxo-M) and 4-PPBP maleate (4-PPBP), have been shown to improve tendon healing in small animal models by stimulating the expansion and differentiation of perivascular CD146+ cells. To enhance intrasynovial flexor tendon healing, small-molecule CTGF mimics were delivered to repaired canine flexor tendons via porous sutures. In vitro studies demonstrated that Oxo-M and 4-PPBP retained their bioactivity and could be released from porous sutures in a sustained manner. However, in vivo delivery of the CTGF mimics did not improve intrasynovial tendon healing. Histologic analyses and expression of tenogenic, extracellular matrix, inflammation, and remodeling genes showed similar outcomes in treated and untreated repairs across two time points. Although in vitro experiments revealed that CTGF mimics stimulated robust responses in extrasynovial tendon cells, there was no response in intrasynovial tendon cells, explaining the lack of in vivo effects. The results of the current study indicate that therapeutic strategies for tendon repair must carefully consider the environment and cellular makeup of the particular tendon for improving the healing response.

TGF-\u03b23 regulates adhesion formation through the JNK/c-Jun pathway during flexor tendon healing

BackgroundThe injured flexor tendon has poor healing ability, which is easy to cause tendon adhesion. It can affect the recovery of tendon function, which is still a long-term and difficult task for surgeons. Transforming growth factor β (TGF-β) has been widely considered to play an important role in flexor tendon repair in recent years.AimThis work was to investigate the anti-adhesion and anti-inflammatory effects of TGF-β3 on flexor digitorum longus (FDL) tendon repair rats.MethodAnastomosis models of tendon laceration in the flexion toes of rats were delivered with no treatment, vehicle, or TGF-β3 -overexpressed adenovirus vector (ad-TGF-β3) locally to the injured tendon area from day 3 to 8. Subsequently, the expression of TGF-β3, TGF-β1/2, Smad3, Smad7, JNK, phosphorylation (p)-JNK, c-Jun, and phosphorylation (p)-c-Jun were detected by western blot, the expression of Mmp9 and Mmp2 by RT-qPCR, the Range of motion (ROM) and gliding resistance by adhesion formation testing, the mechanical strength of tendon healing by biomechanical testing, the pathologic changes of flexor tendon tissues by HE staining, the expression of collagen type III by immunohistochemical staining, and the levels of IL-6, TNF-α, COX2 and IL-1β in serum by ELISA, respectively.ResultsRat models treated with no treatment showed a lower elevation of TGF-β3 and Smad7 expression, and a higher elevation of TGF-β1/2 and Smad3 expression, during day 14 to day 28. Besides, under the treatment of ad-TGF-β3, a significantly increase was reflected in the expression of TGF-β3 and Smad7, ROM, as well as mechanical strength of flexor tendon, whereas significantly reduction was shown in gliding resistance, the content of inflammatory cytokines, the ratio of p-JNK/JNK, p-c-Jun/c-Jun, as well as the expression of TGF-β1/2, Smad3, Mmp9, and Mmp2 genes, as compared to those from vehicle treatment. Meanwhile, TGF-β3 demonstrated a better pathologic recovery process with no obvious necrosis or fracture of collagen fibers. Besides, TGF-β3 revealed a significant reduction of collagen type-III expression in the flexor tendon healing tissues.ConclusionThese findings suggested that TGF-β3 effectively protected against flexor tendon injury via regulating adhesion formation.

Sustained-Release Hydrogel-Based Rhynchophylline Delivery System Improved Injured Tendon Repair

During the injured flexor tendon healing process, tendon tissue is easy to form extremely dense adhesion with the surrounding tissue, which causes the serious influence of hand function recovery. Uncaria is widely used in clinic and its main composition, Rhynchophylline (Rhy), has been reported on its good therapeutic effect, which could effectively inhibit the intra-abdominal adhesion formation. However, the therapeutic effect of Rhy on tendon healing and adhesion formation is still unclear. Due to the short half-life of Rhy, hyaluronic acid (HA) sustained-release system for Rhy delivery was constructed and it could also avoid drug from the undesired loss during the transit. After Rhy delivery system was applied around the injured tendons, adhesion formation, gliding function and healing strength of tendons were evaluated. Our results showed that the gliding excursion and healing strength of repaired tendons were both significantly increased, as well as the adhesion was inhibited. From in vivo experiments, Rhy could be able to increase the expression of Col Ⅰ/Col Ⅲ and helped fibroblasts to ordered organization for tendon tissues. But for adhesion tissues, Rhy promoted the apoptosis and accelerated the degradation of extracellular matrix. In vitro study showed Rhy could help tenocytes stimulated with TGF-β1 to recover to normal cell functions involving cell proliferation and apoptosis level. Through high-throughput sequencing, we found that Rhy was involved in the regulation of Extracellular Matrix (ECM) signaling pathway. We draw a conclusion that Rhy enhanced the tendon healing and prevented adhesion formation through inhibiting the phosphorylation of Smad2. In a word, this sustained release system of Rhy may be a promising strategy for the treatment of injured tendons.

Flexor Tendon Injury and Repair. The Influence of Synovial Environment on the Early Healing Response in a Canine Model.

Environmental conditions strongly influence the healing capacity of connective tissues. Well-vascularized extrasynovial tendons typically undergo a robust wound-healing process following transection and repair. In contrast, avascular intrasynovial tendons do not mount an effective repair response. The current study tests the hypothesis that flexor tendons, as a function of their synovial environment, exhibit unique inflammatory, angiogenic, and metabolic responses to injury and repair. Flexor tendons present a distinct opportunity to test the study hypothesis, as they have proximal regions that are extrasynovial and distal regions that are intrasynovial. In an internally controlled study design, the second and fifth forepaw flexor tendons were transected and repaired in either the extrasynovial or the intrasynovial anatomical region. Histological, gene expression, and proteomics analyses were performed at 3 and 7 days to define the early biological events that drive synovial environment-dependent healing responses. Uninjured intrasynovial tendons were avascular, contained high levels of proteoglycans, and expressed inflammatory factors, complement proteins, and glycolytic enzymes. In contrast, extrasynovial tendons were well vascularized, contained low levels of proteoglycans, and were enriched in inflammation inhibitors and oxidative phosphorylation enzymes. The response to injury and repair was markedly different between the 2 tendon regions. Extrasynovial tendons displayed a robust and rapid neovascularization response, increased expression levels of complement proteins, and an acute shift in metabolism to glycolysis, whereas intrasynovial tendons showed minimal vascularity and muted inflammatory and metabolic responses. The regional molecular profiles of intact and healing flexor tendons revealed extensive early differences in innate immune response, metabolism, vascularization, and expression of extracellular matrix as a function of the synovial environment. These differences reveal mechanisms through which extrasynovial tendons heal more effectively than do intrasynovial tendons. To improve outcomes after operative repair, future treatment strategies should promote features of extrasynovial healing, such as enhanced vascularization and modulation of the complement system and/or glucose metabolism.

Characterization of Scar Tissue Biomechanics During Adult Murine Flexor Tendon Healing

Characterization of Scar Tissue Biomechanics During Adult Murine Flexor Tendon Healing

Nanoparticle-Coated Sutures Providing Sustained Growth Factor Delivery to Improve the Healing Strengths of Injured Tendons

Tendon injuries are more common, and due to the lack of adequate growth factors, the healing capacity of the injured tendon is limited. The objective of this study is to evaluate the effectiveness of Nanoparticle-coated sutures carrying growth factors on accelerating tendon repair. We found that nanoparticles can adhere uniformly to the surface of the suture modified with polydopamine. After stitching, the nanoparticles remain on the surface of the suture, and its loaded proteins can spread in the tendon tissues. After treatment, in the chicken flexor tendon healing model and the rat Achilles healing model, the ultimate strengths of repaired tendons treated with bFGF and VEGFA-releasing sutures was significantly greater than the tendons repaired with control sutures at multiple time-points. At 6 weeks, adhesion scores in the bFGF and VEGFA-releasing suture group were significantly smaller than those of the control suture group. Tendon gliding excursions were significantly greater in the bFGF and VEGFA-releasing suture group than in the unmodified control sutures. Work of digital flexion was significantly decreased in the bFGF and VEGFA-releasing suture group than in the control group. In a word, we developed a novel platform for local and sustained delivery of growth factors based on the Nanoparticle-coated sutures, which can effectively deliver growth factors to tissues and control the release of growth factors. Dual growth factors loaded Nanoparticle-coated sutures can significantly promote tendon healing. This growth factors delivery system is an attractive therapeutic tool to repair injured tendons.

Histopathological and Biomechanical Survey on Effect of CoQ10 in Combination with Chitosan Conduit on Deep Digital Flexor Tendon Healing in Rabbits

Objective- Chitosan is of great interest in regenerative medicine because of its plentiful properties, like biocompatibility, biodegradability and non-toxicity. The objective of the present study was histopathological and biomechanical survey on effect of CoQ10 in combination with chitosan conduit on deep digital flexor tendon (DDFT) healing in rabbits. Design- Experimental Study Animals- Eighteen healthy male white New Zealand rabbits Procedures- The animals were randomized into three groups of 6 animals each. In Controlgroup the DDF tenotomy was performed and the stumps were sutured. In Chitosan group the DDF tenotomy was performed and the stumps were sutured and chitosan conduit was wrapped around the damaged area. In Chit-CoQ10 group the procedure was the same as Chitosan group as well as local administration of 100 µL CoQ10 (100 µg/rabbit) into the Chitosan conduit. The histopathological assessments including inflammation, angiogenesis and collagen fibers arrangement, and biomechanical assessments were performed after 8 weeks. Results- Histopathological observations showed that the conduit was absorbed and adhesion around the tendon was deceased in Chitosan and Chit-CoQ10 groups. The biomechanical parameters showed significant improvement in Chit-CoQ10 group (p < 0.05). There were no noticeable signs of infection and tissue reaction in the granulation tissue in Chit-CoQ10 group compared to other groups (p < 0.05). Conclusion and Clinical Relevance- Local administration of CoQ10 in combination with chitosan conduit could accelerate deep digital flexor tendon healing via decrease in adhesion around the tendon with no signs of excessive tissue reaction or infection in rabbits.

The Effect of Mesenchymal Stem Cell Sheets on Early Healing of the Achilles Tendon in Rats.

Bone marrow-derived mesenchymal stem cells (BMSCs) have potential to accelerate flexor tendon healing and allow for earlier rehabilitation. The ideal BMSC construct and delivery method to the repair site remains unknown. We investigated the efficacy of interposed scaffold-free BMSC sheets on early Achilles tendon healing in rats. BMSCs were isolated from the femora and tibias of male Sprague-Dawley rats aged 8-12 weeks and BMSC sheets were produced on temperature-responsive culture dishes. Ninety-five male Sprague-Dawley rats aged 8-12 weeks were utilized. A bilateral Achilles tendon repair model was created. One side was randomly selected, and the tendon was repaired with the interposed BMSC sheet (BMSC group). The other side was repaired without BMSCs (control group). The bilateral tendons were harvested at 5, 6, 7, 10, and 14 days postoperatively for biomechanical analysis, measurement of the gene expression level of tendon markers scleraxis and tenomodulin by real-time polymerase chain reaction, and histological evaluation. The BMSC group had significantly higher maximum load to failure and stiffness at 5 and 6 days compared with the control group. Moreover, the BMSC group showed significantly increased gene expression of scleraxis and/or tenomodulin at all timepoints. The cross sectional areas in the BMSC group were significantly larger at 5, 6, and 14 days. However, hematoxylin and eosin staining of the central part of the repair site revealed no significant differences at all timepoints. These results suggest that the increased biomechanical strength afforded by BMSC sheet implantation into tendon repair sites may allow for the earlier onset of rehabilitation and improved clinical outcomes in flexor tendon surgery. Impact Statement We investigated the efficacy of interposed bone marrow-derived mesenchymal stem cell (BMSC) sheets on early Achilles tendon healing in rats. The tendons repaired with BMSC sheets revealed significantly increased mechanical strength compared with the control repairs (without the BMSC sheet) at 5 and 6 days. These data reveal that BMSC sheet implantation into tendon repair sites may allow for earlier onset of rehabilitation and improved clinical outcomes in flexor tendon surgery.

Gene-Loaded Nanoparticle-Coated Sutures Provide Effective Gene Delivery to Enhance Tendon Healing.

How to accelerate tendon healing remains a clinical challenge. In this study, a suture carrying nanoparticle/pEGFP-basic fibroblast growth factor (bFGF) and pEGFP-vascular endothelial growth factor A (VEGFA) complexes was developed to transfer the growth factor genes into injured tendon tissues to promote healing. Polydopamine-modified sutures can uniformly and tightly absorb nanoparticle/plasmid complexes. After tendon tissues were sutured, the nanoparticle/plasmid complexes still existed on the suture surface. Further, we found that the nanoparticle/plasmid complexes delivered into tendon tissues could diffuse from sutures to tendon tissues and effectively transfect genes into tendon cells, significantly increasing the expression of growth factors in tendon tissues. Finally, biomechanical tests showed that nanoparticle/pEGFP-bFGF and pEGFP-VEGFA complex-coated sutures could significantly increase the ultimate strengths of repaired tendons, especially at 4weeks after operation. Two kinds of nanoparticle/plasmid complex-coated sutures significantly increased flexor tendon healing strength by 3.7 times for Ethilon and 5.8 times for PDS II, respectively, compared with the corresponding unmodified sutures. In the flexor tendon injury model, at 6weeks after surgery, compared with the control suture, the nanoparticle/plasmid complex-coated sutures can significantly increase the gliding excursions of the tendon and inhibit the formation of adhesion. These results indicate that this nanoparticle/plasmid complex-coated suture is a promising tool for the treatment of injured tendons.

Lesão do tendão flexor: sutura na região avascular ou vascularizada? Estudo biomecânico e histopatológico em coelhos

Objectives The present study aims to analyze the mechanical and histopathological aspects of flexor tendon healing focusing on the suture placement site in a vascular or in an avascular region. Methods A total of 83 rabbits were submitted to a Kessler-type central suture in the vascularized tendon region (TN group) and in the avascular tendon region (FC group). The operated limb was immobilized for 3 weeks. The animals were sacrificed in the immediate postoperative period, and at 2, 3 and 6 weeks after the procedure. The mechanical properties studied were: maximum load, stress at maximum load, modulus of elasticity, energy at maximum load, and energy per area. The contralateral tendon was used as control. The histopathological study was descriptive. Results The analysis of the mechanical properties showed similar behavior in both groups, with stabilization or discrete increased values between the immediate period and 3 weeks after the procedure, and marked increased values at 6 weeks. Histopathology demonstrated that the healing process was similar in the TN and FC groups. Conclusion Central suture placement in the vascularized or avascular fibrocartilaginous region results in no differences in the biomechanical and histopathological aspects of flexor tendon healing in rabbits.

Grafting with double-layered polypropylene mesh for gap healing of mid-metacarpal superficial digital flexor tendon in Equus asinus: clinical and pathological evaluations

Tendon injury is one of the most common causes of wastage in equine. The superficial digital flexor tendon (SDFT) gets affected the most, especially in the mid-metacarpal region. Several studies have focused on the grafting of severed SDFT, but no ideal grafting material has been approved for clinical application. The present study aimed to evaluate the grafting of the mid-metacarpal SDFT in donkeys with a double-layered polypropylene mesh clinically, ultrasonically, macro/microscopically. Clinically healthy adult donkeys (n = 24) were divided randomly and equally into two groups: control (C) and study (S) groups. Tenotomy was performed on all animals by excising a full-thickness segment from the mid-metacarpal SDFT. In the C group, a suture tenorrhaphy was performed. While in the S group, SDFT was grafted with the double-layered polypropylene mesh. The S group showed faster clinical improvements, and earlier appearance of normal newly formed tendinous tissue ultrasonically compared with the C group. Macroscopically, the grafted tendons showed a rapid restoration of normal color and consistency. Moreover, they had minimal peri-tendinous adhesions compared with the non-grafted tendons. Microscopically, the grafted tendons showed earlier vascularization and more mature collagen fibers compared with the non-grafted tendons. In the present study, we have succeeded to graft the gap of the mid-metacarpal SDFT of a donkey using the double-layered polypropylene mesh. This method is an economical way to accelerate the healing process of the SDFT and enhance the clinical recovery in donkeys.

The effect of adipose-derived stem cell sheets and CTGF on early flexor tendon healing in a canine model

Intrasynovial tendon injuries are among the most challenging in orthopedics. Despite significant improvements in operative and rehabilitation methods, functional outcomes continue to be limited by adhesions, gap formation, and rupture. Adhesions result from excessive inflammation, whereas tendon gapping and rupture result from inflammation-induced matrix degradation and insufficient regeneration. Therefore, this study used a combined treatment approach to modulate inflammation with adipose-derived mesenchymal stromal cells (ASCs) while stimulating tendon regeneration with connective tissue growth factor (CTGF). ASCs were applied to the repair surface via cell sheets and CTGF was delivered to the repair center via porous sutures. The effect of the combined treatment was assessed fourteen days after repair in a canine flexor tendon injury model. CTGF, either alone or with ASCs, reduced inflammatory (IL1B and IL6) and matrix degrading (MMP3 and MMP13) gene expression, while increasing anti-inflammatory gene (IL4) expression and collagen synthesis compared to control repairs. The combined treatment was more effective than CTGF treatment alone, reducing the inflammatory IFNG and scar-associated COL3A1 gene expression and increasing CD146+ tendon stem/progenitor cells at the tendon surface and interior along the core suture tracks. Therefore, the combined approach is promising in promoting early flexor tendon healing and worthy of further investigation.

The effects of bi-functional anti-adhesion scaffolds on flexor tendon healing in a rabbit model.

Progressive tendon adhesion is a major challenge in flexor tendon repair. The authors developed a bifunctional anti-adhesion scaffold and hypothesized that its application would reduce adhesion formation and deliver mesenchymal stem cells (MSCs) to enhance tendon healing. The scaffold was fabricated by an electrospinning machine before surface modification. The flexor tendons of 29 New Zealand rabbits underwent surgical repair and randomized to control, scaffold and scaffold loaded with MSC group. At 3 and 8 weeks post-surgery, range of motion (ROM), biomechanical properties, and histology were examined. There was no significant increase in ROM and biomechanical properties between the three groups. The histology showed successful delivery of MSCs but no significant difference in nuclear morphometry. This barrier delivers and retains MSCs within the tendon repair site. However, its sheet form and wrapping around the repair site may not be optimal for tendon healing. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2605-2614, 2018.

Therapeutic strategies for flexor tendon healing by nanoparticle-mediated co-delivery of bFGF and VEGFA genes.

Tendon injuries are a common injury of musculocutaneous system. Due to the lack of sufficient cellularity and low growth factor activity, healing of disrupted digital flexor tendon is troublesome and the process is lengthy and ineffective. bFGF and VEGFA gene were proved to be responsible and critical for promoting tendon healing. How to continuously enhance expression of these genes is a challenge. In this study, we developed a combination therapeutic approach that corrects the fundamental problem underlying intrasynovial tendon healing with introduction of growth factor genes via non-viral vector nanoparticle. PLGA nanoparticles as vehicle were used to delivery bFGF+VEGFA genes into injured tendon tissues. The expression of bFGF and VEGFA was upregulated in the tenocytes after transfection. We injected nanoparticle/bFGF+VEGFA gene complexes into injured tendons producing sufficient amounts of these factors required during early tendon healing period. After treatment, the ultimate strength of repaired tendons treated with nanoparticle/bFGF+VEGFA plasmid complexes was significantly increased, and combination therapy could also enhance flexor tendon gliding function. Therefore, combination gene therapy via nanoparticles may be an effective biological strategy for tendon repair.

The Effects of Autologous Platelet-Rich Fibrin on Flexor Tendon Healing in a Rabbit Model

Platelet-rich plasma containing large amounts of growth factors is purported to increase repaired flexor tendon strength. However, the use of bovine thrombin has the risk of antibody formation. We evaluated the effects of the newer generation autologous platelet-rich fibrin (PRF) on flexor tendon healing. We performed surgical repair of 32 flexor tendons from the index and ring digits of the hind paws of 8 New Zealand white rabbits. In the PRF group, the PRF membrane was either wrapped around or interposed between the repair sites. At 3 weeks after surgery, the tested tendons were subjected to range of motion analysis, cross-sectional area measurement, biomechanics testing, and histological analysis. The results showed no significant increase in range of motion in the PRF group compared with the control group, but there was a significant increase in cross-sectional area of the tendons in the PRF group. The biomechanical testing suggested that the control had a higher load to failure and stress to failure but similar stiffness and modulus to the PRF group. The PRF did not have a major influence on cellular organization. It also had an undesirable effect on the biomechanical properties of repaired flexor tendons. The findings of this study suggest PRF may, in certain situations, hinder rather than enhance, the healing for repaired flexor tendons.