Anterior cruciate ligament reconstruction (ACLR) is a commonly performed procedure in Orthopaedic sports medicine. With advances in surgical techniques providing better positioning and fixation of the graft, subsequent graft failure to certain extent should be accounted by poor graft healing. Although different biological modulations for enhancement of graft healing have been tried in different clinical and animal studies, complete graft incorporation into bone tunnels and the "ligamentization" of the intra-articular part have not been fully achieved yet. Based on the understanding of graft healing process and its failure mechanism, the purpose of this review is to combine both the known basic science & clinical evidence, to provide a much clearer picture of the obstacle encountered in graft healing, so as to facilitate researchers on subsequent work on the enhancement of ACL graft healing.

BACKGROUND AND OBJECTIVE:Restoring the shoulder function is a crucial demand of patients with rotator cuff (RC) tears. Most preclinical studies only focused on biological and mechanical measurements. Functional assessment was less investigated in the preclinical studies. This study aims to review the literature of shoulder function in animal models for RC tears and evaluate the strengths and weaknesses of different shoulder functional assessments and animal models. METHOD:A literature search for studies used RC tear animal models to evaluate changes in shoulder function was performed. We searched databases of PubMed, Embase, Web of Science, and Scopus from inception to September 2019. Animal species, functional parameters, injury and repair types, and study durations were summarised. Cluster analyses were then used to separate animal models with different levels of injury and timings of repair. The reliability and clinical relevance of the included assessments and animal models were then discussed. RESULTS:Fourteen animal studies that related to shoulder function in animal models of RC tears were reviewed. Five methods (gait analysis, passive range of motion test, open field test, staircase test, and running endurance test) to assess shoulder function were identified. Single or massive RC tendon tears and immediate or delayed RC repair models were found. We reported and discussed factors to be considered when researchers would select assessments and animal models for different study purposes. CONCLUSION:Based on current evidences, gait analysis is the most appropriate method to assess changes in shoulder function of animal models of RC tears. More studies are required to further elucidate the reliability of passive range of motion measurement, open field test, staircase test, and running endurance test. Models that use massive tears and delayed repair better represent the clinical condition found in humans. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE:Using more clinically relevant animal models and assessments for shoulder function identified in this review may help to investigate the value of preclinical researches and promote translation of preclinical interventions into clinical practices.

Background/Objective: The treatment of anterior cruciate ligament (ACL) partial tear is controversial. The reconstructive surgery is invasive while the prevalence of subsequent insufficiency after conservative treatment has been reported to range from 11% to 62%. Therefore, a new method that promotes tissue regeneration is needed. The aim of this study was to observe the healing of ACL partial tear biomechanically and histologically after the administration of a thermosensitive hydrogel platelet-rich-plasma (PRP) complex. Methods: The complex was prepared according to a previously published protocol. One hundred and fifty 12-week-old male Sprague-Dawley rats were included and they were allocated into 4 groups. Lesion control group (Group 1), treatment group (Group 2), gel-only group (Group 3) and intact group (Group 4). Biomechanical testing, histological analysis (H&E and immunohistochemical staining) and scoring was performed. Results: On gross observation, the treatment group showed a continuous ACL with slightly thickened synovium or a partially healed ACL at 6-week follow up. In the biomechanical testing at 6 weeks after surgery, the failure load of the treatment group was significantly superior when compared with the lesion control group (52.7±10.8N vs. 41.6±7.8N, p<0.01), but the failure load was not restored to level of the intact group (52.7±10.8N vs. 61.5±9.1N, p=0.037). The maturity index of wound sites showed no significant inter-group differences at any timepoints. However, an increased expression of vascular endothelial growth factor (VEGF) and pro-collagen I was detected. Conclusion: The thermosensitive hydrogel-PRP was shown to be effective in enhancing the healing of ACL partial tear in the rat model, and potentially this complex can be used as a treatment for patients with ACL partial tear. The translational potential of this article: The thermosensitive hydrogel-PRP is potentially translated to clinical use to treat patients with ACL partial tear by injection under arthroscopy or ultrasound guiding.

Background This article systematically reviews the current evidence regarding inflammation in Tendinopathy with the aim to increase understanding of a potential common pathophysiology. Methods Following the PRISMA statements, the terms: (tendinopathy OR (tendons AND rupture)) AND (inflammation OR (inflammation AND cells) OR immune system OR inflammation mediators OR bacteria) were used. One thousand four hundred thirty-one articles were identified which was screened down to 53. Results 39/53 studies mentioned inflammatory cells but had contradicting conclusions. Macrophages were the most common cell type and inflammatory markers were detectable in all the articles which measure them. Conclusions The included studies show different conclusions, but this heterogeneity is not unexpected since the clinical criteria of ‘tendinopathy’ encompass a huge clinical spectrum. Different ‘tendinopathy’ conditions may have different pathophysiology, and even the same clinical condition may be at different disease stages during sampling, which can alter the histological and biochemical picture. Control specimen sampling was suboptimal since the healthy areas of the pathological-tendon may actually be sub-clinically diseased, as could the contralateral tendon in the same subject. Detection of inflammatory cells is most sensitive using immunohistochemistry targeting the cluster of differentiation markers, especially when compared to the conventional haematoxylin and eosin staining methods. The identified inflammatory cell types favour a chronic inflammatory process; which suggests a persistent stimulus. This means NSAID and glucocorticoids may be useful since they suppress inflammation, but it is noted that they may hinder tendon healing and cause long term problems. This systematic review demonstrates a diversity of data and conclusions in regard to inflammation as part of the pathogenesis of Tendinopathy, ranging from ongoing or chronic inflammation to non-inflammatory degeneration and chronic infection. Whilst various inflammatory markers are present in two thirds of the reviewed articles, the heterogenicity of data and lack of comparable studies means we cannot conclude a common pathophysiology from this systematic review.

BACKGROUND:Bone-tendon junction (BTJ) is a unique structure connecting tendon and bone through a fibrocartilage zone. Owing to its unique structure, the regeneration of BTJ remains a challenge. Here, we study the fibrochondrogenic differentiation of human tendon-derived stem/progenitor cells (TSPCs) both in vitro and in vivo. METHODS:TSPCs were isolated from human patellar tendon tissues and investigated for their multidifferentiation potential. TSPCs were cultured in chondrogenic medium with transforming growth factor beta 3 (TGF-β3) and BMP-2 in vitro ​and examined for the expression of fibrochondrogenic marker genes by quantitative real-time reverse transcription polymerase chain reaction, enzyme-linked immunosorbent assay, and immunofluorescence. TSPCs pretreated were also seeded in collage II sponge and then transplanted in immunocompromised nude mice to examine if the fibrochondrogenic characteristics were conserved in vivo. RESULTS:We found that TSPCs were differentiated towards fibrochondrogenic lineage, accompanied by the expression of collagen I, collagen II, SRY-box transcription factor 9 (Sox 9), and tenascin C. Furthermore, after TSPCs were seeded in collagen II sponge and transplanted in immunocompromised nude mice, they expressed fibrochondrogenic genes, including proteoglycan, collagen I, and collagen II. CONCLUSION:Taken together, this study showed that TSPCs are capable of differentiating towards fibrocartilage-like cells, and the fibrochondrogenic characteristics were conserved even in vivo, and thus might have the potential application for fibrocartilage regeneration in BTJ repair. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE:TSPCs are able to differentiate into fibrocartilage-like cells and thus might well be one potential cell source for fibrocartilage regeneration in a damaged BTJ repair.

Background: The anterior cruciate ligament (ACL) has poor regenerative capacity, and an injury leads to loss of function, limiting quality of life and increasing the incidence of osteoarthritis. Surgical interventions can stabilize the joint and improve functional recovery. The delivery of growth factors (GFs) enhances the healing process; however, this is complex in its regulation, is high in costs, has side effects, and can only be accomplished with supraphysiological concentrations and thus is currently not clinically feasible. However, the immobilization of a patient’s endogenous GFs in biomaterials can overcome these problems. Purpose: To develop a method to capture endogenous bone morphogenetic protein–2 (BMP-2) and ultimately show enhanced ACL healing in vivo using this novel methodology. Study Design: Controlled laboratory study. Methods: BMP-2 binding peptides were synthetized, purified, and immobilized on polycaprolactone (PCL) films. The affinity between the peptide and human BMP-2 (hBMP-2) was confirmed with immunofluorescence and enzyme-linked immunosorbent assay. The C2C12 Luc reporter cell line was used to confirm the bioactivity of immobilized BMP-2. For in vivo experiments, the same functionalization technology was applied to the commercially available Polytape, and the functionalized tape was sutured together with the graft used for ACL reconstruction in rats. Each animal underwent reconstruction with either native Polytape (n = 3) or Polytape with BMP-2 binding peptides (n = 3). At 2 and 6 weeks after surgery, the graft was assessed by histology and micro–computed tomography. Results: The covalent immobilization of the peptide in PCL was successful, allowing the peptide to capture hBMP-2, which remained bioactive and led to the osteogenic differentiation of C2C12. In vivo experiments confirmed the potential of the Polytape functionalized with the BMP-2 binding peptide to capture endogenous BMP-2, leading to enhanced bone formation inside the femoral and tibial tunnels and ultimately improving the graft’s quality. Conclusion: The incorporation of BMP-2 binding peptides into materials used for ACL reconstruction can capture endogenous hBMP-2, which enhances the healing process inside the bone tunnels. Clinical Relevance: These results demonstrate the potential of using synthetic peptides to endow biomaterials with novel biological functions, namely to capture and immobilize endogenous GFs.

Osteoarthritis (OA), characterized by insufficient extracellular matrix synthesis and cartilage degeneration, is known as an incurable disease because its pathogenesis is poorly elucidated. Thus far, limited information is available regarding the pathophysiological role of microRNAs (miRNAs) in OA. In this study, we investigated the specific function of miR-146a in OA pathophysiology using mouse OA models. We found that the articular cartilage degeneration of miR-146a knockout (KO) mice was alleviated compared with that of the wild-type (WT) mice in spontaneous and instability-induced OA models. We demonstrate that miR-146a aggravated pro-inflammatory cytokines induced suppressing the expression of cartilage matrix-associated genes. We further identified calcium/calmodulin-dependent protein kinase II delta (Camk2d) and protein phosphatase 3, regulatory subunit B, beta isoform (Ppp3r2, also known as calcineurin B, type II) were essential targets of miR-146a in regulating cartilage homeostasis. Moreover, we found that surgical-induced OA mice treated with a miR-146a inhibitor significantly alleviated the destruction of articular cartilage via targeting Camk2d and Ppp3r2. These results suggested that miR-146a has a crucial role in maintaining cartilage homeostasis. MiR-146a inhibition in chondrocytes can be a potential therapeutic strategy to ameliorate OA.

Citation-based metrics for journal ranking may provide objective measures to quantitate a journal's contribution to scientific progress as reflected by citation, but comparison of journals solely based on citation-metrics is unjustified. There are two major types of citation-based metrics: the count of cites per paper and the count of papers with significant citations, as exemplified by the h-index. Orthopaedic journals are more likely to be underrated by most citation-based metrics, and this is accounted for by the lower citation potentials. Ranking of orthopaedic journals based on different citation metrics demonstrated a reasonably suitable accordance, but numerous orthopaedic journals experienced greater discrepancies in the measures of the journal's popularity and prestige. Citation-based ranking should not be equated with the scholarly performance of a journal; other criteria to evaluate the “impacts” of journals should be explored as well, such as clinical impacts rated by clinicians. Journal rankings and citation metrics are often used by universities, hospitals, research institutions, and granting agencies for performance assessment and resource allocation. The clinical impact and, to a certain extent, the emphasis on the quality of patient care, are not given the deserved recognition and are not priority considerations. This article sets the tone for a comprehensive review of the journal ranking system in orthopaedics.

Introduction Tendon has a very slow self-healing capacity after injury1 and tendon-derived stem cells (TDSCs) can be used in tendon regeneration and tendon wound healing.2 In in-vivo situation and during inflammation, tendon could be subjected to oxidative stress. Studies show that oxidative stress can cause apoptosis in tendon fibroblast and contribute to tendon degeneration.3 Also, oxidative stress can cause senescence in mesenchymal stem cells.4 However, the effects of oxidative stress on tendon-derived stem cells are still unknown. The aim of this study is to investigate the effect of oxidative stress (hydrogen peroxide) on proliferation and differentiation of TDSCs. Methods Proliferation Assays TDSCs were cultured in expansion medium with 0, 0.1 and 0.5 mM hydrogen peroxide (H2O2) with a density of 100 cells/ cm.2 The total number of cells in each well was counted by haemocytometer every two days. Tenogenic differentiation in oxidative environment TDSCs were cultured in expansion medium until confluence and then the medium changed to tenogenic medium (expansion medium plus 25ng/ml cTGF and 25 mM Ascorbic acid) to induce tenogenic differentiation for 14 days with or without the presence of H2O2 (0.1 or 0.5 mM). TDSCs cultured in expansion medium served as a control. Four tenogenic markers, Tenomodulin (Tnmd), Elastin (Eln), Scleraxis (Scx) and Collagen type one (Col1a1) were examined by real time PCR Alizarin red S staining To test if oxidative stress will drive TDSCs towards osteogenic differentiation in tenogenic niche. 2% Alizarin Red S solution was used to indicate the formation of calcium nodules in TDSCs cultured 21 days in tenogenic medium. Results and discussion The proliferation rate of TDSCs is significantly lower in 0.5 mM H2O2 treatment while the difference is not statistically significant in 0.1 mM treatment compared with 0 mM group (Figure 1). Tenogenic differentiation The expression for Tnmd and Eln is significantly decreased (Figure 2) while no significant difference for the expression of Col1a1 and Scx (Data not shown). This implies that high oxidative stress may have adverse effect on TDSC differentiation. Alizarin Red S Staining Small amount of Calcium nodules formed in all the four groups and the absorbance for 0.5 mM H2O2 treatment group is statistically significant compared with 0 mM H2O2 group (data not shown). This implies that oxidative stress may drive TDSCs towards osteogenesis. Acknowledgement This research was made possible by resources donated by Lui Che Woo Foundation Limited. References 1 Brandl et al. J Exp Cell Res 2011;317:1541–1547 2 Ni et al. J Biomaterials 2013;(34):2024–2037 3 Sharama et al. J Musculoskelet Neuronal Interact 2006;6(2):181–190 4 Yuan et al. BBA 2003;1641:35–41

Acute and chronic tendon injuries are very common among athletes and in sedentary population. Most physicians prescribe anti-inflammatory managements to relieve the worst symptoms of swelling and pain, including non-steroidal anti-inflammatory drugs, corticosteroids and physical therapies. However, experimental research shows that pro-inflammatory mediators such as prostaglandins may play important regulatory roles in tendon healing. Noticeably nearly all cases of chronic tendon injuries we treat as specialists have received non-steroidal anti-inflammatory drugs by their physician, suggesting that there might be a potential interaction in some of these cases turning a mild inflammatory tendon injury into chronic tendinopathy in predisposed individuals. We are aware of the fact that non-steroidal anti-inflammatory drugs and corticosteroids may well have a positive effect on the pain control in the clinical situation whilst negatively affect the structural healing. It follows that a comprehensive evaluation of anti-inflammatory management for tendon injuries is needed and any such data would have profound clinical and health economic importance.

We studied the expression of procollagen type I, matrix metalloproteinase 1 (MMP1) and tissue inhibitor of metalloproteinase 1 (TIMP-1) by immunohistochemistry in human patellar tendinosis tissues and healthy patellar tendons. In situ gelatin zymography was used to detect collagenolytic activities. The productions of MMPl, TIMPl and gelatinolytic activities were compared in cell cultures from tendinosis samples and controls. Tendinosis tissues and cultures showed an increase in the expression level of MMPl and a decrease in that of TIMPl, a condition favoring collagen degradation. Gelatinolytic activities in tendinosis tissues and cultures were elevated. Collagenolysis is a striking feature in patellar tendinosis.

We report chondrocyte phenotype and ectopic ossification in a collagenase-induced patellar tendon injury model. Collagenase or saline was injected intratendinously in one limb. The patella tendon was harvested for assessment at different times. There was an increase in cellularity, vascularity, and loss of matrix organization with time after collagenase injection. The tendon did not heal histologically until week 32. Ectopic mineralization as indicated by von Kossa staining started from week 8. Tendon calcification was mediated by endochondral ossification, as shown by expression of type X collagen. viva CT imaging and polarization microscopy showed characteristic bony porous structures and collagen fiber arrangement, respectively, in the calcific regions. Marrow-like cells and blood vessels were observed inside calcific deposits. Chondrocyte-like cells as indicated by morphology, expression of type II collagen, and sox 9 were seen around and embedded inside the calcific deposits. Fibroblast-like cells expressed type II collagen and sox 9 at earlier times, suggesting that erroneous differentiation of healing tendon fibroblasts may account for failed healing and ossification in collagenase-induced tendon degeneration. Because this animal model replicates key histopathological changes in calcific tendinopathy, it can be used as a model for the study of its pathogenesis at the patellar tendon.

Cultured tendon fibroblasts (CTFs) from intact explants are widely used to study tendon healing in vitro. The significance of these findings may rely on similarities between CTFs and healing tendon fibroblasts in situ. Our purpose was to compare CTFs with fibroblasts cultured from healing tendons. We cultured CTFs from intact and healing tendons at day 7 and day 14 postinjury in a rat model of patellar donor site injury. The mRNA expression of COL1A1, COL3A1, decorin, and biglycan, with or without supplementation of 1 ng/mL TGF‐β1, was compared by quantitative real‐time RT‐PCR. The expression of proliferation cell nuclear antigen (PCNA) and α‐smooth muscle actin (α‐SMA) was determined by immunostain. COL3A1 and decorin mRNA in CTFs was lower as compared to day 7 healing fibroblasts, but its biglycan mRNA level was higher than day 14 healing fibroblasts. TGF‐β1 increased COL1A1 and decorin mRNA in CTFs, but decreased the mRNA of all four genes in day 7 healing tendon fibroblasts. CTFs exhibited lower PCNA immunopositivity as compared to day 7 and day 14 healing fibroblasts, but a higher α‐SMA immunopositivity than cultured day 14 healing fibroblasts. These findings showed that CTFs did not resemble healing tendon cells with respect to major cellular activities related to tendon healing. Thus, fibroblasts from healing tendon may be a more appropriate model for studying cellular activities in tendon healing. © 2007 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 26:374–383, 2008