Aims. Stiffness is a common complication after total knee arthroplasty (TKA). Pathogenesis is not understood, treatment options are limited, and diagnosis is challenging. The aim of this study was to investigate if MRI can be used to visualize intra-articular scarring in patients with stiff, painful knee arthroplasties. Methods. Well-functioning primary TKAs (n = 11), failed non-fibrotic TKAs (n = 5), and patients with a clinical diagnosis of fibrosis. 1. (n = 8) underwent an MRI scan with advanced metal suppression (Slice Encoding for Metal Artefact Correction, SEMAC) with gadolinium contrast. Fibrotic tissue (low intensity on T1 and T2, low-moderate post-contrast enhancement) was quantified (presence and tissue thickness) in six compartments: supra/infrapatella, medial/lateral gutters, and posterior medial/lateral. Results. Fibrotic tissue was identified in all patients studied. However, tissue was significantly thicker in fibrotic patients (4.4 mm ± 0.2 mm) versus non-fibrotic (2.5 mm ± 0.4 mm) and normal TKAs (1.9 mm ± 0.2 mm, p = < 0.05). Significant (> 4 mm thick) tissue was seen in 26/48 (54%) of compartments examined in the fibrotic group, compared with 17/30 (57%) non-fibrotic, and 10/66 (15%) normal TKAs. Although revision surgery did improve range of movement (ROM) in all fibrotic patients, clinically significant restriction remained post-surgery. Conclusion. Stiff TKAs contain intra-articular fibrotic tissue that is identifiable by MRI. Studies should evaluate whether MRI is useful for surgical planning of debridement, and as a non-invasive measurement tool following interventions for stiffness caused by fibrosis. Revision for stiffness can improve ROM, but outcomes are sub-optimal and new treatments are required. Cite this article: Bone Joint J 2020;102-B(10):1331–1340

Aims. The antidiabetic agent metformin inhibits fibrosis in various organs. This study aims to elucidate the effects of hyperglycaemia and metformin on knee joint capsule fibrosis in mice. Methods. Eight-week-old wild-type (WT) and type 2 diabetic (db/db) mice were divided into four groups without or with metformin treatment (WT met(-/+), Db met(-/+)). Mice received daily intraperitoneal administration of metformin and were killed at 12 and 14 weeks of age. Fibrosis morphology and its related genes and proteins were evaluated. Fibroblasts were extracted from the capsules of 14-week-old mice, and the expression of fibrosis-related genes in response to glucose and metformin was evaluated in vitro. Results. The expression of all fibrosis-related genes was higher in Db met(-) than in WT met(-) and was suppressed by metformin. Increased levels of fibrosis-related genes, posterior capsule thickness, and collagen density were observed in the capsules of db/db mice compared with those in WT mice; these effects were suppressed by metformin. Glucose addition increased fibrosis-related gene expression in both groups of mice in vitro. When glucose was added, metformin inhibited the expression of fibrosis-related genes other than cellular communication network factor 2 (Ccn2) in WT mouse cells. Conclusion. Hyperglycaemia promotes fibrosis in the mouse knee joint capsule, which is inhibited by metformin. These findings can help inform the development of novel strategies for treating knee joint capsule fibrosis. Cite this article: Bone Joint Res 2024;13(7):321–331

Aims. Dupuytren’s contracture is characterized by increased fibrosis of the palmar aponeurosis, with eventual replacement of the surrounding fatty tissue with palmar fascial fibromatosis. We hypothesized that adipocytokines produced by adipose tissue in contact with the palmar aponeurosis might promote fibrosis of the palmar aponeurosis. Methods. We compared the expression of the adipocytokines adiponectin and leptin in the adipose tissue surrounding the palmar aponeurosis of male patients with Dupuytren’s contracture, and of male patients with carpal tunnel syndrome (CTS) as the control group. We also examined the effects of adiponectin on fibrosis-related genes and proteins expressed by fibroblasts in the palmar aponeurosis of patients with Dupuytren’s contracture. Results. Adiponectin expression in the adipose tissue surrounding the palmar aponeurosis was significantly lower in patients with Dupuytren’s contracture than in those with CTS. The expression of fibrosis-related genes and proteins, such as types 1 and 3 collagen and α-smooth muscle actin, was suppressed in a concentration-dependent manner by adding AdipoRon, an adiponectin receptor agonist. The expression of fibrosis-related genes and proteins was also suppressed by AdipoRon in the in vitro model of Dupuytren’s contracture created by adding TGF-β to normal fibroblasts collected from patients with CTS. Conclusion. Fibrosis of the palmar aponeurosis in Dupuytren’s contracture in males may be associated with adiponectin expression in the adipose tissue surrounding the palmar aponeurosis. Although fibroblasts within the palmar aponeurosis are often the focus of attention when elucidating the pathogenesis of Dupuytren’s contracture, adiponectin expression in adipose tissues warrants closer attention in future research. Cite this article: Bone Joint Res 2023;12(8):486–493

Aims. The aim of this consensus was to develop a definition of post-operative fibrosis of the knee. Patients and Methods. An international panel of experts took part in a formal consensus process composed of a discussion phase and three Delphi rounds. Results. Post-operative fibrosis of the knee was defined as a limited range of movement (ROM) in flexion and/or extension, that is not attributable to an osseous or prosthetic block to movement from malaligned, malpositioned or incorrectly sized components, metal hardware, ligament reconstruction, infection (septic arthritis), pain, chronic regional pain syndrome (CRPS) or other specific causes, but due to soft-tissue fibrosis that was not present pre-operatively. Limitation of movement was graded as mild, moderate or severe according to the range of flexion (90° to 100°, 70° to 89°, < 70°) or extension deficit (5° to 10°, 11° to 20°, > 20°). Recommended investigations to support the diagnosis and a strategy for its management were also agreed. Conclusion. The development of standardised, accepted criteria for the diagnosis, classification and grading of the severity of post-operative fibrosis of the knee will facilitate the identification of patients for inclusion in clinical trials, the development of clinical guidelines, and eventually help to inform the management of this difficult condition. Cite this article: Bone Joint J 2016;98-B:1479–88

Objectives. Rotator cuff tears are among the most frequent upper extremity injuries. Current treatment strategies do not address the poor quality of the muscle and tendon following chronic rotator cuff tears. Hypoxia-inducible factor-1 alpha (HIF-1α) is a transcription factor that activates many genes that are important in skeletal muscle regeneration. HIF-1α is inhibited under normal physiological conditions by the HIF prolyl 4-hydroxylases (PHDs). In this study, we used a pharmacological PHD inhibitor, GSK1120360A, to enhance the activity of HIF-1α following the repair of a chronic cuff tear, and measured muscle fibre contractility, fibrosis, gene expression, and enthesis mechanics. Methods. Chronic supraspinatus tears were induced in adult rats, and repaired 28 days later. Rats received 0 mg/kg, 3 mg/kg, or 10 mg/kg GSK1120360A daily. Collagen content, contractility, fibre type distribution and size, the expression of genes involved in fibrosis, lipid accumulation, atrophy and inflammation, and the mechanical properties of the enthesis were then assessed two weeks following surgical repair. Results. At two weeks following repair, treatment groups showed increased muscle mass but there was a 15% decrease in force production in the 10 mg/kg group from controls, and no difference between the 0 mg/kg and the 3 mg/kg groups. There was a decrease in the expression of several gene transcripts related to matrix accumulation and fibrosis, and a 50% decrease in collagen content in both treated groups compared with controls. Additionally, the expression of inflammatory genes was reduced in the treated groups compared with controls. Finally, PHD inhibition improved the maximum stress and displacement to failure in repaired tendons. Conclusions. GSK1120360A resulted in improved enthesis mechanics with variable effects on muscle function. PHD inhibition may be beneficial for connective tissue injuries in which muscle atrophy has not occurred. Cite this article: J. P. Gumucio, M. D. Flood, A. Bedi, H. F. Kramer, A. J. Russell, C. L. Mendias. Inhibition of prolyl 4-hydroxylase decreases muscle fibrosis following chronic rotator cuff tear. Bone Joint Res 2017;6:57–65. DOI: 10.1302/2046-3758.61.BJR-2016-0232.R1

Aims. To develop an early implant instability murine model and explore the use of intermittent parathyroid hormone (iPTH) treatment for initially unstable implants. Methods. 3D-printed titanium implants were inserted into an oversized drill-hole in the tibiae of C57Bl/6 mice (n = 54). After implantation, the mice were randomly divided into three treatment groups (phosphate buffered saline (PBS)-control, iPTH, and delayed iPTH). Radiological analysis, micro-CT (µCT), and biomechanical pull-out testing were performed to assess implant loosening, bone formation, and osseointegration. Peri-implant tissue formation and cellular composition were evaluated by histology. Results. iPTH reduced radiological signs of loosening and led to an increase in peri-implant bone formation over the course of four weeks (timepoints: one week, two weeks, and four weeks). Observational histological analysis shows that iPTH prohibits the progression of fibrosis. Delaying iPTH treatment until after onset of peri-implant fibrosis still resulted in enhanced osseointegration and implant stability. Despite initial instability, iPTH increased the mean pull-out strength of the implant from 8.41 N (SD 8.15) in the PBS-control group to 21.49 N (SD 10.45) and 23.68 N (SD 8.99) in the immediate and delayed iPTH groups, respectively. Immediate and delayed iPTH increased mean peri-implant bone volume fraction (BV/TV) to 0.46 (SD 0.07) and 0.34 (SD 0.10), respectively, compared to PBS-control mean BV/TV of 0.23 (SD 0.03) (PBS-control vs immediate iPTH, p < 0.001; PBS-control vs delayed iPTH, p = 0.048; immediate iPTH vs delayed iPTH, p = 0.111). Conclusion. iPTH treatment mediated successful osseointegration and increased bone mechanical strength, despite initial implant instability. Clinically, this suggests that initially unstable implants may be osseointegrated with iPTH treatment. Cite this article: Bone Joint Res 2022;11(5):260–269

Thickening of the fibrous element of a peripheral nerve may be caused by repeated friction, traction, constriction, ischaemia or partial rupture. The sequel may be a conduction disorder and a clinical condition such as an entrapment neuropathy or a tardy nerve palsy. Neural fibrosis is typically associated with a pseudoneuroma in continuity which has resulted from scarring and adhesions around the nerve as well as proliferation of the fibrous element within the nerve; the fibrosis may be classified as extraneural, intraneural or dispersive. We report 17 cases treated by external neurolysis, with 14 satisfactory results, and 42 patients treated by internal neurolysis with success in 37. Seven of the eight failures were in cases of dispersive fibrosis. A technique of internal neurolysis is described

We examined soft tissue biopsies from 26 patients with symptomatic nerve root fibrosis and arachnoiditis after a previous laminectomy. Dense fibrous connective tissue was found about the nerve roots and in 14 cases (55%) fibrillar foreign material was seen within it. This material had the histochemical characteristics of cotton fibres from swabs and neurosurgical patties. In two other cases nerve root fibrosis was associated with residual radiopaque lipid thought to derive from earlier myelography. Our findings suggest that risks may be associated with the introduction of foreign material into the vertebral canal, and that microscopic fragments of surgical swabs and patties may have a role in the pathogenesis of postoperative periradicular fibrosis

Eight children with paralytic drop foot after intramuscular injections later developed gluteal fibrosis. Sciatic palsy, presenting as equinovarus or equinus deformity, was diagnosed on average 3.8 months after the intragluteal injections, but gluteal fibrosis was not diagnosed until 5.1 years after the injections. In three patients the equinovarus recurred after surgical correction due to persistent muscle imbalance and the effect of the external rotation contracture of the hip

Objectives

The goal of this study was to determine whether intra-articular administration of the potentially anti-fibrotic agent decorin influences the expression of genes involved in the fibrotic cascade, and ultimately leads to less contracture, in an animal model.

Tendon injuries occur frequently in athletes and the general population, with inferior healing leading to deposition of fibrotic scar tissue. New treatments are essential to limit fibrosis and enable tendon regeneration post-injury. In this study, we tested the hypothesis that rapamycin improves tendon repair and limits fibrosis by inhibiting the mTOR pathway. The left hindlimb of female adult Wistar rats was injured by needle puncture and animals were either given daily injections of rapamycin (2mg/kg) or vehicle. Animals were euthanized 1 week or 3 weeks post-injury (n=6/group). Left and right Achilles tendons were harvested, with the right limbs acting as controls. Tendon sections were stained with haematoxylin & eosin, and scored by 2 blinded scorers, assessing alterations in cellularity, cell morphology, vascularity, extracellular matrix (ECM) organization and peritendinous fibrosis. Immunohistochemistry was performed for the tendon pan-vascular marker CD146 and the autophagy marker LC3. Injury resulted in significantly altered ECM organization, cell morphology and cellularity in both rapamycin and vehicle-treated groups, but no alterations in vascularity compared to uninjured tendons. Rapamycin had a limited effect on tendon repair, with a significant reduction in peritendinous fibrosis 3 weeks after injury (p=0.028) but no change in cell morphology, cellularity or ECM organization compared to vehicle treated tendons at either 1 week or 3 weeks post injury. CD146 labelling was increased at the site of injury, but there was no apparent difference in CD146 or LC3 labelling in rapamycin and vehicle treated tendons. The decrease in peritendinous fibrosis post-injury observed in rapamycin treated tendons indicates rapamycin as a potential therapy for tendon adhesions. However, the lack of improvement of other morphological parameters in response to rapamycin treatment indicates that rapamycin is not an effective therapy for injuries to the tendon core. Acknowledgements: This study was funded by Versus Arthritis (22607)

Pericytes are contractile, motile cells that surround the capillary. Recent studies have shown that pericytes promoted joint fibrosis and induced subchondral bone angiogenesis, indicating the role of pericytes in osteoarthritis (OA). However, whether pericytes are involved in regulating inflammatory and catabolic response, as well as fibrotic repair of cartilage is still unclear. Here we used 2D and 3D models to investigate the communication of pericytes and chondrocytes under inflammatory osteoarthritis conditions. CD34-CD146+ pericytes were isolated and sorted from human bone marrow. Human OA chondrocytes were isolated from OA joints. In 2D studies, monolayer cultured chondrocytes were treated +/- pericyte conditioned media, +/- 1ng/ml IL1β for 24h. In 3D studies, pericytes and chondrocytes were cultured within fibrin gel in 3D polyurethane scaffolds, separately or combined for 7 days, followed by treatment of +/- IL1β for another 7 days (Fig 2A). The inflammatory response, catabolic activity and expression of fibrosis markers of chondrocytes and pericytes were measured by ELISA and/or q-rtPCR. Pericytes had weak inflammatory, catabolic and fibrotic response to IL1β (data not shown). The 2D study showed that pericyte conditioned media promoted inflammation, catabolism and fibrosis markers of chondrocytes, in the absence of IL1β treatment (Figure 1). However, study in 3D showed that coculture of chondrocytes and pericytes reduced the inflammatory and catabolic response of chondrocytes to IL1β and induced fibrosis markers in chondrocytes (Figure 2). Pericytes are involved in regulating inflammatory response, catabolic response and fibrosis of chondrocytes. The opposite results from 2D and 3D experiments indicate the variety of the regulatory role of pericytes in the interaction with chondrocytes within different culture models. The underlying mechanism is under evaluation with on-going studies. Acknowledgements. This study was funded by SINPAIN project, from European Union's Horizon Europe research and innovation programme under Grant Agreement NO. 101057778. Funded by the European Union. Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union. Neither the European Union nor the granting authority can be held responsible for them. For any figures or tables, please contact the authors directly

Dupuytren's disease (DD) is a fibroproliferative soft tissue disease affecting the palmar fascia of the hand causing permanent and irreversible flexion contracture. Aberrant fibrosis is likely to manifest through a combination of extrinsic, intrinsic, and environmental factors, including genetics and epigenetics. However, the role of epigenetics in soft tissue fibrosis in diseases such as DD is not well established. Therefore, we conducted a comprehensive multi-omic study investigating the epigenetic profiles that influence gene expression in DD pathology. Using control (patients undergoing carpal tunnel release) and diseased fibroblasts (patients undergoing Dupuytren's fasciectomy), we conducted ATAC-seq to assess differential chromatin accessibility between control and diseased fibroblasts. Additionally, ChIP-seq mapped common histone modifications (histone H4; H3K4me3, H3K9me3, H3K27me3, H4K16Ac, H4K20Me3) associated with fibrosis. Furthermore, we extracted RNA from control and DD tissue and performed bulk RNA-seq. ATAC-seq analysis identified 2470 accessible genomic loci significantly more accessible in diseased fibroblasts compared to control. Comparison between diseased and control cells identified numerous significantly different peaks in histone modifications (H4K20me3, H3K27me3, H3K9me3) associated with gene repression in control cells but not in diseased cells. Pathway analysis demonstrated a substantial overlap in genes being de-repressed across these histone modifications (Figure 1). Both, ATAC-seq and ChIP-seq analysis indicated pathways such as cell adhesion, differentiation, and extracellular matrix organisation were dysregulated as a result of epigenetic changes. Moreover, de novo motif enrichment analysis identified transcription factors that possibly contributed to the differential gene expression between control and diseased tissue, including HIC1, NFATC1 and TEAD2. RNA-seq analysis found that these transcription factors were upregulated in DD tissue compared to control tissue. The current epigenetic study provides insights into the aberrant fibrotic processes associated with soft tissue diseases such as DD and indicates that epigenetic-targeted therapies may be an interesting viable treatment option in future. For any figures or tables, please contact the authors directly

The April 2024 Shoulder & Elbow Roundup. 360. looks at: Acute rehabilitation following traumatic anterior shoulder dislocation (ARTISAN): pragmatic, multicentre, randomized controlled trial; Prevalence and predisposing factors of neuropathic pain in patients with rotator cuff tears; Are two plates better than one? The clavicle fracture reimagined; A single cell atlas of frozen shoulder capsule identifies features associated with inflammatory fibrosis resolution; Complication rates and deprivation go hand in hand with total shoulder arthroplasty; Longitudinal instability injuries of the forearm; A better than “best-fit circle” method for glenoid bone loss assessment; 3D supraspinatus muscle volume and intramuscular fatty infiltration after arthroscopic rotator cuff repair

In-vitro models of disease are valuable tools for studying disease and analysing response to therapeutics. Recently, advances in patient-derived organoid (PDO) models have been shown to faithfully recapitulate structure, function, and therapeutic response for a wide range of tissues. Frozen shoulder is a rare example of a chronic inflammatory fibrotic disease which is self-limiting, unlike many other soft tissue fibrotic disorders. As no in-vitro 3D models or in-vivo animal models exist for frozen shoulder, establishing an organoid model which recapitulates core diseases features may give insight into fibrosis resolution. Consequently, using biocompatible hydrogels, primary capsular fibroblasts, monocyte-derived macrophages and HUVEC cells, we generated stable PDO cultures which exhibited key disease phenotypes, including vascularization, increased stiffness, and an expanded lining layer over 21 days of culture. Through further investigation of cell-matrix and cell-cell interactions in the organoid model, we intend to unpack the differences between resolving and non-resolving fibrotic disease and uncover clinically relevant therapeutic targets for fibrosis

Stem cell therapy is an effective means to address the repair of large segmental bone defects. However, the intense inflammatory response triggered by the implants severely impairs stem cell differentiation and tissue regeneration. High-dose transforming growth factor β1 (TGF-β1), the most locally expressed cytokine in implants, inhibits osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and promotes tissue fibrosis, severely compromising the efficacy of stem cell therapy. Small molecule inhibitors of TGF-β1 can be used to ameliorate the osteogenic disorders caused by high concentrations of TGF-β1, but systemic inhibition of TGF-β1 function will cause strong adverse effects. How to find safe and reliable molecular targets to antagonize TGF-β1 remains to be elucidated. Orphan nuclear receptor Nr4a1, an endogenous inhibitory molecule of TGF-β1, suppresses tissue fibrosis, but its role in BMSC osteogenesis is unclear. We found that TGF-β1 inhibited Nr4a1 expression through HDAC4. Overexpression of Nr4a1 in BMSCs reversed osteogenic differentiation inhibited by high levels of TGF- β1. Mechanistically, RNA sequencing showed that Nr4a1 activated the ECM-receptor interaction and Hippo signaling pathway, which in turn promoted BMSC osteogenesis. In bone defect repair and fracture healing models, transplantation of Nr4a1-overexpressing BMSCs into C57BL/6J mice or treatment with the Nr4a1 agonist Csn-B significantly ameliorated inflammation-induced bone regeneration disorders. In summary, our findings confirm the endogenous inhibitory effect of Nr4a1 on TGF- β1 and uncover the effectiveness of Nr4a1 agonists as a therapeutic tool to improve bone regeneration, which provides a new solution strategy for the treatment of clinical bone defects and inflammatory skeletal diseases

Background. There are currently no effective treatments for skeletal muscle fibrosis. Myofibroblasts are the major cellular effectors of fibrosis but their origin in muscle is unknown. We report that PDGFRβ (platelet derived growth factor receptor beta) Cre inactivates genes in murine PDGFRβ+ cells and myofibroblasts in muscle with high efficiency. We used this system to delete the integrin αv subunit because of the suggested role of multiple αv integrins as central mediators of fibrosis in multiple organs. Methods. Muscle fibrosis was induced by intramuscular cardiotoxin (CTX) injection. The contribution of PDGFRβ+ cells to fibrosis was assessed in double-flourescent reporter (mTmG) mice under PDGFRβ-Cre control. Itgavflox/flox;PDGFRβ-Cre mice were used to investigate whether loss of αv integrins on PDGFRβ+ cells influences fibrosis development. A small-molecule inhibitor of αv integrins (CWHM12) was used to determine whether pharmacological blockade of αv integrins could attenuate fibrosis. Results. At 21 days following injury PDGFRβ+ cells in mTmG;PDGFRβ-Cre mice were distributed in a manner characteristic of myofibroblasts. PDGFRβ+ cells sorted from injured muscles of mTmG;PDGFRβ-Cre mice showed induction of genes associated with myofibroblastic transition. Itgavflox/flox;PDGFRβ-Cre mice were protected from CTX induced fibrosis, as determined by picrosirius red staining for collagen (p<0.01). Sorted and culture activated αv-null PDGFRβ+ cells demonstrated significant reduction in collagen1 over controls (p<0.05). CWHM12 significantly reduced muscle fibrosis when delivered from the time of injury (prophylactic model: p<0.01) and from day 10 post injury (therapeutic model: p<0.01). Furthermore, CWHM12 inhibited collagen1 expression by PDGFRβ+ cells ex-vivo (p<0.05). Conclusions. PDGFRβ-Cre labels profibrotic cells in skeletal muscle and depletion of αv integrins in these cells reduces muscle fibrosis. Most importantly from a treatment standpoint, pharmacologic inhibition of αv integrins using a small molecule inhibitor may have utility in the prevention and treatment of skeletal muscle fibrosis. Level of Evidence. Basic Science

Subacromial bursa fibrosis are linked to rotator cuff lesion with shoulder stiffness; however, the mechanism underlying this shoulder disorder remain elusive. MicroRNA-29s (miR-29s) are emerging fibrosis inhibitor targeting fibrogenic matrices during tissue fibrosis. This study is aimed to investigate clinical relevance and function of miR-29 signalling to subacromial bursa homeostasis in shoulder stiffness. Subacromial bursa in patients with rotator cuff lesion with or without shoulder stiffness who required open acromioplasty were harvested for assessing fibrosis histopathology using Manson's trichrome staining. Expressions of proinflammatory cytokines, fibrotic matrices, and miR-29s were quantified using RT-PCR and in situ hybridization. Range of motion and pain scores of the stiffness group were higher than those of non-stiffness group. Upregulated proinflammatory cytokines (IL-1β, IL-6, and TNF-α) and fibrotic matrices (collagen 1α1, 3α1, and 4α1) but decreased miR-29a and b expression existed in the stiffness group. Affected tissues exhibited severe fibrotic matrix accumulation, synovial hyperangiogenesis, hyperplasia, and strong miR-29a transcripts. In vitro, IL-1β rather than IL-6 and TNF-α decreased miR-29a expression of subacromial bursa fibroblasts. miR-29a knockdown escalated fibrotic matrix expression, whereas forced miR-29a expression alleviated the IL-1β-induced fibrotic matrix expression. Of interest, miR-29a transgenic mice displayed moderate responses to supraspinatus and infraspinatus tenotomy-induce fibrosis and gait irregularity of affected shoulders. Weak miR-29 signalling causes excessive fibrosis and remodelling in subacromial bursa and ultimately increases the prevalence of shoulder stiffness. This study reveals a new mechanistic underlying shoulder stiffness and highlights that sustained miR-29a potentially ameliorates the severity and function of stiff shoulder

Geriatric syndromes could lead individuals to exhibit significant mobility and psychological deficits resulting in significant healthcare costs. Thus, identifying strategies to delay aging, or prevent progressive loss of tissue homeostasis could dramatically restore the function and independence of millions of elderly patients and significantly improve quality of life. One of the fundamental properties of aging is the accumulation of senescent cells and senescence associated secretory phenotypes (SASPs) that needs to be treated in wide range of therapeutics including orthobiologics. Senolytic compounds selectively target and kill senescent cells and inhibit anti-apoptotic pathways that are upregulated in senescent cells thereby inducing apoptotic cell death and abrogating systemic SASP factors. We have also shown that blocking fibrosis with Losartan (TGF-β1 blocker) can improve musculoskeletal healing and cartilage repair by reducing the amount of fibrosis. Thus, we hypothesize that administration of anti-fibrotic agents will enhance the beneficial effects of orthobiologics. The safety and efficacy of several senolytic and anti-fibrotic agents to delay age-related dysfunction and improve the function of orthobiologics have been demonstrated in a variety of animal models (in vivo). Overall, our innovative approaches target senescent cells (inflammation) and TGF-β1 (fibrosis) to enhance the clinical efficacy and use of orthobiologics for musculoskeletal repair. We will also discuss ongoing active clinical trials on orthobiologics to aiming at evaluating the safety and efficacy of senolytic agent (Fisetin) and anti-fibrotic agent (Losartan), used independently or in combination, to enhance the beneficial effects of orthobiologics for patients afflicted with musculoskeletal diseases and conditions

Aims. Early evidence has emerged suggesting that ceramic-on-ceramic articulations induce a different tissue reaction to ceramic-on-polyethylene and metal-on-metal bearings. Therefore, the aim of this study was to investigate the tissue reaction and cellular response to ceramic total hip arthroplasty (THA) materials in vitro, as well as the tissue reaction in capsular tissue after revision surgery of ceramic-on-ceramic THAs. Patients and Methods. We investigated tissue collected at revision surgery from nine ceramic-on-ceramic articulations. we compared our findings with tissue obtained from five metal-on-metal THA revisions, four ceramic-on-polyethylene THAs, and four primary osteoarthritis synovial membranes. The latter were analyzed to assess the amount of tissue fibrosis that might have been present at the time of implantation to enable evaluation, in relation to implantation time, of any subsequent response in the tissues. Results. There was a significant increase in tissue fibrosis with implantation time for all implant types tested. Interestingly, the tissue fibrosis in ceramic-on-ceramic THAs was significantly increased compared with metal-on-metal and ceramic-on-polyethylene. Additionally, we found ceramic wear particles in the periprosthetic tissue of ceramic implants. Fibroblasts responded with expression of cytokines when cultured on alumina-toughened zirconia (ATZ) and zirconia-toughened alumina (ZTA) ceramic surfaces. This response was more pronounced on ATZ ceramics compared with ZTA ceramics. The same inflammatory response was observed with peripheral blood mononuclear cells (PBMCs) cultured on ZTA and ATZ. Conclusion. Our findings therefore, corroborate the previous findings that ceramic-on-ceramic periprosthetic revision tissue is fibrous and offer an explanation for this observation. We detected a long-term inflammatory response of PBMCs and an inflammatory response of fibroblasts to ATZ and ZTA ceramic. These findings partially explain the fibrotic tissue change in periprosthetic tissue of ceramic-on-ceramic bearings. Cite this article: Bone Joint J 2018;100-B:882–90