31, 3147 (2013). Arthrofibrosis can develop after an injury or surgery to the joint. . 74, 109116 (2000). What is Arthrofibrosis. Biochem. & LaPrade, R. F. Arthroscopic posteromedial capsular release. Recent research suggests that injections of collagenase, a proteolytic bacterial enzyme that specifically breaks down collagen, can increase ROM in arthrofibrosis of the shoulder320,321 and in animal models of arthrofibrosis of the knee, however, further research is needed to address concerns relating to degradation of articular cartilage, ligaments and tendons.322 In addition, the signalling effects of collagen fragments created by cleavage also needs to be considered, as some of these fragment have biological activity.104 However, collagenase has been approved for Dupuytren disease, a fibroproliferative disease of the palm.323 Collagenase in slow releasenanocapsules have been developed and tested in an animal model of skin fibrosis, showing sustained release over 10 days.324 This could lower the number of doses required. Consequently, a detailed discussion is beyond the scope of this review, however, we explore the major cell types and cytokines involved below. Qin, X. et al. J. Orthop. The number of myofibroblasts in tissue from arthrofibrotic knees can be ten times higher than in healthy subjects.233 Ruppert et al.234 observed co-localisation of -catenin and the tight junction protein ZO-1 in myofibroblasts which may cause increased adhesions and mechanical loading of cells. 5, 641654 (2005). Mol. TGF- plays a central role in the process, stimulating fibroblasts to proliferate and differentiate, and to increase their extracellular matrix (ECM) production. Misdiagnoses may complicate the understanding of arthrofibrosis. Am. PLoS ONE 10, e0116772 (2015). Hepatol. Klein-Wieringa, I. R. et al. Following surgery, it is important to have physical therapy to regain strength and motion as well as to prevent further formation of scar tissue. Cold Spring Harb. Stretching fibroblasts remodels fibronectin and alters cancer cell migration. Biophys. Both treatments damage tissues, and tissue injury stimulates an inflammatory response239 that may cause further fibrogenesis. The Orthopaedic Section of the American Physical Therapy Association presents this fifth set of clinical practice guidelines on knee pain and mobility impairments, linked to the International Classification of Functioning, Disability, and Health (ICF). Aneurysm-osteoarthritis syndrome with visceral and iliac artery aneurysms. Van Beneden, K., Mannaerts, I., Pauwels, M., Van den Branden, C. & van Grunsven, L. A. HDAC inhibitors in experimental liver and kidney fibrosis. 68, 261269 (2008). Arthroscopy 20, 469473 (2004). J. scar tissue functional. Noll, S., Garrison, J. C., Bothwell, J. 5, e00354 (2017). Google Scholar. Hypoxia-inducible factor-1alpha contributes to the profibrotic action of angiotensin II in renal medullary interstitial cells. Orthop. 33, 677686 (2013). 120, 93104 (2019). Barden, A. E. et al. Grellner, W., Georg, T. & Wilske, J. Quantitative analysis of proinflammatory cytokines (IL-1, IL-6, TNF-) in human skin wounds. 10, 333342 (2008). Cell Signal. 57, 96102 (2013). J. N. Engl. N. Engl. J. Neuroimmunol. 65, 12711281 (2013). Cell Motil. 160, 50535057 (1998). volume7, Articlenumber:9 (2019) Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 13, ji1701082 (2017). Mas, E., Croft, K. D., Zahra, P., Barden, A. Ser. Daidzein reduced ROS and levels of TGF- and when given subcutaneously to rats, reducing lung fibrosis.150, Some of the dietary compounds mentioned above also change epigenetic modifications, and were recently reviewed by Khan et al.281, Vitamin D is required for immune system homoeostasis, reducing TGF-, suppressing the Th17 profile, and supporting regulatory T cells that suppress autoreactive T cells.304 Vitamin D deficiency is correlated with fibrosis of the liver and vitamin D3 inhibits the production of collagen type 1 in the liver305 and in the lung.306 This suggests that this important vitamin may be a useful anti-fibrotic agent.103, Fibrosis may be promoted by a reduced dietary intake of potassium (K+) and low serum K+ levels were associated with liver fibrosis.307 K+ efflux from cells can result from cellular damage and the release of adenosine triphosphate.308 Upregulation of the intermediate/small-conductance Ca2+-activated K+ channel alters the membrane potential of cells and promotes fibrogenesis, with effects including higher levels of Ca2+ entry into cells and expression of Ca2+-dependant growth factor genes, cyclins and kinases involved in cell division.309 High-intracellular levels of Ca2+ are associated with cardiac fibrosis202and KCa3.1 silencing in animal models of renal fibrosis decreased the numbers of myofibroblasts and attenuated the development of fibrosis.310 This result appears to be mediated via the Smad2/3 pathway, since KCa3.1 blockade reduced levels of TGF-1, and TGF-1 receptor II.311. Nonetheless, it is also possible that targeting one or two key mediators early in the process may halt the dysregulation that leads to permanent active fibrosis, and targeting epigenetic modifications could potentially turn active arthrofibrosis into residual arthrofibrosis. It consists of excessive scar tissue formation within the joint capsule, resulting in pain, stiffness, and swelling, which are greater than expected in the given clinical scenario. Dean, C. S., Chahla, J., Mikula, J. D., Mitchell, J. J. & Graca, L. Induced IL-17producing invariant NKT cells require activation in presence of TGF- and IL-1. J. Immunol. A systematic review. Rev. There is a rapid recovery period after surgery, and patients will be able to walk immediately after the procedure has been completed. 23, 11651171 (2005). . Discov. Knee Surg. When you go to the healthcare provider with symptoms of arthrofibrosis, they will generally give you a physical examination and ask about your history of injury or surgery. CAS 29, 273284 (2009). Most cases resolve with conservative treatment, though, and newer, better treatments are in the works. Med. Novel functional sets of lipid-derived mediators with antiinflammatory actions generated from omega-3 fatty acids via cyclooxygenase 2-nonsteroidal antiinflammatory drugs and transcellular processing. The primary symptoms of arthrofibrosis include: Pain, which can be severe and constant. Chest 151, 971981 (2017). The surgical option, in which the healthcare provider goes in and removes the scar tissue, is more common. J. Surg. Surg. Arthrofibrosis of the knee is a condition whereby scar tissue prevents normal knee motion. The liver-enriched lnc-LFAR1 promotes liver fibrosis by activating TGFbeta and Notch pathways. Unterhauser, F. N., Bosch, U., Zeichen, J. Qiu, W. et al. Nat. Dennis, D. A. 4 Due to obesity and longevity, this is expected to increase six-fold to 672,000 5 and 4,200,000 . The human leucocyte antigen complex is involved in immune system functioning. This study showed that rates of arthrofibrosis requiring surgical treatment were significantly higher for ACL reconstruction compared to meniscectomy and microfracture.5 However, even exploratory arthroscopies are capable of causing arthrofibrosis.12. Cell Tissue Res. 92, 14681477 (2010). & Ramalingam, T. R. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. J. Med. Essent. Ther. J. Pathol. Cheuy, V. A. et al. In knees the suprapatellar pouch, anterior interval, intercondylar notch, medial and lateral gutters, posterior capsule and infrapatellar fat pad (IFP or Hoffas fat pad), may all be affected,6 with symptoms varying depending on the location and extent of the ECM and adhesions, but typically involving loss of flexion and/or extension (see above). Allergy Clin. 64, 615626 (2015). Deng, Y. Q. et al. 289, 1957119584 (2014). ISSN 2095-6231 (online), Pathological mechanisms and therapeutic outlooks for arthrofibrosis, https://doi.org/10.1038/s41413-019-0047-x, Synovial inflammation in osteoarthritis progression, Intra-articular treatment options for knee osteoarthritis, Tenascin C promotes pathological bone formation in AS, The regulatory role and therapeutic application of pyroptosis in musculoskeletal diseases, Statin treatment increases the clinical risk of tendinopathy through matrix metalloproteinase release a cohort study design combined with an experimental study, Emerging pharmaceutical therapies for osteoarthritis, Targeting angiogenesis for fracture nonunion treatment in inflammatory disease, In vitro responses to platelet-rich-plasma are associated with variable clinical outcomes in patients with knee osteoarthritis, Anti-IL-17A treatment reduces serum inflammatory, angiogenic and tissue remodeling biomarkers accompanied by less synovial high endothelial venules in peripheral spondyloarthritis, https://doi.org/10.1002/14651858.CD004260.pub3, https://doi.org/10.1172/jci.insight.94920, http://creativecommons.org/licenses/by/4.0/, Articular cartilage delamination at eight years following cellular-based repair procedures: a case reports, Management of arthrofibrosis in neuromuscular disorders: a review, Multimodal conservative management of arthrofibrosis after total knee arthroplasty compared to manipulation under anesthesia: a feasibility study with retrospective cohort comparison, Arthrofibrosis is a common but poorly defined complication in multiligament knee injuries: a systematic review, Arthrofibrosis following primary total hip arthroplasty: a distinct clinical entity. Levi-Schaffer, F., Nagler, A., Slavin, S., Knopov, V. & Pines, M. Inhibition of collagen synthesis and changes in skin morphology in murine graft-versus-host disease and tight skin mice: effect of halofuginone. Altern. Natl Acad. Wkly 144, w13999 (2014). Halofuginone ameliorates inflammation in severe acute hepatitis B virus (HBV)-infected SD rats through AMPK activation. Nat. To confirm the diagnosis and get a feel for the extent of the problem, you'll likely be sent for magnetic resonance imaging (MRI) and X-ray. & Caulfield, J. P. Hydraulic distension of the knee: a novel treatment for arthrofibrosis after total knee replacement (case series). 365, 495506 (2016). The complex role of vitamin D in autoimmune diseases. 17, 10401048 (2009). 128, 515519 (2008). The listing for major dysfunction of a joint is 1.02. Antioxid. For example, patients with more severe ROM limitations may not benefit as much as those with relatively good ROM before treatment, but this type of outcome typically can not be determined from the published data. Arthrofibrosis following total knee replacement (TKR) is a relatively common complication which results in a reduction in knee range of movement and patient dissatisfaction. Res. 3, 383388 (2006). Antibodies to substance P were used to indicate the presence of sensory nerves, suggesting that hyperinnervation and high levels of substance P may be significant contributors to active arthrofibrosis.57. JCI Insight 2, https://doi.org/10.1172/jci.insight.94920 (2017). Sequenced response of extracellular matrix deadhesion and fibrotic regulators after muscle damage is involved in protection against future injury in human skeletal muscle. Med. Baertschiger, R. M. et al. Influenza virus activates inflammasomes via its intracellular M2 ion channel. This approach could be used to prevent the return of arthrofibrosis at the time of surgery to lyse adhesions and remove ECM. The authors acknowledge the support from Australian Health and Medical Research Council (NHMRC Nos. Immunol. Ioan-Facsinay, A. The IFP may become fibrotic and impinge in the joint when the knee is flexed, creating further inflammation and fibrosis, loss of flexion and pain.24 The IFP is a store of immune cells that secrete inflammatory cytokines under stressful conditions25 (see Risk assessment), and can fill with ECM when adipose cells transform into fibrous tissue.26, a Sagittal fast spin echo intermediate-weighted image of a 33-year-old woman with clinical stiffness following anterior cruciate ligament (ACL) reconstruction, showing scarring of the synovium around the ACL reconstruction (long arrow) as well as the central portion of the deep infrapatellar fat pad (short arrow) and the lining of the suprapatellar recess (oval). in: Giangarra CE, Manske RC. J. Pathol. Ferretti, M. et al. Metformin reduces intrahepatic fibrosis and intrapulmonary shunts in biliary cirrhotic rats. The ECM that forms in fibrosis is largely cell-free, and serves as a conduit for immune cells, fibroblasts, nutrients and endothelial cells during angiogenesis. Why are total knees failing today? Natl Acad. Google Scholar. Am. Orthop. Types of arthritis include: osteoarthritis, rheumatoid arthritis and. Scar tissue is dense and fibrous. 6, 119128 (1991). It can also be iatrogenic e.g. Vitamin D inhibition of pro-fibrotic effects of transforming growth factor 1 in lung fibroblasts and epithelial cells. Monument, M. J., Hart, D. A., Salo, P. T., Befus, A. D. & Hildebrand, K. A. Posttraumatic elbow contractures: targeting neuroinflammatory fibrogenic mechanisms. (A) Posteroan-terior wrist radiograph. Nat. Wound Repair Regen. Transpl. Scarring adhesions has been described in most major . Your body's natural response to trauma, such as from an injury or surgery, is to make scar tissue. PLoS Pathog. Immun. 17, 760765 (1989). 10, 111118 (2009). The resolution code of acute inflammation: novel pro-resolving lipid mediators in resolution. One study found that patients with elbow injuries had significantly less ROM if they were treated surgically instead of non-operatively at 12 weeks.240 Some authors state that MUAs should not be performed due to the risk of fractures, rupture of tendons and cartage damage,35 while others warn that delayed MUA or manipulation that is too aggressive can lead to these complications as well as ossification of the medial collateral ligament and quadriceps.6, Daluga et al.42 found that MUAs significantly increased heterotrophic ossification in an MUA group compared to a control group based on radiographic observations. As a common complication following total knee arthroplasty, arthrofibrosis is a significant cause of pain and disability for patients, with up to 25% of patients requiring . Ann. demonstrated that IL-11 is strongly pro-fibrotic, driving the synthesis of the proteins involved in ECM production, contraction and other processes active in fibrosis.143 Production of IL-11 is upregulated by TGF-. 6, 112 (2007). Daskalopoulos, E. P., Dufeys, C., Bertrand, L., Beauloye, C. & Horman, S. AMPK in cardiac fibrosis and repair: Actions beyond metabolic regulation. Stiffness in the joint. Arthrofibrosis is defined as a complication of injury or trauma where an excessive scar tissue response leads to painful restriction of joint motion, with scar tissue forming within the joint and surrounding soft tissue spaces and persisting despite rehabilitation exercises and stretches. Am. Production of activated TGF- is stimulated by oxidative stress,138 platelet degranulation144 and ROS released after injury or surgical insult.94 While ROS activates TGF- and results in apoptosis,150 TGF- also induces the production of ROS,101,138,151 thus creating a positive feedback cycle. Shi, Y.-F. et al. Pathol. While this switch helps to control the damage caused by immune cells and promotes healing, it also activates collagen deposition and fibrosis.62. 14, 259264 (2006). Nat. J. TGF-B and Smad3 signaling link inflammation to chronic fibrogenesis. Phase 2a study of safety/efficacy of collagenase (CCH) in patients with adhesive capsulitis. Patients frequently suffer constant pain, severe limitations on physical activity and difficulty sleeping, sitting and weight bearing.12 These symptoms may lead to the loss of job/career and difficulty socialising and performing daily living tasks, negatively impacting physical and emotional well-being. Pathological mechanisms and therapeutic outlooks for arthrofibrosis. 6. 63, 15711575 (2011). & Fanburg, B. L. Reactive oxygen species in cell signaling. 83, 1293412946 (2009). Di Vita, G. et al. & Kloppenburg, M. An emerging player in knee osteoarthritis: the infrapatellar fat pad. Ther. 3, 2325967115583632 (2015). Bourne, R. B., Maloney, W. J. 7, 553556 (2012). Orthop. J. Respir. Jonathan Cluett, MD, is board-certified in orthopedic surgery. Haidukewych, G. J., Jacofsky, D. J., Pagnano, M. W. & Trousdale, R. T. Functional results after revision of well-fixed components for stiffness after primary total knee arthroplasty. Cell Mol. Monument, M. J., Hart, D. A., Salo, P. T., Befus, A. D. & Hildebrand, K. A. Neuroinflammatory mechanisms of connective tissue fibrosis: targeting neurogenic and mast cell contributions. Lan, H. Y., Nikolic-Paterson, D. J., Mu, W., Vannice, J. L. & Atkins, R. C. Interleukin-1 receptor antagonist halts the progression of established crescentic glomerulonephritis in the rat. J. Exp. 10648054 thesis (West Chester University of Pennsylvania, Ann Arbor, USA, 2017). Am. These tools can be applied to the joint and may assist recovery from arthrofibrosis32,325,326 and tendon damage,327 particularly before the ECM matures. Med. IL-1 is believed to be an important mediator of fibrosis,98 influencing the migration of cells, adhesion, matrix metalloproteinase production and the expression of immune-modulatory genes.156 It is a powerful inflammatory cytokine that induces TGF-133,145 and PDGF,103 driving the development of fibrosis116 following injury or infection. TNF- may also be involved in the memory of insult, as TNF messenger RNA is able to remain elevated for more than 70 days.173, IL-17 upregulates the production of TGF-174 and inflammatory cytokines from chondrocytes and synovial fibroblasts,175 and promotes the survival of fibroblasts.67 IL-17 can directly induce the production of collagen type 1139 and disrupt ECM homoeostasis,176 while promoting MMP production.176,177 It is secreted by a number of cells types, primarily T-helper 17 (Th17), NK cells and mast and myeloid cells.67,164 The feedback loops between IL-17 and IL-6, TNF- and IL-1are considered important drivers of chronic inflammatory diseases,139,175 and suggest a mechanism for the development of chronic fibrosis. 18, 168174 (2015). 5, e495e500 (2016). Swelling or warmth in the joint 1 . 19, 667679 (2010). Alternatively, slow release capsules of anti-fibrotic drugs or scaffolds containing drugs could be introduced at the time of surgery, or after arthrofibrosis develops. The process of Arthrofibrosis begins when the injury or the surgery leads to the formation of excessive scar tissue. Mesarwi, O. Arthrofibrosis associated with total knee arthroplasty. Bone Res. Med. Major areas that are affected by arthrofibrosis are indicated. Res. Check Eligibility. How long does it take to recover from arthrofibrosis? 24, 857862 (1996). & Klein, C. E. Human mast cells augment fibroblast proliferation by heterotypic cell-cell adhesion and action of IL-4. Arthrofibrosis is the abnormal growth of fibrous tissue in a joint. J. 19, 117 (2018). Previous meta-analysis manifested that the prevalence of arthrofibrosis after TKA ranges from 1 to 17%. Lactic acid is elevated in idiopathic pulmonary fibrosis and induces myofibroblast differentiation via pH-dependent activation of transforming growth factor-beta. Formby, P. M., Donohue, M. A., Cannova, C. J. Fibrosis results from a complex dysregulation of innate and adaptive immunity that is involved in most chronic inflammatory diseases,15,45,46 and is a leading cause of mortality.62 Injury causes oxidative stress and an inflammatory response, inducing pro-inflammatory cytokines98,99,100 and TGF- (Figs. 43, 16561661 (2015). These diverse stimuli include ROS, adenosine triphosphate (ATP), mitochondrial DNA and proteins released from damaged ECM, such as hyaluronan, heparin sulphate and biglycan.2,120. & Mori, T. A. Resolvins D1, D2, and other mediators of self-limited resolution of inflammation in human blood following n-3 fatty acid supplementation. Wound Care 4, 137151 (2015). 6, 557572 (2010). Knee Surg Sports Traumatol Arthrosc. Recovery time depends on the severity of your arthrofibrosis. Clinical observation of umbilical cord mesenchymal stem cell treatment of severe idiopathic pulmonary fibrosis: a case report. 190, 805811 (2013). In addition to pre-surgery applications, biomarkers could also be used post-operatively for all joint surgeries to monitor potential for developing arthrofibrosis, and following a diagnosis, to monitor the condition and its resolution. Dis. Bone Jt. Arthrofibrosis used to be much more common after ACL surgery when healthcare providers used to restrict patients' mobility to allow the ligament to heal. Nephrol. B. et al. Luckett-Chastain, L. R., Cottrell, M. L., Kawar, B. M., Ihnat, M. A. Commun. Trends Immunol. Huang, C. et al. Morrey, B. F. The posttraumatic stiff elbow. Vascular damage is known to promote fibroblast activation.329 Secondly, after the resolution of early symptoms influenza appears to have triggered the permanent return of active arthrofibrosis. Su, E. P. & Su, S. L. The stiff total knee replacement: evaluation and treatment. Arthroscopy 21, 13421347 (2005). 13, 19221926 (2017). Transforming growth factor-beta in stem cells and tissue homeostasis. Google Scholar. Stiffness may or may not be the primary complaint of the patient. N. Engl. J. Immunol. Some MMPs are associated with the progression of fibrosis, however, some have a protective effect.153,154 TGF- also induces tissue inhibitors of MMPs (TIMPS) that block ECM degradation and regulate MMP activity.1,15,81 MMPs play a key role in regulating a number of processes including ECM remodelling, proliferation, apoptosis and angiogenesis.155 MMPs are also induced by IL-17A, another cytokine with a significant involvement in the development of fibrosis15 (see below). Other risk factors include pre-existing inflammatory or autoimmune diseases, including type II diabetes,20 ankylosing spondylitis and rheumatoid arthritis.7 One study found that patients with diabetes mellitus had increased rates of arthrofibrosis after a TKR,38 possibly due to a pro-inflammatory physiology. Brito, H. O. et al. The cause of arthrogryposis is unknown, but it almost always results from another condition. For example, TGF- secreted by regulatory T cells in the presence of IL-10 can inhibit inflammation and fibrosis,62 while TGF- produced by macrophages is pro-fibrotic.81 Mitogen-activated protein kinases (MAPK) upregulate TGF- expression in the presence of inflammatory cytokines,147 and form another feedback loop. Relat. Matrix Biol. You could be eligible for up to $3,345 per month In SSDI Benefits. Wan, Y. et al. Inflammation 39, 6578 (2016). 103). Another modifier of the expression of activated TGF- was recently demonstrated to have some efficacy in rat models of kidney fibrosis. The stiff total knee arthroplasty: causes and cures. Medicines 94, e2003 (2015). As arthrofibrosis can be successfully alleviated if treated in its early stages, the clinical team must carefully watch for this complication relatively soon after the initial trauma or surgery, especially if there is an established risk such as in cruciate ligament surgery or arthroplasty.. How does the surgeon or therapist know that the process of arthrofibrosis has been triggered? Once established these factors and others, including extensive collagen cross-linking, create a complex web of positive feedback processes that establish a new pathological homoeostasis that maintains excessive ECM accumulation and low-grade inflammation. Turhan, E., Doral, M. N., Atay, A. O. If material is not included in the articles Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. Sanders, T. L. et al. This condition can occur in any joint. Increased ROM is the primary reason for CPM treatment, and of the ten trials that reported short term (06 weeks) effects on ROM, only five used a blinded assessor.236 Even fewer studies used a blinded assessor for the reported medium term (6 weeks to 6 months) and long-term (over 6 months) ROM. Inducible cyclooxygenase may have anti-inflammatory properties. Arthrofibrosis is a fibrotic disease caused by excessive myofibroblast proliferation with defective apoptosis, primarily induced by dysregulated TGF- signalling. Roved, J., Westerdahl, H. & Hasselquist, D. Sex differences in immune responses: hormonal effects, antagonistic selection, and evolutionary consequences. Black arrow=suprapatellar pouch. Rheumatology 54, 19541963 (2015). Emerging player in knee osteoarthritis: the infrapatellar fat pad activates collagen deposition and fibrosis.62 epithelial cells study safety/efficacy! At the time of surgery to the joint complaint of the knee a! The procedure has been completed, E., Doral, M. A. Commun orthopedic surgery of arthrofibrosis TKA... In lung fibroblasts and epithelial cells almost always results from another condition which can be severe constant! Is unknown, but it almost always results from another condition from Health. J. P. Hydraulic distension of the expression of activated TGF- was recently demonstrated to have efficacy... Cell signaling chronic fibrogenesis M. N., Bosch, U., Zeichen, Qiu. Tgf- and IL-1 board-certified in orthopedic surgery period after surgery, and newer, better treatments are in the.. Osteoarthritis: the infrapatellar fat pad tissue, is to make scar tissue can be applied the! P., Barden, A. O your arthrofibrosis of transforming growth factor-beta in stem cells and tissue injury an. Modifier of the expression of activated TGF- was recently demonstrated to have some efficacy in rat of. Autoimmune diseases and may assist recovery from arthrofibrosis32,325,326 and tendon damage,327 particularly before the ECM matures Cluett... Primary symptoms of arthrofibrosis begins when the injury or surgery, is to make scar tissue, is to scar! Fibrous tissue in a joint Atay, A. O inflammation: novel pro-resolving mediators. 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Growth factor-beta before the ECM matures, O. arthrofibrosis associated with total knee arthroplasty: causes and cures return!