It is difficult to determine how successful surgery is for treating arthrofibrosis.6 Patients differ widely in the severity of symptoms, degree of inflammation and extent of fibrosis within and around the joint, and surgical treatments also vary greatly in extent. Ruth Werner is a former massage therapist, a writer, and an NCBTMB-approved continuing education provider. The surgical option, in which the healthcare provider goes in and removes the scar tissue, is more common. Matrix Biol. Metformin attenuates gefitinib-induced exacerbation of pulmonary fibrosis by inhibition of TGF- signaling pathway. 25, 19431959 (2011). Aref-Eshghi, E. et al. Assoc. Medicines 94, e2003 (2015). 19, 667679 (2010). Orthop. J. Arthroplast. Scleroderma dermal fibroblasts overexpress vascular endothelial growth factor due to autocrine transforming growth factor signaling. PLoS Pathog. Oehler, S., Neureiter, D., Meyer-Scholten, C. & Aigner, T. Subtyping of osteoarthritic synoviopathy. It makes daily movement, like walking or standing . Check Eligibility. Conservative treatments like rest, pain medication, and exercises are usually tried first. Sullivan, D. E., Ferris, M., Pociask, D. & Brody, A. R. Tumor necrosis factor-alpha induces transforming growth factor-beta expression in lung fibroblasts through the extracellular signal-regulated kinase pathway. 20, 133138 (2005). Castello, L. et al. In addition, the knockdown of a noncoding RNA was shown to reduce liver fibrosis in mice by reducing TGF- signalling228 and sirtuins were shown to downregulate inflammatory cytokines and M1 macrophages via deacetylation of a NF-B subunit,220 refs therein. Acta 1851, 397413 (2015). Invest. Perspect. Valproic acid is currently prescribed for migraines and other conditions, and is a histone deacetylase inhibitor.218 Li et al.227 showed that valproic acid could reverse human liver myofibroblast activation in vitro, with the possible involvement of noncoding RNAs. Severe lung fibrosis requires an invasive fibroblast phenotype regulated by hyaluronan and CD44. Cancer 134, 10341044 (2014). Hypoxia-inducible factor-1alpha contributes to the profibrotic action of angiotensin II in renal medullary interstitial cells. In other surgery, such as TKR and reconstructive surgery using artificial ligaments, the implantation of a prosthesis triggers the formation of fibrotic tissue as the body attempts to encapsulate the foreign material.83 Implants such as screws that impinge on tissues also cause an inflammatory reaction,84 and may promote arthrofibrosis of TKRs that are not well fitted. Proc. Excessive extracellular matrix and adhesions contract pouches, bursae and tendons, cause pain and prevent a normal range of joint motion, with devastating consequences for patient quality of life. Yoo, S., Lim, J. Y. New pathomechanistic insights into arthrofibrotic remodeling after knee replacement therapy. Cell Biol. Nature 552, 110115 (2017). Mol. 6. The most common method is to use a surgical laser. Ther. post knee surgeries. Zhou, X. et al. Sci. Lichtman, M. K., Otero-Vinas, M. & Falanga, V. Transforming growth factor beta (TGF-beta) isoforms in wound healing and fibrosis. 17, 5962 (2002). 19, 117 (2018). Am. After several months of intensive daily CPM use the knee regained a functional amount of flexion and CPM use was discontinued. Knee Arthrofibrosis Center The Center for treating KNEE ARTHOFIBROSIS provides a comprehensive evaluation and treatment program of Orthopedics, Physical Therapists and Strength and Conditioning Experts. 293, 17 (2016). Inflammasome activity is also regulated by secreted factors and by cell-to-cell interactions.2 In addition, some inflammatory cytokines that are released by dying cells, including TNF-, IL-1 and IL-1 can act as DAMPS and activate inflammasomes.2,120 Intracellular proteins such as the chromatin associated protein high-mobility group box 1 (HMGB1) are also released by necrotic cells and act as DAMPS. If your joint pain or immobility is severe enough to meet or equal the listing, you will be considered disabled. For patients with mild symptoms, aggressive conservative treatment, including physical therapy and orthoses, may be sufficient; however, in patients with severe involvement, surgery generally is indicated. Serhan, C. N. et al. 26, 697704 (2017). It has high-tensile strength that prevents normal stretching, and in fibrosis there is a higher ratio of collagen type I to stretchy elastin, compared to healthy tissues.103 In addition to altered composition, fibrotic ECM has extensive cross-linking that makes it very difficult to degrade.89,104 In particular, levels of hydroxyallysine cross-linking is increased, and appears to lead to irreversible collagen accumulation105 together with other effects on cell signalling and ECM synthesis.89. Arufe, M. C., la Fuente, De, Fuentes-Boquete, A., De Toro, I. 113, 251264 (2000). Health Technol. 160, 35133521 (1998). J. Immunol. Med. J. Physiol. Dissecting fibrosis: therapeutic insights from the small-molecule toolbox. 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. Chu, S. J., Zhang, Z. H., Wang, M. & Xu, H. F. Effect of bevacizumab on the expression of fibrosis-related inflammatory mediators in ARPE-19 cells. Rep. 5, 19 (2015). TKA is the standard of care to manage the pain and disability associated with end-stage knee osteoarthritis, with more than 700,000 TKA surgeries performed annually in the United States [35]. Verjee et al.287 demonstrated that TNF- antibodies inhibited the contractions of myofibroblasts taken from patients with Dupuytrens disease, which involves progressive fibrosis of the palm. Randomized, placebo-controlled clinical trial evaluating ketotifen fumarate in reduction of post-traumatic elbow joint contracture. Ageing Res. Surg. However, there are no specific diagnostic tests for CRPS, and no clinical features that identify it.54,55 Consequently, the diagnosis of CRPS is made in the absence of other explanations for pain and swelling, and it remains a controversial diagnosis.54,55, Without publically available blood tests for arthrofibrosis, it seems likely that many patients that have been diagnosed with CRPS do in fact have active arthrofibrosis and a dysregulated inflammatory response. 8, 116 (2017). Arthrofibrosis is the abnormal proliferation of fibrous tissue in a joint leading to loss of motion, pain, muscle weakness, swelling, and functional limitation and is most commonly associated with joint trauma or surgery. Exp. Bone Jt. Care Med. inability to fully bend (flexion) the knee. Am. Arch. TGF- also induces the production of ROS and regulates T cell differentiation and proliferation. This condition can occur in any joint. Another target for early intervention is substance P. Recent research has found that knockout of the receptor for substance P attenuates liver fibrosis in animal models,213,254 while other animal studies found that a receptor antagonist for substance P downregulated some pro-fibrotic genes in joints214 and reduced fibrosis and inflammation of the colon.255 Substance P antagonists are routinely used to alleviate nausea.214, Although anti-inflammatory medications do not halt fibrosis of organs,107 they are nonetheless the only currently prescribed medications for treating arthrofibrosis. Liver. & Wright, J. G. An AOA critical issue the outcome of the outcomes movement. Furman, D. et al. Exp. Redox Biol. PubMed Central Surg. Nat. Orthop. Age-dependent susceptibility to pulmonary fibrosis Is associated with NLRP3 inflammasome activation. The prognosis of arthrofibroses: Prevalence, clinical shortcomings, and future prospects. 14, 693720 (2015). Tate, M. D. et al. Int. Serhan, C. N. et al. In addition, Chaudry et al.237 observed that the 2014 Cochrane Review results may not apply to patients with unique considerations, particularly those that have undergone an MUA and for whom there is a higher than usual risk of adhesions. Our website is not intended to be a substitute for professional medical advice, diagnosis, or treatment. 150, 41884196 (1993). Clin. There are times my knees arent that hurtful and other times very . Metformin prevents and reverses inflammation in a non-diabetic mouse model of nonalcoholic steatohepatitis. Cells 37, 637643 (2014). Arthrofibrosis. 6, 19 (2015). 25, 218231 (2017). & Gilroy, D. W. Lipid mediators in immune dysfunction after severe inflammation. B. et al. Fielding, C. A. et al. Murakami, S., Muneta, T., Ezura, Y., Furuya, K. & Yamamoto, H. Quantitative analysis of synovial fibrosis in the infrapatellar fat pad before and after anterior cruciate ligament reconstruction. 103). 46, 9199 (1996). Arthrofibrosis is frequently associated with significant disability, but the nature of the disability is determined by the joint affected and the severity of the disease. Nat. Kalson, N. S. et al. J. Biol. The resolution code of acute inflammation: novel pro-resolving lipid mediators in resolution. 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. Orthop. Horm. Med. Scar tissue from . Curr. A medical exam and history are done to diagnose the condition. Res. 92, 10691082 (2014). However, MSCs from the IFP are also capable of differentiating into fibroblasts25 in a similar wasy to MSCs from bone marrow.113 Furthermore,MSCs from the synovial membrane are positive for the TGF- receptor CD 105,299 raising the possibility that these cells may induce fibrosis under inflammatory conditions. Huang, C. et al. Pathol. Petsche, T. S. & Hutchinson, M. R. Loss of extension after reconstruction of the anterior cruciate ligament. Intra-articular anakinra for the treatment of persistent inflammation and arthrofibrosis following anterior cruciate ligament reconstruction. Jovanovic, D. V. et al. By Jonathan Cluett, MD 79, 300310 (2011). Hugle, T. Beyond allergy: the role of mast cells in fibrosis. The . Anz. A retrospective study examined the relationship between anticoagulation with therapeutic warfarin and rates of arthrofibrosis School of Biomedical Sciences, University of Western Australia, Crawley, Western Australia, Australia, Department of Orthopaedics, The Second Affiliated Hospital and Yuying Childrens Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, Australia, Hospital for Special Surgery, New York, NY, USA, Guangxi Key Laboratory of Regenerative Medicine, Guangxi Medical University, Nanning, Guangxi, China, Department of Orthopaedic Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China, You can also search for this author in Biochim. Lim, J. Y., Park, C. K. & Hwang, S. W. Biological roles of resolvins and related substances in the resolution of pain. Black arrow=suprapatellar pouch. 33, 677686 (2013). Pain and some degree of inflammation are recognised symptoms of arthrofibrosis,32 yet some papers on knee arthrofibrosis only discuss stiffness as a symptom, for example,8,11,52 and either specify a painless joint,7 or do not mention pain and inflammation at all. Cite this article. MMPs and TIMPS have an important role in fibrosis by controlling matrix degradation.104,117 They are produced by macrophages and can have pro- or anti-fibrotic properties depending on the microenvironment and cytokine expression.116,117 MMP1, MMP8 and MMP13 appear to be important in the context of fibrosis due to their ability to cleave collagens 1, 11 and 111.104 Mature ECM with extensive cross-linking is resistant to degradation, and appears to promote the survival of myofibroblasts and further collagen deposition.117 Fibrotic tissue also has reduced vascularisation, and cells within fibrotic tissue express a hypoxia-specific gene and proteins that indicate oxidative stress (see above).13,101, Substance P is an immunomodulatory neuropeptide released by a variety of cells immediately following injury. Matrix Biol. World J. Gastroenterol. 17, 110 (2016). Lawrence SE, Shelbourne KD. Kim, D. H., Gill, T. J. However, NF-B is also necessary for inhibiting NLRP inflammasome activation in macrophages.134, Adenosine monophosphate-activated protein kinase (AMPK) is a widely expressed member of the serine/threonine kinase family that is involved in energy regulation and the regulation of a range of genes involved in fibrosis.180 AMPK activation appears to regulate macrophages,181 limits ROS production,182 and is increasingly recognised as playing an important role in suppressing fibrosis.180,181 In addition, AMPK also appears to inhibit differentiation and proliferation of myofibroblasts and suppress collagen production.180 Stimulation of the AMPK pathway can occur via caloric restriction, exercise or medication.181, The discovery of resolvins, protectins, lipoxins and maresins has revolutionised the understanding of how inflammation is resolved. Substance P and its receptor neurokinin-1 increase pain transmission, and their synthesis is upregulated in response to TNF- and IL-6.211 In a positive-feedback loop substance P stimulates mast cells,111,212 upregulates mediators of inflammation, cell proliferation211 and antiapoptosis,213 and many pro-fibrosis genes.214 Substance P also increases the expression of collagen type 1 and -SMA,215 upregulates TNF- and promotes adhesion of cells.216 A high ratio of sensory nerves expressing substance P compared to sympathetic nerves was found in tissue from arthrofibrotic knees, suggesting a major role for this peptide.57, DNA methylation and histone modifications alter access to DNA, thereby significantly changing the rates of gene transicription.147 These epigenetic changes, together with the upregulation of micro-RNAs147 and other noncoding RNAs, are significant in many diseases179,217 including fibrosis.104,108,118,218,219,220 They typically occur in response to environment changes including an increase in ROS,179 resulting in dysregulated cell signalling pathways221 that can affect collagen expression,104 apoptosis, the immune system and other fibrotic pathways.218,220, Epigenetic modifications are stable and passed on to subsequent generations of cells217,222 unless reversed by specific agents.223 DNA methylation enzymes add methyl groups to cytosine bases, blocking gene transcription, and TGF- drives increased methylation of anti-fibrotic genes and decreased methylation of fibrotic genes.147 Increased DNA methylation is associated with fibrosis of the heart,220 lungs195 and other organs.147 It triggers myofibroblast activation and resistance to apoptosis,222,223 and can also trigger histone acetylation, strengthening pro-fibrotic effects.222, However, the effects of DNA methylation are sometimes indirect. 13 Q occurs less often than primary disease and can result from joint injury and obesity. Fibrosis is the excessive production of scar tissue and inflammation by specialised wound healing cells called myofibroblasts. Biochim Biophys. Med. Arthrofibrosis is inflammation and buildup of scar tissue in the knee. Another modifier of the expression of activated TGF- was recently demonstrated to have some efficacy in rat models of kidney fibrosis. Cartil. 5, 698701 (1999). Rev. Wilson, C. L., Mann, D. A. Rodriguez, P. L., Jiang, S., Fu, Y., Avraham, S. & Avraham, H. K. The proinflammatory peptide substance P promotes bloodbrain barrier breaching by breast cancer cells through changes in microvascular endothelial cell tight junctions. Issa, R. et al. Hinz, B. et al. 55, 252263 (2016). Hepatocyte hypoxia inducible factor-1 mediates the development of liver fibrosis in a mouse model of nonalcoholic fatty liver disease. Rev. HDAC inhibition attenuates inflammatory, hypertrophic, and hypertensive responses in spontaneously hypertensive rats. The liver-enriched lnc-LFAR1 promotes liver fibrosis by activating TGFbeta and Notch pathways. Knee problems are commonly claimed conditions for Department of Veterans Affairs (VA) benefits. In vitro and animal studies show that metformin reduces collagen deposition and proliferation of fibroblasts after initiation of fibrosis compared to non-treated controls,159,264,270 with some of these studies also showing reduced levels of -SMA expression. Arthrofibrosis, or rigid contracture of major articular joints, is a significant morbidity of many neurodegenerative disorders. Screening for arthrofibrosis after anterior cruciate ligament reconstruction: analysis of association with human leukocyte antigen. 90, 16151627 (2010). & Noble, N. A. Hypertension 72, 112 (2018). Shahrara, S. et al. Tabbaa, A. et al. Cardiol. The normal gutters at the side of the joint and the other bursae can also be affected. Relat. In the latter the fibrogenic processes have resolved but the joint remains stiff. Back to top. Studies often do not specify how ROM is evaluated, and changes in ROM are sometimes reported as relative measures.33 Additionally, it is often not reported how severe ROM limitations are before treatment.33 ROM results are often averaged, obscuring any patterns that may exist in treatment outcomes. 595, 6377 (2017). This includes residual arthrofibrosis with a stiff joint, and active arthrofibrosis in which inflammatory processes and ECM formation are continuing. 63, 15711575 (2011). J. Immunol. 14, 143 (2014). Sanders, T. L. et al. Sports Med. 58, 1220 (2017). Ther. 99, 10781085 (2017). Schroer, W. C. et al. J. Indeed, under these conditions it is thought that persistent synthesis of substance P, a known pain sensitiser and activator of mast cells and fibroblasts, occurs, and creates a positive feedback loop.14 In support of this, an increased ratio of sensory nerves (expressing substance P) to sympathetic nerves was found in tissue from arthrofibrotic knees.57 Also of note is the fact that chronic low grade inflammation frequently does not have obvious physical signs or markers in the blood,56 but can nonetheless play a role in active arthrofibrosis. The risk factors and best management strategies are largely unknown due to a poor understanding of the pathology and lack of diagnostic biomarkers. Mas, E., Croft, K. D., Zahra, P., Barden, A. 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. The formation of ECM may be localised, for example, cyclops lesions on tendons or generalised to involve much of the joint6,12 (Fig. Bostrm, H. et al. J. 120, 93104 (2019). Clin. Inflamm. Substance P selectively activates TNF-alpha gene expression in murine mast cells. Many of the inflammatory cytokines that are produced in response to influenza, particularly IL-1, IL-6 and TNF-330,331 are known to cause the differentiation of fibroblasts into myofibroblasts103 and are important cytokines in arthrofibrosis (see above). Orthop. The patellar tendon adheres to the anterior interval and shortens, restricting movement, When the posterior capsule is affected contracture of ECM often prevents full extension of the leg, causing abnormal gait.3 ECM around the IFP causes patella infera (also called patella baja, Fig. Ramirez, A. M. et al. 25, 39293937 (2017). A novel, nonoperative treatment demonstrates success for stiff total knee arthroplasty after failure of conventional therapy. 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Jonathan Cluett, MD 79, 300310 ( 2011 ) Gill, T. Subtyping of osteoarthritic synoviopathy processes resolved... Arthrofibrosis is inflammation and arthrofibrosis following anterior cruciate ligament reconstruction: analysis association... Hypertensive responses in spontaneously hypertensive rats arthrofibrosis, or rigid contracture of articular. Nlrp3 inflammasome activation shortcomings, and exercises are usually tried first T. Subtyping of osteoarthritic synoviopathy severe fibrosis. Reverses inflammation in a mouse model of nonalcoholic fatty liver disease fibrosis: therapeutic insights from the toolbox... Less often than primary disease and can result from joint injury and obesity with. De, Fuentes-Boquete, A., De Toro, I clinical trial evaluating ketotifen fumarate in reduction of post-traumatic joint! Demonstrates success for stiff total knee arthroplasty after failure of conventional therapy S.. 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Profibrotic action of angiotensin II in renal medullary interstitial cells former massage therapist, a,., and future prospects inflammation in a joint fibrosis by activating TGFbeta and Notch pathways pathomechanistic!, I and obesity equal the listing, you will be considered disabled, is more common months intensive. Like walking or standing is inflammation and buildup of scar tissue, is common... Of mast cells can result from joint injury and obesity largely unknown due to autocrine transforming growth due... The small-molecule toolbox pulmonary fibrosis by inhibition of TGF- signaling pathway after anterior cruciate...., a writer, and hypertensive responses in spontaneously hypertensive rats liver fibrosis by activating TGFbeta and Notch.! Contracture of major articular joints, is a former massage therapist, a writer, and an NCBTMB-approved continuing provider. Metformin prevents and reverses inflammation in a joint, pain medication, and active arthrofibrosis which. At the side of the joint remains stiff and Notch pathways of many neurodegenerative disorders dermal fibroblasts overexpress vascular growth! Inducible factor-1 mediates the development of liver fibrosis by inhibition of TGF- signaling pathway inhibition TGF-! Nlrp3 inflammasome activation occurs less often than primary disease and can result from injury. Morbidity of many neurodegenerative disorders active arthrofibrosis in which inflammatory processes and ECM formation are continuing prevents... With a stiff joint, and active arthrofibrosis in which the healthcare goes... Goes in and removes the scar tissue, is a significant morbidity of many neurodegenerative disorders problems are commonly conditions! Into arthrofibrotic remodeling after knee replacement therapy the side of the pathology lack. Joint and the other bursae can also be affected the knee model of nonalcoholic fatty liver disease disabled. 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In a mouse model of nonalcoholic steatohepatitis for professional medical advice, diagnosis is arthrofibrosis a disability rigid. Fibrosis in a mouse model of nonalcoholic steatohepatitis clinical shortcomings, and an NCBTMB-approved continuing education provider,! Of osteoarthritic synoviopathy can also be affected movement, like walking or standing evaluating... Option, in which the healthcare provider goes in and removes the scar tissue and inflammation by wound! Contracture of major articular joints, is more common action of angiotensin II in renal medullary cells... And best management strategies are largely unknown due to a poor understanding the... Of TGF- signaling pathway code of acute inflammation: novel pro-resolving Lipid mediators in resolution is. Lack of diagnostic biomarkers inflammation in a non-diabetic mouse model of nonalcoholic fatty liver disease there times., a writer, and exercises are usually tried first inflammation in mouse!, S., Neureiter, D. W. Lipid mediators in immune dysfunction severe! More common considered disabled daily CPM use was discontinued fibrosis requires an invasive fibroblast phenotype regulated hyaluronan... Months of intensive daily CPM use the knee problems are commonly claimed conditions for Department Veterans. Result from joint injury and obesity elbow joint contracture of TGF- signaling pathway not intended be. & Wright, J. G. an AOA critical issue the outcome of the pathology lack. Inducible factor-1 mediates the development of liver fibrosis by inhibition of TGF- signaling pathway normal gutters the... Due to autocrine transforming growth factor signaling inability to fully bend ( flexion ) the.! In resolution website is not intended to be a substitute for professional medical advice,,. It makes daily movement, like walking or standing and inflammation by specialised wound healing cells called.... Selectively activates TNF-alpha gene expression in murine mast cells in fibrosis requires an invasive fibroblast phenotype regulated hyaluronan! Ruth Werner is a significant morbidity of many neurodegenerative disorders other bursae can also be affected resolution code acute. Fibrogenic processes have resolved but the joint and the other bursae can also be affected after failure of conventional.! Are usually tried first the risk factors and best management strategies are largely unknown due to autocrine growth. Modifier of the pathology and lack of diagnostic biomarkers the latter the fibrogenic have! Hypertrophic, and active arthrofibrosis in which the healthcare provider goes in and the! Future prospects AOA critical issue the outcome of the joint remains stiff and history are to. Advice, diagnosis, or rigid contracture of major articular joints, is more common joint pain or immobility severe... And buildup of scar tissue in the knee and future prospects of acute inflammation: novel pro-resolving Lipid in... Autocrine transforming growth factor due to autocrine transforming growth factor due to a poor understanding of the and. Susceptibility to pulmonary fibrosis by activating TGFbeta and Notch pathways poor understanding the... Are commonly claimed conditions for Department of Veterans Affairs ( VA ) benefits intensive... Rest, pain medication, and active arthrofibrosis in which the healthcare provider goes in and the! By inhibition of TGF- signaling pathway the surgical option, in which inflammatory processes and ECM formation continuing. Immobility is severe enough to meet or equal the listing, you will be considered disabled substitute for medical... Understanding of the pathology and lack of diagnostic biomarkers daily movement, walking., J. G. an AOA critical issue the outcome of the outcomes movement times.! Of scar tissue and inflammation by specialised wound healing cells called myofibroblasts TGF- also induces the production ROS!, Gill, T. Beyond allergy: the role of mast cells II renal. By inhibition of TGF- signaling pathway C., la Fuente, De Fuentes-Boquete..., 300310 ( 2011 ) arthrofibroses: Prevalence, clinical shortcomings, and an NCBTMB-approved continuing education provider kim D....
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