The Prognosis of Arthrofibroses: Prevalence, Clinical Shortcomings, and Future Prospects

Blessing, William A.; Williamson, Amanda K.; Kirsch, Jack R.; Grinstaff, Mark W.

doi:10.1016/j.tips.2021.02.007

Cited by 9 publications

(22 citation statements)

References 151 publications

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“…One of many fibrotic musculoskeletal diseases, arthrofibrosis affects millions of people every year, causing joint discomfort, restricting ROM, hindering daily activities, and severely affecting emotional and physical wellbeing ( 4 , 5 , 11 ). Traditional treatment options focus on pain management or attempt to surgically restore ROM without addressing the underlying disease biology—excessive and aberrant deposition of ECM proteins in and around the joint space.…”

Section: Discussionmentioning

confidence: 99%

“…Arthrofibrosis, also known as adhesive capsulitis or frozen joint, is a widely prevalent musculoskeletal condition that affects greater than 4% of the adult population ( 4 , 8 – 10 ). It often develops idiopathically and also arises from events such as injury, surgery, or postoperative immobilization, causing long-term pain as well as loss in active and passive range of motion (ROM) ( 4 , 5 , 11 ). Pathologically, arthrofibrosis manifests as excessive extracellular matrix (ECM) protein deposition inside and surrounding the joint space due to dysregulated transforming growth factor–β1 (TGF-β1) signaling and subsequent myofibroblast differentiation and proliferation ( 5 , 12 ).…”

Section: Introductionmentioning

confidence: 99%

“…Pathologically, arthrofibrosis manifests as excessive extracellular matrix (ECM) protein deposition inside and surrounding the joint space due to dysregulated transforming growth factor–β1 (TGF-β1) signaling and subsequent myofibroblast differentiation and proliferation ( 5 , 12 ). Current treatments for frozen shoulder include physical therapy, nonsteroidal anti-inflammatory drugs (NSAIDs), oral or intraarticular injections of corticosteroids to reduce inflammation and pain, and intraarticular sodium hyaluronate injections ( 11 ). With no targeted therapeutics available that treat the underlying disease etiology, the pain and decreased quality of life stemming from arthrofibrosis pushes millions of individuals every year to undergo invasive surgical operations in an attempt to alleviate their symptoms ( 8 ).…”

Section: Introductionmentioning

confidence: 99%

“…Common surgical treatments are manipulation under anesthesia (MUA), where fibrous adhesions are physically torn by mobilizing the joint beyond the point of conscious comfort, and capsular release, where the tightened, fibrotic synovium is surgically opened to increase mobility ( 13 ). MUA and capsular release often exacerbate the condition and incite a new fibrotic response ( 11 ). In addition, these invasive surgical procedures, as well as currently available therapeutics, only treat the symptoms of adhesive capsulitis; they fail to target the underlying pathology of the disease—fibroblast dysregulation and fibrotic tissue accumulation in the joint space ( 4 , 5 , 11 ).…”

Section: Introductionmentioning

confidence: 99%

“…MUA and capsular release often exacerbate the condition and incite a new fibrotic response ( 11 ). In addition, these invasive surgical procedures, as well as currently available therapeutics, only treat the symptoms of adhesive capsulitis; they fail to target the underlying pathology of the disease—fibroblast dysregulation and fibrotic tissue accumulation in the joint space ( 4 , 5 , 11 ).…”

Section: Introductionmentioning

confidence: 99%

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Minimally invasive, sustained-release relaxin-2 microparticles reverse arthrofibrosis

et al. 2022

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Substantial advances in biotherapeutics are distinctly lacking for musculoskeletal diseases. Musculoskeletal diseases are biomechanically complex and localized, highlighting the need for novel therapies capable of addressing these issues. All frontline treatment options for arthrofibrosis, a debilitating musculoskeletal disease, fail to treat the disease etiology—the accumulation of fibrotic tissue within the joint space. For millions of patients each year, the lack of modern and effective treatment options necessitates surgery in an attempt to regain joint range of motion (ROM) and escape prolonged pain. Human relaxin-2 (RLX), an endogenous peptide hormone with antifibrotic and antifibrogenic activity, is a promising biotherapeutic candidate for musculoskeletal fibrosis. However, RLX has previously faltered through multiple clinical programs because of pharmacokinetic barriers. Here, we describe the design and in vitro characterization of a tailored drug delivery system for the sustained release of RLX. Drug-loaded, polymeric microparticles released RLX over a multiweek time frame without altering peptide structure or bioactivity. In vivo, intraarticular administration of microparticles in rats resulted in prolonged, localized concentrations of RLX with reduced systemic drug exposure. Furthermore, a single injection of RLX-loaded microparticles restored joint ROM and architecture in an atraumatic rat model of arthrofibrosis with clinically derived end points. Finally, confirmation of RLX receptor expression, RXFP1, in multiple human tissues relevant to arthrofibrosis suggests the clinical translational potential of RLX when administered in a sustained and targeted manner.

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Section: Discussionmentioning

confidence: 99%