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

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.

Diagnostic Modalities for Acute Compartment Syndrome of the Extremities: A Systematic Review.

IMPORTANCE: Acute compartment syndrome (ACS) can cause catastrophic tissue damage leading to permanent muscle and nerve loss. Acute compartment syndrome is a clinical diagnosis, with intracompartmental pressure (ICP) used in equivocal cases. There are no reliable diagnostic methods. The clinical evaluation is impossible to standardize, and the threshold for ICP has been known to be unreliable; thus, guidelines for diagnosis can result in overtreatment or delayed diagnosis. OBJECTIVE: To present and review the advantages and disadvantages of each diagnostic modality and identify gaps that need to be addressed in the future and to review the most used and appropriate animal and human ACS models. EVIDENCE REVIEW: We included clinical studies and animal models investigating diagnostic modalities for ACS of the extremities. A MEDLINE and Web of Science search was performed. The protocol for the study was registered on PROSPERO (CRD42017079266). We assessed the quality of the clinical studies with Newcastle-Ottawa scale and reported level of evidence for each article. FINDINGS: Fifty-one articles were included in this study, reporting on 38 noninvasive and 35 invasive modalities. Near-infrared spectroscopy and direct ICP measurement using a Stryker device were the most common, respectively. Cadaveric studies used saline infusions to create an ACS model. Most studies with human participants included injured patients with acquired ACS or at risk of developing ACS. In healthy human participants, tourniquets formed the most commonly used ACS model. Application of tourniquets and infusion of saline or albumin were the most used ACS models among animal studies. CONCLUSIONS AND RELEVANCE: This article reports on the most common as well as many new and modified diagnostic modalities, which can serve as inspiration for future investigations to develop more effective and efficient diagnostic techniques for ACS. Future studies on diagnostic modalities should include the development of tools for continuous assessment of ICP to better identify the earliest alterations suggestive of impending ACS. With the advent of such technologies, it may be possible to develop far less aggressive and more effective approaches for early detection of ACS.