Exploratory study on the effect of osteoactivin on muscle regeneration in a rat volumetric muscle loss model.

Jinjin Ma,Anthony Calabro,Kathleen A Derwin,Andrew R Baker,Atsushi Asakura

doi:10.1371/journal.pone.0175853

Abstract

Wounds causing extensive injury loss of muscle, also known as volumetric muscle loss (VML), are frequently associated with high-energy civilian trauma and combat-related extremity injuries. Currently, no effective clinical therapy is available for promoting de novo muscle tissue regeneration to restore muscle function following VML. Recent studies have shown evidence that osteoactivin (OA), a transmembrane glycoprotein, has the ability to prevent skeletal muscle atrophy in response to denervation. Therefore the objective of this study is to investigate the potential regenerative effect of OA embedded and delivered via a cross-linked gelatin hydrogel within a volumetric tibialis anterior muscle defect in a rat model. After 4 weeks, however, no evidence for muscle formation was found in defects treated with either low (5 μg/ml) or high (50 μg/ml) OA. It is possible that a different delivery scaffold, delivery kinetics, or OA concentration may have yielded an alternate outcome, or it is also possible that the spaciostructural environment of VML, or the local (versus systemic) delivery of OA, simply does not support any potential regenerative activity of OA in VML. Together with prior work, this study demonstrates that an efficacious and scalable therapy for regenerating muscle volume and function in VML remains a veritable clinical challenge worthy of continued future research efforts.

Highlights

Wounds causing extensive damage and loss of muscle, known as volumetric muscle loss (VML), are frequently associated with high-energy civilian trauma and combat-related extremity injuries
The total amount of OA released from the gel after 5 days of in vitro incubation was 0.036±0.003μg (3.6% of the total OA embedded in the gel) in low OA group and 0.75±0.282 μg (7.5% of the total OA embedded in the gel) in high OA group (S1 File)
The defect created in the tibialis anterior (TA) muscle was equivalent to more than 20% of the entire TA muscle mass, and this model is commonly chosen for VML studies

Summary

Introduction

Wounds causing extensive damage and loss of muscle, known as volumetric muscle loss (VML), are frequently associated with high-energy civilian trauma and combat-related extremity injuries. These injuries commonly have a high projected healthcare cost and affect the quality of many patients’ lives. Surgical reconstruction (i.e., free muscle transfer) is performed with the intent to restore partial function. Donor site morbidity and chronic pain are frequently associated with the reconstruction. Many patients eventually face or choose amputation due to the functional deficits from the injury site [2]. No effective clinical therapy is available for promoting de novo muscle tissue

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