A Porcine Urinary Bladder Matrix Does Not Recapitulate the Spatiotemporal Macrophage Response of Muscle Regeneration after Volumetric Muscle Loss Injury

Abstract

Volumetric muscle loss (VML) results in irrecoverable loss of muscle tissue making its repair challenging. VML repair with acellular extracellular matrix (ECM) scaffolds devoid of exogenous cells has shown improved muscle function, but limited de novo muscle fiber regeneration. On the other hand, studies using minced autologous and free autologous muscle grafts have reported appreciable muscle regeneration. This raises the fundamental question whether an acellular ECM scaffold can orchestrate the spatiotemporal cellular events necessary for appreciable muscle fiber regeneration. This study compares the macrophage and angiogenic responses including the remodeling outcomes of a commercially available porcine urinary bladder matrix, MatriStem™, and autologous muscle grafts. The early heightened and protracted M1 response of the scaffold indicates that the scaffold does not recapitulate the spatiotemporal macrophage response of the autograft tissue. Additionally, the scaffold only supports limited de novo muscle fiber formation and regressing vessel density. Furthermore, scaffold remodeling is accompanied by increased presence of transforming growth factor and α-smooth muscle actin, which is consistent with remodeling of the scaffold into a fibrotic scar-like tissue. The limited muscle formation and scaffold-mediated fibrosis noted in this study corroborates the findings of recent studies that investigated acellular ECM scaffolds (devoid of myogenic cells) for VML repair. Taken together, acellular ECM scaffolds when used for VML repair will likely remodel into a fibrotic scar-like tissue and support limited de novo muscle fiber regeneration primarily in the proximity of the injured musculature. This is a work of the US Government and is not subject to copyright protection in the USA. Foreign copyrights may apply. Published by S. Karger AG, Basel

Skeletal Myoblast-Seeded Vascularized Tissue Scaffolds in the Treatment of a Large Volumetric Muscle Defect in the Rat Biceps Femoris Muscle

“…40 While implanted myoblasts can regenerate muscle fibers and integrate with host tissue, 41 their regenerative capacity may be significantly reduced compared to the use of freshly isolated satellite cells due to a reduction in proliferation and increase in differentiation, thus limiting the numbers of available progenitors. 15,42 In addition, the regeneration within the large VML defects used here may have been influenced by the local factors such as the inflammatory environment 43 or the presence of fibroblasts. 44 The inflammatory response postmuscle injury has been well studied and important roles have been ascribed to macrophage polarization.…”

“…Acellular scaffolds used to treat VMLs have shown functional improvement, 58 compared to muscle autografts. 43 The use of myogenic cellseeded and vascularized scaffolds used in this study represents attempts to recreate the benefits of autografts. Quiescent satellite cells undergo asymmetric division on activation (e.g., postinjury) to generate stem cells that may return to quiescence and replenish the satellite cell population as well as myoblasts that, after further symmetric division (expansion) and fusion, ultimately form myofibers.…”

Biomimetic sponges for regeneration of skeletal muscle following trauma

“…A clinically approved therapy for repair and regeneration of large muscle defects currently does not exist. Many of the tissue‐engineered scaffolds are either mechanically unsuitable or fail to enhance tissue‐resident stem cell activity . We are only aware of one other study where LM‐111 was delivered to the site of VML injury using hydrogels composed of hyaluronic acid and poly(ethylene glycol) .…”

Decellularized extracellular matrices for tissue engineering applications

“…Although the use of SIS increased the rate of healing and reduced the incidence of ulcer recurrence, scarless healing and complete regeneration of skin was not observed [43]. In rodent models of traumatic volumetric muscle loss (VML) injuries, DECM scaffolds such as rodent muscle-derived ECM [8,44], commercially available SIS-ECM [45] and porcine UBM matrix (MatriStem TM , ACell , Inc.) [13,46], did not appreciably regenerate muscle fiber in vivo and remodeled into a fibrotic scar. In a clinical case study by Mase et al, a military service member with traumatic skeletal muscle injury was treated with a porcine SIS scaffold into the defect site that resulted in functional improvement at 16 weeks without significant muscle fiber regeneration [47].…”