Asynchronous inflammation and myogenic cell migration limit muscle tissue regeneration mediated by acellular scaffolds

Abstract

Volumetric muscle loss (VML) following orthopaedic trauma results in chronic loss of strength and can contribute to disability. Tissue engineering and regenerative medicine approaches to regenerate the lost skeletal muscle and improve functional outcomes are currently under development. At the forefront of these efforts, decellularized extracellular matrices (ECMs) have reached clinical testing and provide the foundation for other approaches that include stem/progenitor cell delivery. ECMs have been demonstrated to possess many qualities to initiate regeneration, to include stem cell chemotaxis and pro-regenerative macrophage polarization. However, the majority of observations indicate that ECM-repair of VML does not promote appreciable muscle fiber regeneration. In a recent study, ECM-repair of VML was compared to classical muscle fiber regeneration (Garg et al., 2014, Cell & Tissue Research) mediated by autologous minced grafts. The most salient findings of this study were: 1) Satellite cells did not migrate into the scaffold beyond ~0.5 mm from the remaining host tissue, although other migratory stem cells (Sca-1+) were observed throughout the scaffold;2) Macrophage migration to the scaffold was over two-times that observed with muscle grafts, but they appeared to be less active, as gene expression of pro- and anti-inflammatory cytokines (TNF-α, IL-12, IL-4, IL-10, VEGF, and TGF-β1) was significantly reduced in scaffold-repaired muscles; And, 3) scaffolds did not promote appreciable muscle fiber regeneration. Collectively, these data suggest that the events following ECM transplantation in VML are either incongruous or asynchronous with classical muscle fiber regeneration.

Skeletal Muscle Tissue Engineering: Biomaterials-Based Strategies for the Treatment of Volumetric Muscle Loss

“…Decellularized ECM is a scaffold prepared by removing cells from source mammalian tissue or whole organs, leaving behind the native ECM with preserved structural and chemical composition. Decellularized ECM has been used as a biomaterial because it contains the native ligands, ECM proteins, and growth factors found in skeletal muscle which are known to play an instrumental role in SC chemotaxis and proliferation, the inflammatory response, myotube differentiation and, ultimately, functional tissue regeneration [63,[127][128][129]. These ECM molecules include collagens, laminin, fibronectin, heparin sulfate, chondroitin sulfate, HA, VEGF, FGF2, and TGF-β [130][131][132][133].…”

Aligned nanofibers of decellularized muscle ECM support myogenic activity in primary satellite cells in vitro

“…Looking forward, the defects created in VML injuries are large, empty, amorphous gaps in the muscle tissue. Promoting adequate proliferation of satellite cells and myogenic progenitors are one of the major challenges of VML repair [4,7,26,47]. Implantation of autologous satellite cells in vivo have proven inefficient due to low viability and survival post-implantation [65,66].…”

“…The D-ECM scaffolds containing key basement membrane structural proteins, growth factors, and glycosaminoglycans (GAG) have been shown to support vascularization and functional recovery post-VML injury [4,17,[22][23][24][25]. However, D-ECM scaffolds have been unable to regenerate muscle fiber following VML appreciably, and often result in fibrotic tissue deposition (reviewed in [26]). In a rodent muscle VML injury model, transplantation of a decellularized porcine UBM resulted in fibrotic scar tissue deposition with little to no muscle fiber regeneration.…”

The effect of the chemical composition and structure of polymer films made from resorbable polyhydroxyalkanoates on blood cell response

“…Particular consideration was given to the response of monocytes to polymer films of Studies of poly(ε-caprolactone)-scaffolds [56] and polydioxanone-scaffolds [57] showed that increased hydrophilicity and elasticity exerted favorable effects on this type of cells.…”