Vascularized and Innervated Skeletal Muscle Tissue Engineering

Abstract

Volumetric muscle loss (VML) is a devastating loss of muscle tissue that overwhelms the native regenerative properties of skeletal muscle and results in lifelong functional deficits. There are currently no treatments for VML that fully recover the lost muscle tissue and function. Tissue engineering presents a promising solution for VML treatment and significant research has been performed using tissue engineered muscle constructs in preclinical models of VML with a broad range of defect locations and sizes, tissue engineered construct characteristics, and outcome measures. Due to the complex vascular and neural anatomy within skeletal muscle, regeneration of functional vasculature and nerves is vital for muscle recovery following VML injuries. This review aims to summarize the current state of the field of skeletal muscle tissue engineering using 3D constructs for VML treatment with a focus on studies that have promoted vascular and neural regeneration within the muscle tissue post-VML.

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

“…Immediately upon injury damaged myofibers, blood vessels, and neurons undergo necrosis. This is due to membrane damage which permits an influx of extracellular calcium and triggers autodigestion via calcium-dependent proteases such as calpains [30,[48][49][50]. In addition to cellular damage, disruption of the blood vessels and basement membrane surrounding myofibers also occurs upon injury.…”

“…Prolonged in vitro culture times make TEMG clinical scalability, cost-effectiveness, off-the-shelf availability, and regulatory compliance more challenging than in situ and in vivo tissue engineering approaches. Implanted TEMGs have resulted in varied degrees of skeletal muscle regeneration, which is likely due to vast assortment of scaffold biomaterials, cell types, culture time and conditions, construct sizes, stimulation regimes, custom bioreactors, and preclinical models evaluated [49].…”

Biofabricating murine and human myo-substitutes for rapid volumetric muscle loss restoration

“…A variety of approaches including acellular gels [48], cell sheetderived [49], minced muscle [50] or tissue engineering grafts [29] have been proposed for VML treatment. Among these strategies, as described in a recent excellent review on this topic [20], the use of grafts delivered in combination with a myogenic cell source should be preferred to the other methods. In fact, acellular gels, as ultimately demonstrated in a recent study by Corona [51] do not offer any beneficial effect for VML recovery.…”

“…These approaches, while promising, are still far from satisfactorily addressing the second key challenge of SMTE -i.e. the development of macroscopic tissue-equivalents of a size suitable for treating volumetric muscle loss (VML): a condition resulting from large traumatic injury or massive surgical ablation upon tumor removal [20,21]. VML, which is characterized by muscular mass loss, functional deficit and permanent disability, is currently treated by surgical tissue transfer (autologous transplantation).…”

Commitment of Autologous Human Multipotent Stem Cells on Biomimetic Poly-L-Lactic Acid-Based Scaffolds Is Strongly Influenced by Structure and Concentration of Carbon Nanomaterial

“…Neither transplant nor other traditional medicine approaches can solve this problem, at least so far, thus prompting muscle-tissue engineering research as a promising solution for these issues. Moreover, the coordinated regeneration of muscle and nerves is needed because of their complex interconnection, mediating motor co-ordination [4].…”