Biomimetic scaffolds for regeneration of volumetric muscle loss in skeletal muscle injuries

Abstract

Skeletal muscle injuries typically result from traumatic incidents such as combat injuries where soft-tissue extremity injuries are present in one of four cases. Further, about 4.5 million reconstructive surgical procedures are performed annually as a result of car accidents, cancer ablation, or cosmetic procedures. These combat- and trauma-induced skeletal muscle injuries are characterized by volumetric muscle loss (VML), which significantly reduces the functionality of the injured muscle. While skeletal muscle has an innate repair mechanism, it is unable to compensate for VML injuries because large amounts of tissue including connective tissue and basement membrane are removed or destroyed. This results in a significant need to develop off-the-shelf biomimetic scaffolds to direct skeletal muscle regeneration. Here, the structure and organization of native skeletal muscle tissue is described in order to reveal clear design parameters that are necessary for scaffolds to mimic in order to successfully regenerate muscular tissue. We review the literature with respect to the materials and methodologies used to develop scaffolds for skeletal muscle tissue regeneration as well as the limitations of these materials. We further discuss the variety of cell sources and different injury models to provide some context for the multiple approaches used to evaluate these scaffold materials. Recent findings are highlighted to address the state of the field and directions are outlined for future strategies, both in scaffold design and in the use of different injury models to evaluate these materials, for regenerating functional skeletal muscle.

Statement of significance: Volumetric muscle loss (VML) injuries result from traumatic incidents such as those presented from combat missions, where soft-tissue extremity injuries are represented in one of four cases. These injuries remove or destroy large amounts of skeletal muscle including the basement membrane and connective tissue, removing the structural, mechanical, and biochemical cues that usually direct its repair. This results in a significant need to develop off-the-shelf biomimetic scaffolds to direct skeletal muscle regeneration. In this review, we examine current strategies for the development of scaffold materials designed for skeletal muscle regeneration, highlighting advances and limitations associated with these methodologies. Finally, we identify future approaches to enhance skeletal muscle regeneration.

Keywords: Biomaterials; Fibrin; Microthreads; Skeletal muscle regeneration; Tissue engineering.

Figure 1

Schematic illustration showing the hierarchical arrangement of skeletal muscle tissue. Skeletal muscle tissue is a highly organized series of cable like structures, with the smallest functional unit referred to as a myofibril. Bundles of myofibrils form myofibers, which in turn are grouped together to form fascicles, which are bundled to form the muscle belly.

Figure 2

Schematic representation of native skeletal muscle regeneration. (A) SCs can be identified by their position between the sarcolemma and basal lamina of mature skeletal muscle. (B) Upon injury, SCs are recruited to the wound site and begin to proliferate. (C) These proliferating SCs will eventually fuse together to form immature myofibers, (D) which will fuse with the existing healthy myofibers, and will then mature by expressing more contractile proteins to regenerate functional tissue. In VML injuries, (E) the basal lamina is destroyed or removed, facilitating the migration of fibroblasts into the wound site. (F) In the absence of proper signaling cues, fibroblasts begin to deposit collagen, (G) ultimately leading to massive scar tissue formation.

Figure 3

Schematic representation of scaffold mediated repair of volumetric muscle loss (VML). (A) VML injuries span large portions of the muscle belly, and (B) can be repaired using bulk scaffolds to fill this void space. These scaffolds support tissue repair, but functional regeneration is limited by disorganized myofiber and scar tissue formation. (C) Scaffolds with precisely engineered topographic cues to direct aligned tissue growth, such as microthreads, will guide organized myofiber formation for more robust functional tissue regeneration.