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Review
. 2024 Sep;52(9):2325-2347.
doi: 10.1007/s10439-024-03541-w. Epub 2024 Jul 31.

Tissue Engineered 3D Constructs for Volumetric Muscle Loss

Sonal Gahlawat  1 , Doga Oruc  1 , Nikhil Paul  1 , Mark Ragheb  1 , Swati Patel  1 , Oyinkansola Fasasi  1 , Peeyush Sharma  1 , David I Shreiber  1 , Joseph W Freeman  2
Affiliations
Review

Tissue Engineered 3D Constructs for Volumetric Muscle Loss

Sonal Gahlawat et al. Ann Biomed Eng. 2024 Sep.

Abstract

Severe injuries to skeletal muscles, including cases of volumetric muscle loss (VML), are linked to substantial tissue damage, resulting in functional impairment and lasting disability. While skeletal muscle can regenerate following minor damage, extensive tissue loss in VML disrupts the natural regenerative capacity of the affected muscle tissue. Existing clinical approaches for VML, such as soft-tissue reconstruction and advanced bracing methods, need to be revised to restore tissue function and are associated with limitations in tissue availability and donor-site complications. Advancements in tissue engineering (TE), particularly in scaffold design and the delivery of cells and growth factors, show promising potential for regenerating damaged skeletal muscle tissue and restoring function. This article provides a brief overview of the pathophysiology of VML and critiques the shortcomings of current treatments. The subsequent section focuses on the criteria for designing TE scaffolds, offering insights into various natural and synthetic biomaterials and cell types for effectively regenerating skeletal muscle. We also review multiple TE strategies involving both acellular and cellular scaffolds to encourage the development and maturation of muscle tissue and facilitate integration, vascularization, and innervation. Finally, the article explores technical challenges hindering successful translation into clinical applications.

Keywords: Biomaterials; Decellularization; Electrospinning; Hydrogels; Scaffolds; Skeletal muscle regeneration; Tissue engineering; Volumetric muscle loss.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Fig. 1
Fig. 1
Schematic representation of the challenges associated with VML. Significant mass loss due to injury impairs the migration of satellite cells at the injury site, leading to lack of regeneration cues and metabolic activity. VML also results in the recruitment of fibroblasts at the injury site, causing deposition of unorganized ECM that lacks orientation and vasculature. The lack of phenotypic switching of macrophages into M2 prolongs the inflammatory environment at the injury site. Created with Biorender.com
Fig. 2
Fig. 2
Biophysical and biochemical cues used for designing biomaterials in skeletal muscle TE. Biophysical and biochemical cues can be used synergistically for designing biomaterials for skeletal muscle TE. Biophysical cues include geometry, topography, stiffness and viscoelasticity, porosity and pore size, and degradation. Biochemical cues include spatiotemporal delivery of genetic material, growth factors, small molecules, cytokines, proteins and peptides, and ECM components. In combination, biophysical and biochemical cues provide a biomimetic architecture to guide cellular functions and tissue regeneration. Created with Biorender.com
Fig. 3
Fig. 3
Different ways to engineer skeletal muscle using in situ, in vitro, and in vivo TE approaches. In situ TE relies on implanting an acellular scaffold, combining biophysical and/or biochemical cues, for stimulating endogenous tissue regeneration. In vivo TE transplants a cell-seeded scaffold and bioactive molecules for stimulating tissue regeneration. In vitro TE utilizes the implantation of a living, fully functional TE construct generated in vitro. Created with Biorender.com
Fig. 4
Fig. 4
dECM-based scaffolds for skeletal muscle TE. I Porcine small intestinal submucosa (SIS)-based scaffold demonstrated the formation of skeletal muscle fibers in their native state, similar to native tissue. A: native tissue, B: SIS (uncrosslinked), C: SIS (crosslinked), and D: autologous tissue graft. Figure reprinted with permission from [66]. II Decellularized urinary bladder matrix scaffolds for repairing skeletal muscle injuries in animal model demonstrated extensive fibrosis in muscle after stained with Mason Trichrome’s (blue: connective tissue, red: skeletal muscle, and purple: nuclei). Figure reprinted with permission from [70]
Fig. 5
Fig. 5
Hydrogels as scaffolds for promoting muscle regeneration. I A Wnt7a-loaded injectable and bioadhesive PEG-maleimide hydrogel, when treated with C2C12 cells, led to highly aligned myotubes due to effective controlled delivery of Wnt7a in-vitro. Figure modified and reprinted with permission from [103]. II A methacrylic acid-collagen based hydrogel, when implanted at the site of VML promoted muscle regeneration with enhanced vascularization and phenotypic switching of macrophages into an anti-inflammatory M2 state. The hydrogel exhibited enhanced diameter of the centronucleated Muscle Fibers (MFs) compared to other polymeric systems. Figure modified and reprinted with permission from [105]
Fig. 6
Fig. 6
Overview of electrospinning for generating random and aligned nanofibers. I. During electrospinning, a high voltage is applied to a liquid droplet formed by the polymer solution, which results in the elongation of the droplet at the tip of the needle because of the overpowering of the surface tension by the large repulsive force. A “Taylor cone” is formed at a threshold voltage, leading to liquid discharge from the needle that eventually gets deposited on the collector in the form of fibers. II Generation of randomly aligned fibers using (a) a flat plate collector or (b) a drum collector rotating at low speeds. (c) Highly aligned fibers are obtained when the drum collector is rotating at high speeds. Created in Biorender.com and reprinted with permission from [121, 122]
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