Abstract
Despite the regenerative capacity of muscle, tissue volume is not restored after volumetric muscle loss (VML), perhaps due to a loss-of-structural extracellular matrix. We recently demonstrated the structural and functional restoration of muscle tissue in a mouse model of VML using an engineered “bioconstruct,” comprising an extracellular matrix scaffold (decellularized muscle), muscle stem cells (MuSCs), and muscle-resident cells (MRCs). To test the ability of the cell-based bioconstruct to restore whole-muscle biomechanics, we measured biomechanical parameters in uninjured muscles, muscles injured to produce VML lesions, and in muscles that were injured and then treated by implanting either the scaffolds alone or with bioconstructs containing the scaffolds, MuSCs, and MRCs. We measured the active and passive forces over a range of lengths, viscoelastic force relaxation, optimal length, and twitch dynamics. Injured muscles showed a narrowed length-tension curve or lower force over a narrower range of muscle lengths, and increased passive force. When treated with bioconstructs, but not with scaffolds alone, injured muscles showed active and passive length-tension relationships that were not different from uninjured muscles. Moreover, injured muscles treated with bioconstructs exhibited reduced fibrosis compared to injured muscles either untreated or treated with scaffolds alone. The cell-based bioconstruct is a promising treatment approach for future translational efforts to restore whole-muscle biomechanics in muscles with VML lesions.
Highlights
Volumetric muscle loss (VML) is a severe traumatic injury or surgery excision that limits the ability of the patient to perform activities of daily living, resulting in significant functional loss.[1]
Biophysical measurements, such as active and passive force analysis, are the gold standard for assessments in skeletal muscle physiology. With this aim in mind, we decided to investigate the biomechanical properties of muscles with volumetric muscle loss (VML) injuries that received: (1) injury but no-treatment; (2) treatment with extracellular matrix-derived scaffold; and (3) treatment with scaffolds that were seeded with muscle stem cells (MuSCs) and muscle-resident cells (MRCs)
Muscles from all four groups fell along a line of proportionally increasing force and mass, with the VML group treated with scaffolds and cells falling between the untreated VML group and the VML group treated with scaffold only, positioned on the lower end, and the uninjured control group on the upper end (Fig. 1a)
Summary
Volumetric muscle loss (VML) is a severe traumatic injury or surgery excision that limits the ability of the patient to perform activities of daily living, resulting in significant functional loss.[1]. A treated muscle must recreate the native whole-muscle biomechanics, which arise from muscle architecture. We achieved force recovery to near uninjured levels in an animal model of VML by implanting tissueengineered “bioconstructs” comprised of extracellular matrix scaffolds injected with satellite cells (or muscle stem cells (MuSCs) and other muscle-resident cells (MRCs).[5] To test the ability of the cell-based bioconstruct treatment to restore whole-muscle biomechanics, we measured in the current studies the active and passive forces over a range of lengths, viscoelastic force relaxation, optimal length, and twitch dynamics, as well as fibrosis of the injured muscles, whether treated or untreated
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