Biomechanics show stem cell necessity for effective treatment of volumetric muscle loss using bioengineered constructs

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.

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

“…This suggests that the heterogeneous resident cell population supports MDPC viability within the implanted scaffolds. Additionally, injuries treated with ECM scaffolds co-seeded with MDPCs and muscle resident cells demonstrated active and passive length-tension relationships that were equivalent to control uninjured muscle [228]. Injuries treated with co-seeded scaffolds also exhibited less fibrosis compared to untreated injuries and treatment with scaffolds alone.…”

“…Another commonly investigated scaffold for in vivo tissue engineering strategies is decellularized ECM [222][223][224][225][226][227][228][229]. Early work studied the delivery of acellular or autologous myoblast-seeded decellularized muscle ECM to the obliqui abdominis muscle of rats [223].…”

Extracellular Matrix From Decellularized Wharton’s Jelly Improves the Behavior of Cells From Degenerated Intervertebral Disc

“…The cell count percentage has been performed comparing the positive cells with all the nuclei present in the field (the number multiplied per 100). Percentage of seeded area, defined as DAPI fluorescence in all the seeded area (panoramic picture of the whole sections was made), and laminin and fibronectin mean fluorescence intensity has been calculated using Fiji 30 software as already performed elsewhere (Kim et al, 2016;Quarta et al, 2017Quarta et al, , 2018 using 8 bit image and threshold (n = 6, 10 fields per each sample). All counts were made by two blinded operators.…”

Regenerative medicine for skeletal muscle loss: a review of current tissue engineering approaches

“…Acellular scaffolds have been used however their utility appears limited, in some cases being completely reabsorbed without any appreciable skeletal muscle regeneration [ 13 , 74 ]. Pre-population of scaffolds with myoblasts significantly enhances myocyte regeneration, this may in part be due to endogenous satellite cell depletion following VML [ 17 , 26 , 74 , 75 ].…”