Multiscale analysis of a regenerative therapy for treatment of volumetric muscle loss injury

Aguilar, Carlos A.; Greising, Sarah M.; Watts, Alain; Goldman, Stephen M.; Peragallo, Chelsea; Zook, Christina; Larouche, Jacqueline; Corona, Benjamin T.

doi:10.1038/s41420-018-0027-8

Cited by 105 publications

(114 citation statements)

References 49 publications

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“…Skeletal muscle has a remarkable regenerative capacity following mild or moderate injuries. In severe muscle traumas such as a volumetric muscle loss (VML), the critical‐sized defect exceeds the body's regenerative capacity resulting in chronic loss of function and permanent disability (Aguilar et al, ; Corona, Rivera, Owens, Wenke, & Rathbone, ; Garg et al, ). Initially, the loss of vital regenerative elements such as satellite cells and the basal lamina limit muscle fiber regeneration.…”

Section: Introductionmentioning

confidence: 99%

Decellularized extracellular matrix gelloids support mesenchymal stem cell growth and function in vitro

Talovic

Patel

Schwartz

et al. 2019

J Tissue Eng Regen Med

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Volumetric muscle loss (VML) injuries are irrecoverable due to a significant loss of regenerative elements, persistent inflammation, extensive fibrosis, and functional impairment. When used in isolation, previous stem cell and biomaterial‐based therapies have failed to regenerate skeletal muscle at clinically relevant levels. The extracellular matrix (ECM) microenvironment is crucial for the viability, stemness, and differentiation of stem cells. Decellularized‐ECM (D‐ECM) scaffolds are at the forefront of ongoing research to develop a viable therapy for VML. Due to the retention of key ECM components, D‐ECM scaffolds provide an excellent substrate for the adhesion and migration of several cell types. Mesenchymal stem cells (MSCs) possess regenerative and immunomodulatory properties and are currently under investigation in clinical trials for a wide range of medical conditions. However, a major limitation to the use of MSCs in clinical applications is their poor viability at the site of transplantation. In this study, we have fabricated spherical scaffolds composed of gelatin and skeletal muscle D‐ECM for the adhesion and delivery of MSCs to the site of VML injury. These spherical scaffolds termed “gelloids” supported MSC survival, expansion, trophic factor secretion, immunomodulation, and myogenic protein expression in vitro. Future studies would determine the therapeutic efficacy of this approach in a murine model of VML injury.

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Section: Introductionmentioning

confidence: 99%

Decellularized extracellular matrix gelloids support mesenchymal stem cell growth and function in vitro

Talovic

Patel

Schwartz

et al. 2019

J Tissue Eng Regen Med

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“…In this issue of Cell Death and Discovery , Aguilar et al 5 addresses this issue by characterizing the pathophysiologic response to VML using a multi-scale approach, and contrasting those results to surgical implantation of a regenerative therapy (minced muscle grafts-MMGs). The investigators tracked the molecular phenomenology after VML over 56 days using muscle function testing, histology, and gene expression profiling using high-throughput sequencing (RNA-sequencing).…”

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confidence: 99%

Robust inflammatory and fibrotic signaling following volumetric muscle loss: a barrier to muscle regeneration

et al. 2018

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“…Of particular interest, VML injury results in a heightened and persistent inflammatory response that overwhelms its innate capacity for regeneration . In a recent study, it was shown that muscle trauma prompts robust and persistent overexpression of inflammatory transcripts, which contributes to fibrotic tissue deposition and may impair satellite cell‐mediated repair . It has been suggested that both M1 (pro‐inflammatory) and M2 (anti‐inflammatory) macrophage phenotypes are necessary for muscle regeneration .…”

Section: Challenges With Existing Technologies and Future Trendsmentioning

confidence: 99%

“…Studies show that M1 macrophages are found close to proliferating myogenic cells while M2 macrophages interact with differentiating myocytes . Prolonged and heightened inflammation characterized by the persistent presence of M1 macrophages, often seen in orthopedic trauma, dysregulates the regenerative process and impairs satellite cell activity …”

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confidence: 99%

“…10 Prolonged and heightened inflammation characterized by the persistent presence of M1 macrophages, often seen in orthopedic trauma, dysregulates the regenerative process and impairs satellite cell activity. 35,36 Therefore, a greater understanding of satellite cells and their niche components-resident stem cells and ECM proteins is of considerable therapeutic value. This review highlights the studies that have explored the functional capacity of stem cells and bioengineered scaffolds for skeletal muscle regeneration.…”

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confidence: 99%

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Biomaterial and stem cell‐based strategies for skeletal muscle regeneration

Dunn

Talovic

Patel

et al. 2019

Journal Orthopaedic Research

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Adult skeletal muscle can regenerate effectively after mild physical or chemical insult. Muscle trauma or disease can overwhelm this innate capacity for regeneration and result in heightened inflammation and fibrotic tissue deposition resulting in loss of structure and function. Recent studies have focused on biomaterial and stem cell‐based therapies to promote skeletal muscle regeneration following injury and disease. Many stem cell populations besides satellite cells are implicated in muscle regeneration. These stem cells include but are not limited to mesenchymal stem cells, adipose‐derived stem cells, hematopoietic stem cells, pericytes, fibroadipogenic progenitors, side population cells, and CD133+ stem cells. However, several challenges associated with their isolation, availability, delivery, survival, engraftment, and differentiation have been reported in recent studies. While acellular scaffolds offer a relatively safe and potentially off‐the‐shelf solution to cell‐based therapies, they are often unable to stimulate host cell migration and activity to a level that would result in clinically meaningful regeneration of traumatized muscle. Combining stem cells and biomaterials may offer a viable therapeutic strategy that may overcome the limitations associated with these therapies when they are used in isolation. In this article, we review the stem cell populations that can stimulate muscle regeneration in vitro and in vivo. We also discuss the regenerative potential of combination therapies that utilize both stem cell and biomaterials for the treatment of skeletal muscle injury and disease. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1246–1262, 2019.

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Multiscale analysis of a regenerative therapy for treatment of volumetric muscle loss injury

Cited by 105 publications

References 49 publications

Decellularized extracellular matrix gelloids support mesenchymal stem cell growth and function in vitro

Decellularized extracellular matrix gelloids support mesenchymal stem cell growth and function in vitro

Robust inflammatory and fibrotic signaling following volumetric muscle loss: a barrier to muscle regeneration

Biomaterial and stem cell‐based strategies for skeletal muscle regeneration

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