Cell and Growth Factor-Loaded Keratin Hydrogels for Treatment of Volumetric Muscle Loss in a Mouse Model

Abstract

Wounds to the head, neck, and extremities have been estimated to account for ∼84% of reported combat injuries to military personnel. Volumetric muscle loss (VML), defined as skeletal muscle injuries in which tissue loss results in permanent functional impairment, is common among these injuries. The present standard of care entails the use of muscle flap transfers, which suffer from the need for additional surgery when using autografts or the risk of rejection when cadaveric grafts are used. Tissue engineering (TE) strategies for skeletal muscle repair have been investigated as a means to overcome current therapeutic limitations. In that regard, human hair-derived keratin (KN) biomaterials have been found to possess several favorable properties for use in TE applications and, as such, are a viable candidate for use in skeletal muscle repair. Herein, KN hydrogels with and without the addition of skeletal muscle progenitor cells (MPCs) and/or insulin-like growth factor 1 (IGF-1) and/or basic fibroblast growth factor (bFGF) were implanted in an established murine model of surgically induced VML injury to the latissimus dorsi (LD) muscle. Control treatments included surgery with no repair (NR) as well as implantation of bladder acellular matrix (BAM). In vitro muscle contraction force was evaluated at two months postsurgery through electrical stimulation of the explanted LD in an organ bath. Functional data indicated that implantation of KN+bFGF+IGF-1 (n = 8) enabled a greater recovery of contractile force than KN+bFGF (n = 8)***, KN+MPC (n = 8)**, KN+MPC+bFGF+IGF-1 (n = 8)**, BAM (n = 8)*, KN+IGF-1 (n = 8)*, KN+MPCs+bFGF (n = 9)*, or NR (n = 9)**, (*p < 0.05, **p < 0.01, ***p < 0.001). Consistent with the physiological findings, histological evaluation of retrieved tissue revealed much more extensive new muscle tissue formation in groups with greater functional recovery (e.g., KN+IGF-1+bFGF) when compared with observations in tissue from groups with lower functional recovery (i.e., BAM and NR). Taken together, these findings further indicate the general utility of KN biomaterials in TE and, moreover, specifically highlight their potential application in the treatment of VML injuries.

Therapeutic Approaches for Volumetric Muscle Loss Injury: A Systematic Review and Meta-Analysis

“…The adjusted overall ES was still highly significant and its magnitude would be considered moderate. Potential conflicts of interest were evaluated by involvement of the company developing the treatment tested, noted in one study 35 that disclosed funding, support, or gift in kind for the treatment tested (this study had two independent injury models) directly, and four studies [52][53][54][55] noted authors with roles in various corporations. Five collaborative research groups were identified across the included studies.…”

Biomaterial and stem cell‐based strategies for skeletal muscle regeneration

“…In another study, Baker et al loaded kerateine hydrogels with skeletal MPCs with or without IGF‐1 or bFGF to treat volumetric muscle loss (VML) injury in the latissimus dorsi muscle in a mouse model . After 2 months, keratin hydrogels loaded with both growth factors but without MPCs yielded a greater recovery of contractile force than the other treatment groups and promoted extensive new muscle tissue formation.…”

In Vivo Evaluation of Three-Dimensional Printed, Keratin-Based Hydrogels in a Porcine Thermal Burn Model

“…Keratin-based biomaterials have been successfully used for the delivery of growth factors (e.g., insulin-like growth factor-1, basic fibroblast growth factor [bFGF]), 30,31 progenitor cells (e.g., skeletal muscle myoblasts), 16 and antimicrobial agents (ciprofloxacin), 32 among other molecules. In this study, we studied Halofuginone-laden keratin scaffolds for the in vivo treatment of burn, particularly the development of an individualized keratin-based dressing capable of encouraging quick wound healing with the release of Halofuginone.…”