Controlled delivery of SDF-1α and IGF-1: CXCR4⁺ cell recruitment and functional skeletal muscle recovery

Abstract

Therapeutic delivery of regeneration-promoting biological factors directly to the site of injury has demonstrated its efficacy in various injury models. Several reports describe improved tissue regeneration following local injection of tissue specific growth factors, cytokines and chemokines. Evidence exists that combined cytokine/growth factor treatment is superior for optimizing tissue repair by targeting different aspects of the regeneration response. The purpose of this study was to evaluate the therapeutic potential of the controlled delivery of stromal cell-derived factor-1alpha (SDF-1α) alone or in combination with insulin-like growth factor-I (SDF-1α/IGF-I) for the treatment of tourniquet-induced ischemia/reperfusion injury (TK-I/R) of skeletal muscle. We hypothesized that SDF-1α will promote sustained stem cell recruitment to the site of muscle injury, while IGF-I will induce progenitor cell differentiation to effectively restore muscle contractile function after TK-I/R injury while concurrently reducing apoptosis. Utilizing a novel poly-ethylene glycol PEGylated fibrin gel matrix (PEG-Fib), we incorporated SDF-1α alone (PEG-Fib/SDF-1α) or in combination with IGF-I (PEG-Fib/SDF-1α/IGF-I) for controlled release at the site of acute muscle injury. Despite enhanced cell recruitment and revascularization of the regenerating muscle after SDF-1α treatment, functional analysis showed no benefit from PEG-Fib/SDF-1α therapy, while dual delivery of PEG-Fib/SDF-1α/IGF-I resulted in IGF-I-mediated improvement of maximal force recovery and SDF-1α-driven in vivo neovasculogenesis. Histological data supported functional data, as well as highlighted the important differences in the regeneration process among treatment groups. This study provides evidence that while revascularization may be necessary for maximizing muscle force recovery, without modulation of other effects of inflammation it is insufficient.

Fibrin‐based stem cell containing scaffold improves the dynamics of burn wound healing

“…Synthetic modification of fibrin with PEG improves the stability of the fibrin scaffold without changing its biochemical properties. We have previously used P‐fibrin gels to successfully achieve controlled delivery of various growth factors in vivo . Here we report on the feasibility of using stem cell‐loaded P‐fibrin gel for immediate burn wound coverage following surgical burn eschar excision via single application.…”

Biomaterials for skeletal muscle tissue engineering

“…Controlled delivery of IGF-1 has also been demonstrated to recruit Pax7+ muscle cells into a scaffold, resulting in higher muscle formation [40]. Muscle stem cells may also be recruited through the delivery of SDF-1α, which was shown to increase the number of CXCR4+ cells, as well as promote angiogenesis in injured muscle [41]. In a study of volumetric muscle loss (VML), delivery of hepatocyte growth factor enhanced the contractile force of newly formed muscle by increasing the number of differentiated myoblasts and promoting angiogenesis [42].…”

Engineered matrices for skeletal muscle satellite cell engraftment and function

“…Recently, a number of investigations have utilized PEG-based scaffolds (PEG-fibrinogen constructs) to deliver skeletal muscle-derived pericytes [128] and mesoangioblasts [129,130], and demonstrated that cell delivery in such materials promotes myogenic differentiation and skeletal muscle regeneration. Furthermore, controlled delivery of IGF-1 and SDF-1 using PEG-fibrin hydrogels also contributes to skeletal muscle regeneration [131,132]. In order to gain more precise control over building the cellular niche, PEG hydrogels that utilize maleimide crosslinking reaction chemistry also have been explored to culture C2C12 myoblasts in 3D [83].…”