Improved vascular organization enhances functional integration of engineered skeletal muscle grafts

Abstract

Severe traumatic events such as burns, and cancer therapy, often involve a significant loss of tissue, requiring surgical reconstruction by means of autologous muscle flaps. The scant availability of quality vascularized flaps and donor site morbidity often limit their use. Engineered vascularized grafts provide an alternative for this need. This work describes a first-time analysis, of the degree of in vitro vascularization and tissue organization, required to enhance the pace and efficacy of vascularized muscle graft integration in vivo. While one-day in vitro was sufficient for graft integration, a three-week culturing period, yielding semiorganized vessel structures and muscle fibers, significantly improved grafting efficacy. Implanted vessel networks were gradually replaced by host vessels, coupled with enhanced perfusion and capillary density. Upregulation of key graft angiogenic factors suggest its active role in promoting the angiogenic response. Transition from satellite cells to mature fibers was indicated by increased gene expression, increased capillary to fiber ratio, and similar morphology to normal muscle. We suggest a “relay” approach in which extended in vitro incubation, enabling the formation of a more structured vascular bed, allows for graft-host angiogenic collaboration that promotes anastomosis and vascular integration. The enhanced angiogenic response supports enhanced muscle regeneration, maturation, and integration.

Integration and Regression of Implanted Engineered Human Vascular Networks During Deep Wound Healing

“…The survival of tissue-engineered organs during transplantation depends on rapid vascularization and anastomosing with the host's vasculature [2,3]. One promising approach is the transplantation of fully functionalized microvascular networks that can rapidly integrate with the host's circulatory system [3][4][5].…”

“…The survival of tissue-engineered organs during transplantation depends on rapid vascularization and anastomosing with the host's vasculature [2,3]. One promising approach is the transplantation of fully functionalized microvascular networks that can rapidly integrate with the host's circulatory system [3][4][5]. Many studies have used natural matrices, such as collagen, fibrin, and Matrigel (BD Biosciences, San Diego, CA, http://www.bdbiosciences.com), to study the prevascularization potential of various human stem cells, including embryonic stem cell-derived endothelial cells [6 -8], endothelial progenitor cells (EPCs) [9,10], endothelial colony-forming cells (ECFCs) [11,12], and mesenchymal stem cells [9,13].…”

Immunomodulatory effect of a decellularized skeletal muscle scaffold in a discordant xenotransplantation model

“…The field continues to expand and tissue bioengineering has provided, or is close to delivering, functional human organ replacements elsewhere (6,7,(13)(14)(15)(16)(17). The ability to produce innervated and revascularized muscles would hugely extend the possible applications of regenerative medicine (18)(19)(20)(21)(22)(23)(24)(25)(26).…”

Morphogenesis of 3D vascular networks is regulated by tensile forces

“…This study demonstrates the regulatory role of forces in angiogenesis and their capacities in vessel structure manipulation, which can be exploited to improve scaffolds for tissue repair. T echniques to generate vascularized tissues bear significant clinical value in regenerative medicine because they ensure sufficient oxygen and nutrient supply within the host tissue, cardinal to transplant integration and survival (1)(2)(3)(4)(5)(6)(7). Recent works have attempted to optimize blood vessel network properties, such as geometry, maturity, and stability, by supplementing cultures with biological factors (8), biomaterials (9), and geometrical constraints (10,11).…”