Self-Feeding of Engineered Tissues via Controlled Glucose Release Facilitates Survival and Vascularization of Living Implants

Abstract

Engineering living matter has great clinical potential to deliver functional replacement organs. However, clinical translation remains hampered by the current inability to maintain viability of clinically relevant-sized constructs. During the pre-vascular phase, implants rely on nutrient diffusion for survival, which is insufficient at clinically relevant length scales. It is commonly reported that this diffusion limitation causes anoxia-induced cell death, inevitably resulting in implant failure. We, here report that implant survival does not depend on oxygen availability, but rather that anoxia causes rapid nutrient depletion causing starvation-induced cell death. The screening of a comprehensive metabolic library revealed that sugars are the most efficient nutrient type to achieve continued cell survival under chronic anoxia. A controlled glucose release system based on polycaprolactone and glucose crystals was developed, which was used to engineered self-feeding living matter and lead to preserved cell viability and intense secretion of pro-angiogenic factors. Subcutaneous implantation in mice revealed that while conventional living implants formed acellular cores, self-feeding living implants were characterized by full-thickness viability and significantly higher levels of vascularization. Self-feeding engineered living materials therefore represent a high potential biomaterial strategy to realize the engineering of clinically-relevant sized replacement organs that maintain their viability and function upon implantation.