Self‐Oxygenation of Tissues Orchestrates Full‐Thickness Vascularization of Living Implants

Abstract

Bioengineering of tissues and organs has the potential to generate functional replacement organs. However, achieving the full-thickness vascularization that is required for long-term survival of living implants has remained a grand challenge, especially for clinically sized implants. During the pre-vascular phase, implanted engineered tissues are forced to metabolically rely on the diffusion of nutrients from adjacent host-tissue, which for larger living implants results in anoxia, cell death, and ultimately implant failure. Here it is reported that this challenge can be addressed by engineering self-oxygenating tissues, which is achieved via the incorporation of hydrophobic oxygen-generating micromaterials into engineered tissues. Self-oxygenation of tissues transforms anoxic stresses into hypoxic stimulation in a homogenous and tissue sizeindependent manner. The in situ elevation of oxygen tension enables the sustained production of high quantities of angiogenic factors by implanted cells, which are offered a metabolically protected pro-angiogenic microenvironment. Numerical simulations predict that self-oxygenation of living tissues will effectively orchestrate rapid full-thickness vascularization of implanted tissues, which is empirically confirmed via in vivo experimentation. Self-oxygenation of tissues thus represents a novel, effective, and widely applicable strategy to enable the vascularization living implants, which is expected to advance organ transplantation and regenerative medicine applications.

Enzyme‐Mediated Alleviation of Peroxide Toxicity in Self‐Oxygenating Biomaterials

“…Interestingly, the addition of CPO increased the swelling properties of the hydrogel, which indicated that the hydrophilic nature of CPO played a significant role in the absorption and retention of aqueous solutions. [ 46 ]…”

“…Despite the longer exposure to UV‐light for the CPO‐laden hydrogels, it is likely that the hydrogels are crosslinked to a lesser degree, and thus degrade at a faster rate. [ 46 ]…”

“…In a previous study we demonstrated that host‐tissue vascularization already occurs after seven days when using oxygen‐generating biomaterials in GelMA hydrogels. [ 46 ] Thus, viability studies were performed for up to seven days. In line with the measured H 2 O 2 levels, C2C12 myoblasts in hydrogel containing CITG demonstrated a significantly higher viability (≈70% for all HOGMP tested concentrations) compared to all other catalase formulations ( Figure A,B).…”

“…This is most likely due to the hypoxic microenvironment, which is known to decrease cell proliferation for many cell types due to a lack of oxygen. [ 46 , 54 ] Moreover, an initial low viability (≈70%) was noticed for most of the samples. In line with the literature, this phenomenon could stem from the photo‐crosslinking process to fabricate hydrogels and cell culture under hostile environmental conditions (severe hypoxia).…”

“…Interestingly, the addition of CPO increased the swelling properties of the hydrogel, which indicated that the hydrophilic nature of CPO played a significant role in the absorption and retention of aqueous solutions. [46] Biodegradation of hydrogels was simulated by immersing various hydrogels in DPBS or DPBS supplemented with 0.5 U/mL collagenase type II at 37 °C for seven days (Figure 1G). As expected, the HOGMP-laden hydrogels degraded at a similar rate to the plain GelMA hydrogels after approximately five to six days, irrespective of the addition of catalase.…”