Redox chemistry in biomaterials and tissue engineering

The goal of tissue engineering and regenerative medicine is the development of effective therapies for degenerative diseases and traumatic injuries for which limited therapeutic options exist. The classical 'triad' of tissue engineering consists of cells, scaffolds, and small molecules combined in order to potentiate tissue repair. One often-overlooked aspect affecting all three of these components is redox chemistry in the synthesis and degradation of scaffold materials as well as overall cellular metabolism.;Reactive oxygen species (ROS) play critical roles in the degradation kinetics of biomaterials. We demonstrated a potential degradation mechanisms of poly(ethylene glycol)-based (PEG) materials via ROS, a byproduct of inflammatory cells and local tissue environment. Specifically, we evaluated the early inflammatory response of PEG hydrogels within different tissue environments in the rat such as the dorsal subcutaneous space, abdominal cavity, and postlateral muscle. The postlateral muscle contains a depot of fat which allowed us to examine adipose tissue, while avoiding mechanical differences. We found adipose tissue to elicit the highest inflammatory response, a critical finding for tissue engineering and regenerative medicine applications.;Given the complexity of regenerative medicine, there is a need to tailor biomaterials for specific applications. For example, PEG and PEG-copolymers play critical roles ranging from PEGylation therapeutics to hydrogel scaffolds; however PEG's nondegadability is a major limitation. To overcome this issue, efforts have been made to introduce biodegradability into PEG or to make copolymers of PEG and biodegradable polymer moieties such as esters. However, polyesters degrade into carboxylic acid terminal groups which can induce tissue toxicity. We developed a simple synthetic scheme of incorporating minimal random hemiacetals within the PEG backbone allowing hydrolytic degradation to nonacidic byproducts.;Finally, we examined the bioenergetics and redox state of human adipose-derived stem cells (ASC) in combination with biomaterials and small molecules. We cultured ASCs in monolayer and observed that ROS levels increased during adipogenic differentiation and decreased during osteogenic differentiation. In both adipogenic and osteogenic cells, oxidative phosphorylation increased and glycolysis decreased. We then encapsulated ASCs in PEG (non adherent) and PEG-RGD (adherent) hydrogels and saw increased mitochondrial membrane potential and decreased ROS levels with the PEG-RGD scaffolds. After observing the cellular metabolic profiles, we exploited the information to modulate tissue production. We utilized camitine, a small metabolite with purported antioxidant effects, to reduce ROS levels and increases tissue production in osteogenic cells encapsulated in PEG-RGD hydrogels. These results suggest that one can manipulate tissue production by modulating cell metabolism.