Clarifying engineered bioabsorbable metals tissue-biomaterial interface and regeneration - The long-term goal of research in my laboratory is to develop a technical design framework that can be used as a platform to engineer precision bioabsorbable metal materials capable of instructing the wound healing / tissue regeneration response – a pathway that all implantable biomaterials evoke. Bioabsorbable metals are attractive biomaterials to create fully regenerative medical implants for a variety of clinical applications. While the biocorrosion mechanism of bioabsorbable metals has been described extensively in vitro, it remains ambiguous, and unpredictable in vivo. We hypothesize this is due to the complex temporal interactions from wound healing and inflammation. Research from my lab has demonstrated how bioabsorbable metal materials interact with reactive oxygen and reactive nitrogen species (ROS-RNS) produced from lipopolysaccharide stimulated macrophages, independent of physiological antioxidant mechanisms. Importantly, this has been correlated with changes in the materials bioabsorption rate, detailing an intimate feedback loop between bioabsorbable material biocorrosion and inflammatory ROS-RNS generation. We have also shown that small changes in bioabsorbable metals yield dramatic differences in inflammation / wound healing. In this MIRA, my lab will determine the mechanisms of in vivo biocorrosion and uncover the most dominating biomaterial factors which govern the overall tissue-material response. Our goal is to address this gap in knowledge by elucidating the complex material - inflammation driven ROS/RNS axis, unique to bioabsorbable metal implants due to their redox active biocorrosion process. We will accomplish this by having three primary focus areas. In focus area 1, we will study how bioabsorbable metal material characteristics affect the progression of inflammation and wound healing in a generalized subcutaneous implant model. We will employ serial bioluminescent imaging with commercially available bioluminescent reporter mice and injectable ROS/RNS sensitive probes to quantitatively measure inflammation progression vs. material characteristics. In our second focus area, we will determine the inflammation driven corrosion mechanism of bioabsorbable metals by using well established in vivo cell depletion models towards macrophages and neutrophils (key cellular modulators of tissue regeneration) at different healing phases. This will provide valuable insight into the biocorrosion sensitivity of bioabsorbable metals to inflammation. In the third focus area, we will use semi-quantitative elemental imaging at the interface of implanted biomaterials to describe how implant derived metals are accumulating. Our previous work using elemental imaging of implants has found that macrophages situated at the interface directly interact with implant derived metal containing biocorrosion products. Two major outcomes from this work will be a 1) a precise description of the inflammation driven corrosion mechanism of bioabsorbable metals and 2) technical design framework, that can be used to engineer bioabsorbable materials. My expertise in biomedical engineering, material science, and cellular/organ physiology positions me to execute this research program.
