A Novel Immune-interactive Surface Coating Approach to Induce Implant Osseointegration in Diabetic Conditions

Titanium (Ti) orthopedic devices are often used to restore the function of damaged bones. However, reciprocal effects between implant surfaces and tissues can affect the success and performance of the implant due to corrosion, micro motion, dislocation, infection, or the inflammatory response of surrounding tissues. Additionally, diabetic patients receiving implants exhibit higher rates of implant failure due to impaired osseointegration and systemic complications compared to non-diabetic patients, which contribute to poor outcomes in orthopedic treatments, such as fracture healing. Because there is an increasing diabetic population that will require the use of implants, there is an urgent need to determine underlying mechanisms of diabetes-induced poor osseointegration and bone repair. Retrieved implants and in vitro testing of discs in simulated diabetic environments were first analyzed to understand how diabetes affects Ti implant surfaces. All retrieved implants have some degree of surface damage (pitting attack, discoloration, scratches, delamination, etc.). Therefore, the goal of this dissertation was to develop a coating that mitigates failure modes and improves the predictability of implants in immunocompromised conditions. Two multifunctional dicationic imidazolium-based ionic liquids (IonLs) containing phenylalanine (1,10-bis(3-methylimidazolium-1-yl)decane diphenylalanine) and methionine (1,10-bis(3-methylimidazolium-1-yl)decane dimethionine) were first investigated as thin films to prevent direct adsorption and temporarily immobilize exogenous proteins on Ti surfaces. The selected protein for this study was High Mobility Group Box 1 (HMGB1), which has been shown to be involved in the recruitment of inflammatory and mesenchymal stem cells to implantation sites, contributing to healing and implant integration. The optimal IonL coating was chosen based on in vitro and in silico analysis. It was demonstrated that HMGB1 is stable when anchored by the IonL containing phenylalanine, which prevents protein denaturation from surface adherence. However, HMGB1 is redox sensitive and exists in different isoforms (fully- reduced HMGB1 (FR), a recombinant version of FR resistant to oxidation (3S), disulfide HMGB1 (DS) and inactive sulfonyl HMGB1(SO)), that can each have distinct biological functions in health and disease. Each isoform was applied to the IonL-Phe thin film and implanted subcutaneously to assess the inflammatory effects of surrounding tissues in response to the coating. From these studies, the 3S HMGB1 was selected as the most favorable with regard to tissue healing, to be further applied to orthopedic implants in a model of open reduction fracture fixation (ORIF) in tibias of diabetic rats. This coating conformation (Ti-IonL-HMBG1) was then used in the ORIF model to assess the fracture healing and osseointegration potential in diabetic and normoglycemic conditions. Overall, the results for the new coating pointed to beneficial outcomes in fracture healing of diabetic rats, achieving healing parameters comparable to non-diabetic rats. Altogether, this dissertation demonstrates the design and assessment of ionic liquid and exogenous HMGB1 as an immunomodulatory coating to improve osseous healing in diabetic conditions.