Platelet-derived extracellular vesicles formulated with hyaluronic acid gels for application at the bone-implant interface: An animal study

Abstract

Platelet derived extracellular vesicles (pEV) are promising therapeutical tools for bone healing applications. In fact, several in vitro studies have already demonstrated the efficacy of Extracellular Vesicles (EV) in promoting bone regeneration and repair in various orthopedic models. Therefore, to evaluate the translational potential in this field, an in vivo study was performed. Here, we used hyaluronic acid (HA) gels formulated with pEVs, as a way to directly apply pEVs and retain them at the bone defect. In this study, pEVs were isolated from Platelet Lysate (PL) through size exclusion chromatography and used to formulate 2% HA gels. Then, the gels were locally applied on the tibia cortical bone defect of New Zeland White rabbits before the surgical implantation of coin-shaped titanium implants. After eight weeks, the bone healing process was analyzed through biomechanical, micro-CT, histological and biochemical analysis. Although no biomechanical differences were observed between pEV formulated gels and non-formulated gels, biochemical markers of the wound fluid at the interface presented a decrease in Lactate dehydrogenase (LDH) activity and alkaline phosphatase (ALP) activity for pEV HA treated implants. Moreover, histological analyses showed that none of the treatments induced an irritative effect and, a decrease in the fibrotic response surrounding the implant for pEV HA treated implants was described. In conclusion, pEVs improve titanium implants biocompatibility at the bone-implant interface, decreasing the necrotic effects of the surgery and diminishing the fibrotic layer associated to the implant encapsulation that can lead to implant failure.