Abstract In our parent R 01 application, we have shown that the presence of dopants in HA influences the bone remodeling process and phase stability in coating while improving coating interfacial mechanical properties processed via laser and plasma. Specific dopants like magnesium (Mg), zinc (Zn), and silicon (Si) in their oxide form help in osteogenesis and angiogenesis. However, those dopants have limited influence on osteoinductivity or osteoclastogenesis, and both are needed to minimize aseptic loosening. The objective of this follow-up application is to understand osteogenesis mechanisms via in vitro gene expressions and in vivo studies using rat and rabbit distal femur models of doped HA-coated implants with plant-derived compounds (PDCs) such as gingerol from ginger, allicin from garlic, and carvacrol from oregano. It is envisioned that PDCs will be responsible for osteoinduction and reduced osteoclastogenesis to improve bone tissue-material interactions, minimize aseptic loosening and implant migration. Over 1 million total joint arthroplasties have been performed in 2019 in the United States alone. Aseptic loosening is still considered one of the most common failure modes in these surgeries' coming days. Metal implants such as Ti6Al4V are widely used for arthroplasties due to their excellent biocompatibility in vivo. Although Ti6Al4V is osteoconductive, cementless implants for joint replacement depend on stringent initial mechanical stability for bone ingrowth/apposition to occur. Initial implant integration and avoidance of late aseptic loosening are even more challenging in the revision scenario, in which the bone-bed is often sclerotic and dysvascular. We hypothesize that: 1) addition of PDCs with selected dopants in HA coating will modulate release kinetics and control bone remodeling in vivo; 2) PDCs will locally increase bone density and introduce osteoinductivity, especially for patients with compromised bone in revision surgeries; and 3) an easily introduced oxide layer between the metal substrate and HA coating will maintain stronger bonding between the metal implant and the ceramic coating. Our design goals are: 1) improve bioactivity and introduce osteoinductivity to minimize healing time and 2) enhance interfacial mechanical properties between the HA coating and the implant to increase coating in vivo lifetime. We propose the following two specific aims: (1) Aim 1: Understanding of gene expressions for PDC added doped HA coatings on Ti6Al4V; (2) Aim 2: Evaluate effects of PDC release from doped HA-coated Ti6Al4V on early-stage bone cell – materials interactions and in vivo biological response. The following outcome measures will judge this project's success: quantitative and qualitative control of PDC added doped HA coatings on Ti6Al4V in terms of enhanced osteoinductivity, uniformity in microstructure leading to higher interfacial mechanical strength, improved cellular differentiation, and bone-tissue integration. This prog...