Therapeutic Agent Coating on Structure Modified Metallic Bio-implant Surface to Improve Biological Activity

Abstract

Metallic implants have been widely used because of its excellent mechanical, chemical and biological stability for numerous surgical applications such as orthopedic implants, dental implants, and cardiovascular stents. However, due to the complicate biological environment in human body, the additive biological functions are desired to achieve successful cure by the metallic implants for several applications. Therapeutic agent delivery for biomedical metallic implant have received attention as a promising strategy to achieve enhanced bioactivity and additive biological functions. Therefore, various type of delivery platforms have been developed and investigated to provide desirable properties to the metallic implants, including polymeric coating, nano-porous ceramic coating, and chemical surface modifications. In this study, we introduced a target-ion induced plasma sputtering (TIPS)-treated surface as a platform for the delivery of therapeutic agent on metallic implant surface. A mechanically stable porous surface on metal implant created by TIPS treatment have been studied for the delivery of various type of therapeutic agent such as growth factors, antimicrobial agent, and antiproliferatvie drugs for dental and cardiovascular stent application. Firstly, the TIPS-treated surface was applied on Ti surface to deliver the growth factor and antimicrobial agent for the improved performance of dental implant. Dental implant is the most extensively used device to substitute of problematic teeth. The dental implant is generally composed of fixture, abutment, and crown. Since the role of fixture is fixation of dental implant by being embedded in and interlocked with the jawbone, enhancement of osseointegration is required for fixture part. Therefore, bone morphogenetic protein-2 (BMP-2) was applied on the sandblasting with large grit and acid-etching (SLA) Ti surface treated with TIPS (SLA/TIPS) with optimum condition (1200 V, 10 min) for the increased BMP-2 loading efficiency. The loading efficiency enhancement were confirmed by loading and release test, and the biological effectiveness was assess by in vitro cell test using MC3T3-E1 cells. The biological activity of BMP-2 loaded SLA/TIPS surface showed significant enhancement in terms of attachment and differentiation of cells, and the osseointegration enhancement was proved by in vivo animal test using dog mandible model. This study demonstrated that the BMP-2 delivery by SLA/TIPS surface is effective for the enhancement of bioactivity of dental fixture. For the abutment part, antimicrobial property is important, thus we coat the nano-scale silver (Ag) on TIPS treated Ti surface by conventional sputtering process on TIPS-treated surface varying the sputtering time form 10 s to 120 s. The antibacterial properties and the cytotoxicity of different content of Ag was evaluated using Escherichia coli and L929 fibroblast cells. The antibacterial activity was very effective regardless of the Ag content, but the cytotoxicity was increased as the Ag content increased. Only 10 s (TIPS-Ag10) sample didnt show the cytotoxicity in terms of cell viability. This study proved that the ultrasmall content of Ag on TIPS nano-structure can provide the additive antimicrobial property avoiding the cytotoxic effect of nano-scale Ag for dental abutment application. In the second study, TIPS surface was introduced on Co-Cr surface for the delivery of antiproliferative agents for polymer-free drug eluting stent application. To overcome the problem of in stent restenosis, drug eluting stent containing the antiproliferative drug was invented. The conventional drug eluting stent has polymeric coating layer for the stable loading, and sustained release of antiproliferative drug. However, the polymeric coating layer on the stent surface has been found to be a critical reason for late stent thrombosis which is a very dangerous side-effect. For this reason, the delivery of antiproliferative agent having stable loading and sustained release property without polymer coating is desirable. Paclitaxel which is a kind of antiproliferative drug was loaded on the TIPS-treated Co-Cr surface varying substrate bias (800 V and 1600 V). The loading stability under deformation was tested by strain test using Instron, and the drug on TIPS-treated surface was stably remained without delamination by mechanical anchoring effect. The release behavior of paclitaxel was also prolonged by the TIPS-treated surface. In the case of 800 V, the release behavior sustained until 21 days, and 1600 V sample showed further prolonged release behavior even until 28 days. The effectiveness of remained drug was evaluated by in vitro test using vascular smooth muscle cell. The attachment and proliferation was strongly inhibited by remained paclitaxel on 1600 V sample even after 21 days of release. Thus, the in vivo animal test using atherosclerosis rabbit model was conducted using bare Co-Cr stent, paclitaxel loaded bare Co-Cr stent and paclitaxel loaded 1600 V TIPS-treated Co-Cr stent. The restenosis was effectively inhibited by paclitaxel delivery by 1600 V TIPS-treated Co-Cr stent, compared to bare Co-Cr stent and paclitaxel loaded Co-Cr stent.