Osteogenic Calcium Phosphate Nanoparticles with Designable Drug Release Kinetics

描述（由申请人提供）：此K99/R 00指导研究职业发展奖申请正在提交给牙科和颅面研究（NIDCR）的国家研究所。候选人Vuk Uskokovic博士是一名物理化学家和纳米技术专家，他希望通过该奖项获得细胞培养实验和其他生物分析方法领域的额外培训。他的目标是发展多功能和纳米结构生物材料领域的研究技能，用于修复硬组织。该提案的目标将提高Uskokovic博士对智能生物材料制造的知识，用于同时时间控制药物释放和患病硬组织再生。提出了磷酸钙/聚合物复合颗粒的合成，该颗粒包封克林霉素（一种用于治疗骨髓炎的药物），以及测试给定材料的体外抗微生物性质和骨诱导性能。所提出的研究的中心假设是，磷酸钙的化学计量和粒度可用于调节包封药物的释放动力学。Uskokovic博士将在专家指导团队的指导下开展培训和研究活动，该团队包括Tejal Desai博士、Grayson马歇尔博士、Stefan Habelitz博士、吴莉博士和Peter Loomer博士。他还将接受Mauro Ferrari、Antoni Tomsia和Charles Hoover博士的额外咨询。鉴于口腔和颅面组织再生的生物工程和生物材料研究方法已被NIDCR选为优先目标之一（目标I-5，目标1，NIDCR 2009-2013年战略计划），当前申请的目标将解决高度实际的口腔，牙齿和颅面健康问题。Uskokovic博士通过这个途径独立奖，在他在材料科学和工程方面的专业知识以及UCSF牙科学校的支持下，这是过去15年来NIH资助最多的一所牙科学校，也符合NIDCR战略计划目标2的所有三个目标。Dr. Uskokovic将进行一项研究，该研究将涉及：a）通过超声搅拌乳剂的共沉淀法合成多功能治疗性和骨诱导性磷酸钙纳米颗粒; B）细菌和细胞培养物中的药物释放研究。相对于所提出的假设，本研究的中心目的是获得基于磷酸钙的载体的溶出速率和药物递送效率与其化学组成和微观结构之间的基本相关性。本K99/R 00奖励旨在获得R 01补助金，补助金的撰写将在奖励期结束前开始。 公共卫生相关性：这项研究培训计划将使候选人Vuk Uskokovic博士能够获得细胞培养实验和表征和测试生物方法的专业知识，从而补充他在材料科学和适用于生物医学目的的纳米颗粒工程方面的背景。Uskokovic博士的研究重点将是含克林霉素的磷酸钙/聚合物复合材料，他将测试药物释放速率可以通过改变磷酸钙颗粒的化学计量和尺寸来控制的假设。本研究的目的是建立一种时间可调的药物释放载体，同时延长抗生素的性能和再生的病变硬组织。

DESCRIPTION (provided by applicant): This K99/R00 Mentored Research Career Development Award application is being submitted to the National Institute on Dental and Craniofacial Research (NIDCR). The candidate, Dr. Vuk Uskokovic, is a physical chemist and nanotechnologist who seeks to obtain additional training in the area of cell culture experimentation and other biological methods of analysis through this award. His aim is to develop research skills in the area of multifunctional and nanostructured biomaterials for reparation of hard tissues. The goals of this proposal would enhance Dr. Uskokovic's knowledge of fabrication of smart biomaterials for simultaneous time-controlled drug release and regeneration of diseased hard tissues. Proposed is the synthesis of calcium phosphate/polymer composite particles that encapsulate clinmadycin, a drug used in the treatment of osteomyelitis, as well as testing of the antimicrobial properties and osteinductive performance of the given material in vitro. The central hypothesis of the proposed study is that stoichiometry and the particle size of calcium phosphates can be used to tune the kinetics of the release of the encapsulated drug. Dr. Uskokovic will conduct his training and research activities under the guidance of an expert mentoring team that includes Drs. Tejal Desai, Grayson Marshall, Stefan Habelitz, Wu Li, and Peter Loomer. He will receive additional consulting from Drs. Mauro Ferrari, Antoni Tomsia, and Charles Hoover. Given that bioengineering and biomaterials research approaches to regeneration of oral and craniofacial tissues has been selected as one of the prioritized goals by the NIDCR (Objective I-5, Goal 1, NIDCR Strategic Plan 2009-2013), the goals of the current application will address highly actual oral, dental and craniofacial health problems. Training Dr. Uskokovic through this Pathway to Independence Award on top of his expertise in materials science and engineering and support by the UCSF Dental School, the most funded one by the NIH in the past 15 years, also complies with all three objectives of Goal 2 of the NIDCR Strategic Plan. Dr. Uskokovic will conduct a study which will involve: a) Synthesis of multifunctional therapeutic and osteoinductive calcium phosphate nanoparticles by means of co-precipitation from ultrasonically agitated emulsions; b) Drug release studies in bacterial and cell cultures. With respect to the proposed hypothesis, the central aim of this study is to derive fundamental correlations between the dissolution rate and drug delivery efficiency of calcium phosphate based carriers and their chemical composition and microstructure. This K99/R00 award is conceived to lead to an R01 grant, the writing of which will begin before the end of the award period. PUBLIC HEALTH RELEVANCE: This research training program will enable the candidate, Dr. Vuk Uskokovic, to obtain expertise in cell culture experimentation and biological methods of characterization and testing, and thus complement his background in materials science and engineering of nanosized particles applicable for biomedical purposes. The material that will present the focus of Dr. Uskokovic's research will be clindamycin-containing calcium-phosphate/polymer composite, and he will be testing the hypothesis that the drug release rates could be controlled by varying stoichiometry and size of the calcium phosphate particles. The research aim is to build a time-tunable drug release carrier for the simultaneous prolonged antibiotic performance and regeneration of diseased hard tissues.