Complex Nanocomposites for Bone Regeneration

描述(由申请人提供)：本生物工程研究伙伴关系提案由加州大学(UC)系统的多学科科学家合作提交。牵头机构是劳伦斯·伯克利国家实验室，在加州大学伯克利分校和加州大学旧金山分校设有组件小组。该BRP汇集了材料科学、化学、生物学和牙科/医学方面的专业知识，开始了该项目的翻译阶段。我们的目标是开发用于组织工程的生物材料，消除手术风险，并允许立即恢复功能。我们将开发和测试能够支持间充质干细胞和骨再生的新植入材料，方法是将仿生学与考虑解剖和功能需求的全新设计理念相结合，根据骨骼缺陷定制支架。最终目标是开发一系列骨诱导植入材料或支架，使其与周围的自然组织和谐发挥作用。这一长期目标将为颅面和骨科骨缺损的最佳修复提供材料，否则将需要从第二个手术部位进行骨移植。首先，将合成具有不同机械响应和生物降解率的水凝胶。不同的官能团将被添加到水凝胶结构中，以模板磷灰石和其他生物矿物的仿生矿化-并促进细胞黏附。其次，这些材料，以及其他已经为我们目前的拨款开发的材料，将用于制备具有不同成分和结构的支架，包括受解剖学启发的设计，它考虑了由机器人铸造(3-D打印)制成的皮质和松质功能解剖，以及使用我们实验室开发的基于悬浮液冷冻铸造的新技术制备的板层结构。第三，将系统地探索在这些多孔支架上添加不同的功能。被认为表现出最佳机械反应的材料将在细胞培养中进行测试，然后在小鼠体内进行测试，使用标准化的骨形成试验来评估新骨形成的速度和程度。根据这些结果，我们将选择具有最大平移潜力的支架。这些干细胞将与自体多能干细胞一起在已建立的中型(兔)和大型(小型猪)动物模型中进行促进骨形成的能力测试，利用一致的生物力学和生物测试方案，这些测试也将用于评估确定支架整合的关键生物学过程。这些研究的成功完成将导致识别出适合用于修复人类头面部和骨科骨骼缺陷的测试的新材料。目前对这些缺陷的护理标准可能会改变，以消除骨移植，降低患者的风险，改善生活质量，并增加临床医生的设施。与公共卫生相关：用于辅助或替代器官功能的生物材料的需求正在迅速增加。每年，美国有100多万骨缺陷症患者需要进行骨移植手术。这项应用将开发新的生物材料，用于优化修复颅面和骨科骨缺损，否则将需要从第二个手术部位进行骨移植。植入物的改进将改善数百万未来需要植入物的人的健康和生活质量。

DESCRIPTION (provided by applicant): This Bioengineering Research Partnership proposal is submitted by a multidisciplinary collaboration of scientists in the University of California (UC) system. The lead institution is Lawrence Berkeley National Laboratory, with component groups at UC Berkeley and UC San Francisco campuses. This BRP brings together expertise in materials sciences, chemistry, biology, and dental/medical science to begin the translational phase of this project. Our goal is to develop biomaterials for tissue engineering that will eliminate surgical risks and allow immediate return of function. We will develop and test new implant materials that can support mesenchymal stem cells and bone regeneration, by combining biomimetics with radically new design philosophies that consider anatomic and functional needs, customizing the scaffold to the skeletal defect. The ultimate goal is to develop a range of osteoinductive implant materials or scaffolds that function harmoniously with the surrounding native tissue. This long-term goal will provide materials for optimal repair of craniofacial and orthopedic skeletal defects that would otherwise require a bone graft from a second surgical site. First, hydrogels with varying mechanical responses and biodegradation rates will be synthesized. Different functional groups will be added to the hydrogel structure to template biomimetic mineralization of apatite and other biominerals-and to promote cell adhesion. Second, these materials, and others already developed for our current grant, will be used in the preparation of scaffolds with various compositions and architectures, including anatomically-inspired designs that considers both cortical and cancellous functional anatomy made by robocasting (3-D printing) and lamellar structures prepared using a novel technology developed in our laboratory based on freeze-casting of suspensions. Third, the addition of diverse functional capabilities to these porous scaffolds will be systematically explored. Materials deemed to display optimal mechanical responses will be tested in cell culture and then in vivo in mice, using standardized bone formation assays that allow assessment of the rate and extent of new bone formation. Based on these results, we will select scaffolds that have the greatest translational potential. These will be tested in combination with autologous multipotent stem cells for the ability to promote bone formation in established medium-sized (rabbit) and large-sized (mini-pig) animal models utilizing a consistent protocol of biomechanical and biological assays that will also serve to asses key biological process that determine scaffold integration. Successful completion of these studies will result in the identification of new materials suitable for testing for the repair of craniofacial and orthopedic skeletal defects in humans. The present standard of care for such defects may be altered to eliminate bone grafts, decrease risks to patients, improve quality of life, and increase the armamentarium of the clinician. PUBLIC HEALTH RELEVANCE: The demand for biomaterials to assist or replace organ functions is rapidly increasing. Every year, more than one million patients in the United States with skeletal defects require bone graft procedures. This application will develop novel biomaterials for optimal repair of craniofacial and orthopedic skeletal defects that would otherwise require a bone graft from a second surgical site. Improvement of implants will result in improved health and quality of life for the millions of people who will need implants in the future.