CAREER: Adaptive Biomaterials that Enable Cell-Induced Remodeling and Drug Release

ID：MPS/DMR/BMAT(7623)0846363 PI：海尔肖恩，莎拉·ORG：斯坦福标题：Career：实现细胞诱导重塑和药物释放的适应性生物材料该奖项由2009年美国复苏和再投资法案(公共法律第111-5号)资助。为了实现这一更广泛的目标，该项目的重点是开发新的设计策略，以适应经历可预测的细胞诱导重塑的生物材料。所有这些材料都是使用重组蛋白质工程技术制造的，这种技术允许在分子水平上对整个一级结构进行精确控制。由于这种精细的控制水平，生物材料的初始机械性能、降解曲线和细胞粘附性可以独立和准确地调整。通过对这些适应性生物材料的精确设计，生物材料和嵌入细胞之间实现了动态双向通信。这种双向的细胞-支架通讯将使用封装在这些适应性生物材料中的神经前体细胞进行研究。在目标1中，将确定初始生物材料特性(弹性和细胞-受体-配体密度)和细胞表型响应(三维突起生长和蛋白酶分泌)之间的关系。PI假设轴突的生长可以通过材料设计来指导。在目标2中，PI将开发一个理论模型来预测降解曲线，并将该模型与细胞诱导重塑的实验测量进行比较。假设细胞-支架的相互作用可以通过对降解速率的精确局部调节来动态控制。在目标3中，PI将探索使用细胞诱导的重塑作为触发从生物材料中释放多肽药物。假设生物材料降解率和多肽扩散速率的定制将提供可预测的交付轮廓。BROADER影响：该计划包括一个综合教育计划，促进多个群体的教与学。在高中阶段，来自代表性不足群体的学生将参与实践研究，在课堂上与同龄人和老师分享他们的经验，并在他们开始大学生涯的过程中接受持续的指导。这一新计划的成功将在斯坦福大学科学外展办公室的帮助下进行评估，结果将在国家会议和工程教育期刊上传播。综合教育计划还包括通过新课程开发以及正式和非正式指导方案促进本科生和研究生的多样性和跨学科培训的活动。这项研究通过提供新的方法来设计具有适应性的高度定制的生物材料，从而影响了更广泛的科学界。目前，还没有通用的策略来控制植入后生物材料的适合率。这些类型的适应性生物材料是开发脊髓再生疗法所必需的，并可能引导未来与宿主组织整合的假体接口，例如与孩子一起成长的植入型假体。

ID: MPS/DMR/BMAT(7623) 0846363 PI: Heilshorn, Sarah ORG: StanfordTitle: CAREER: Adaptive Biomaterials that Enable Cell-Induced Remodeling and Drug ReleaseThis award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).INTELLECTUAL MERIT: No current therapies exist to induce complete spinal cord regeneration; however, the clinical community suggests that a combined approach involving biodegradable materials, cell transplantation, and drug delivery offers the best hope. Towards this broader goal, the focus of this project is to develop new design strategies for adaptable biomaterials that undergo predictable, cell-induced remodeling. All of these materials are fabricated using recombinant protein engineering technology, which allows precise molecular-level control over the entire primary structure. Due to this exquisite level of control, the initial mechanical properties, degradation profile, and cell adhesivity of the biomaterial can be independently and exactly tuned. Through precise design of these adaptable biomaterials, dynamic two-way communication is enabled between the biomaterial and embedded cells. This two-way cell-scaffold communication will be studied using neural progenitor cells encapsulated within these adaptable biomaterials. In Aim 1, the relationship between initial biomaterial properties (elasticity and cell-receptor-ligand density) and cell phenotypic response (three-dimensional neurite outgrowth and protease enzyme secretion) will be determined. The PI hypothesizes that neurite outgrowth can be directed through material design. In Aim 2, the PI will develop a theoretical model to predict degradation profiles and compare this model to experimental measurements of cell-induced remodeling. It is hypothesized that cell-scaffold interactions can be dynamically controlled through precise local tuning of the degradation rate. In Aim 3, the PI will explore the use of cell-induced remodeling as a trigger to release peptide pharmaceuticals from biomaterials. It is hypothesized that tailoring of the biomaterial degradation rate and the peptide diffusion rate will provide predictable delivery profiles.BROADER IMPACTS: This program includes an integrated education plan that promotes teaching and learning across multiple groups. At the high school level, students from under-represented groups will participate in hands-on research, share their experiences with peers and teachers in the classroom, and receive continued mentoring as they embark on their collegiate careers. Success of this new program will be assessed with help from the Stanford Office for Science Outreach, and results will be disseminated at national conferences and in engineering education journals. The integrated education plan also includes activities to promote diversity and interdisciplinary training for undergraduate and graduate students through new course development as well as formal and informal mentoring programs. The research impacts the broader scientific community by providing new approaches to design highly tailored biomaterials with adaptive properties. Currently, no general strategy exists to control the rate of biomaterial adaptation after implantation. These types of adaptive biomaterials are required to develop therapies for spinal cord regeneration and may guide the way towards future prosthetic interfaces that integrate with host tissue, such as implanted prosthetics that grow with a child.