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

ID：MPS/DMR/BMAT（7623）0846363 PI：Heilshorn，Sarah ORG：斯坦福大学职称：职业：该奖项由2009年美国恢复和再投资法案（公法111-5）资助。智力优势：目前还没有诱导脊髓完全再生的疗法;然而，临床界认为，涉及生物可降解材料、细胞移植和药物递送的联合方法提供了最好的希望。为了实现这一更广泛的目标，该项目的重点是开发适应性生物材料的新设计策略，这些材料经历可预测的细胞诱导的重塑。 所有这些材料都是使用重组蛋白工程技术制造的，该技术允许对整个一级结构进行精确的分子水平控制。 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精确地调节。 通过这些适应性生物材料的精确设计，在生物材料和嵌入的细胞之间实现了动态双向通信。 这种双向细胞-支架通讯将使用封装在这些适应性生物材料中的神经祖细胞进行研究。 在目标1中，将确定初始生物材料性质（弹性和细胞受体配体密度）与细胞表型反应（三维神经突生长和蛋白酶分泌）之间的关系。 PI假设可以通过材料设计指导神经突生长。 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值进行比较。假设细胞-支架相互作用可以通过精确的局部调节降解速率来动态控制。 在目标3中，PI将探索使用细胞诱导的重塑作为从生物材料中释放肽药物的触发器。据推测，定制的生物材料的降解速率和肽的扩散速率将提供可预测的交付profiles.BroADER IMPLEMENTARY：该计划包括一个综合的教育计划，促进跨多个群体的教学和学习。在高中阶段，来自代表性不足群体的学生将参加实践研究，在课堂上与同龄人和教师分享他们的经验，并在他们开始大学生涯时接受持续的指导。这项新计划的成功将在斯坦福大学科学推广办公室的帮助下进行评估，结果将在全国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辅导方案，促进本科生和研究生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自适应特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应率。这些类型的自适应生物材料是开发脊髓再生疗法所必需的，并且可能为未来与宿主组织整合的假体界面（例如与儿童一起生长的植入假体）提供指导。

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.