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CAREER: Engineering Biomaterials that Leverage Size-Dependent Biological Effects of Hyaluronic Acid to Promote Spinal Cord Regeneration

职业：利用透明质酸尺寸依赖性生物效应促进脊髓再生的工程生物材料

基本信息

批准号：
1653730
负责人：
Stephanie Seidlits
金额：
$ 50万
依托单位：
University of California-Los Angeles
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-01 至 2022-02-28
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1653730&HistoricalAwards=false
关键词：
CAREER Engineering Biomaterials Leverage Size

项目摘要

PI: Seidlits, StephanieProposal #: 1653730Over 1 million people in the USA live with spinal cord injury (SCI) for which no current clinical treatment can restore function. Barriers to spinal cord regeneration include loss of functional neural circuits, extensive cell death, astrocyte induced scar formation, and chronic inflammation. Hyaluronic acid (HA)---a viscous fluid carbohydrate that is the main structural component of the extracellular matrix (ECM)--is an important mediator in each of these events. In healthy spinal cord, HA remains in its native, high molecular weight form (nHA, molecular weight 300 kDA) and acts to maintain tissue structure, protect against oxidative stress, and promote quiescence of astrocytes and neural stem cells (NSCs). Immediately after injury, nHA is degraded into a range of smaller fragments (fHA, molecular weight = 1-100 kDa), which are thought to have size-dependent actions on wound-healing processes including direct effects on astrocyte proliferation, angiogenesis and NSC recruitment. Studies examining the effects of HA biomaterials relative to reducing scarring and promoting NSC differentiation have produced conflicting results. The PI posits that these discrepancies arise from failure to experimentally control for differences in HA molecular weight. Thus, the goal of this project is to provide a fundamental understanding of how the diverse biological effects of HA can be leveraged to engineer biomaterials that effectively direct tissue repair after SCI by investigating: 1) how the molecular weight of HA incorporated into crosslinked hydrogels affects cell-biomaterial interactions and 2) how these molecular weight-dependent effects can be used to design HA biomaterials with improved therapeutic benefits. The integrated research and education plan includes mentored laboratory experiences for high school, undergraduate and graduate students that are designed to generate enthusiasm for science and engineering in medicine that will motivate future career goals, e.g.: 1) fluorescent reporters that enable students to visualize subcellular processes in real-time and 2) the promise of new clinical treatments for spinal cord repair. Research results will be integrated into two UCLA undergraduate bioengineering courses with unique hands-on, laboratory components, including the CAPSTONE design course where groups of seniors work closely with an interdisciplinary team of academic and industry mentors to design and construct new solutions to important biomedical problems.As part of the long-term goal to engineer improved therapies to promote nerve regeneration, the focus of this project is to improve understanding of how the molecular weight-dependent bioactivities of HA affect spinal cord repair. Specifically, the PI aims to identify the molecular weight-dependent effects of HA on human cells relevant to SCI (NSCs and astrocytes) and apply this information to design HA-releasing biomaterials to guide spinal cord regeneration. Multiple studies have demonstrated that nHA--which degrades to fHA after SCI-- inhibits astrocyte proliferation and reactivity. In opposition, disruption of the nHA matrix promotes astrocyte proliferation and activation and, as a result, increased glial scarring. A few studies have reported similar effects on NSCs. Despite the known dependence of HA bioactivity on molecular weight, HA chain size has not been a significant consideration in the development of regenerative biomaterials. Aim 1 will investigate how the molecular weight of HA crosslinked into hydrogel biomaterials affects CD44 (a receptor for HA)-mediated bioactivity of cells integral to spinal cord repair (NSCs and astrocytes). Aim 2 will characterize the molecular weight profile of HA fragments released from biomaterials during biodegradation and assess the effects of its products on chemotaxis and proliferation of NSCs and astrocytes. Aim 3 will work towards clinical translation by developing HA-based hydrogels that are injectable, support robust cell infiltration and enable temporal control over HA molecular weight. This aim includes the novel fabrication of injectable, macroporous scaffolds with defined HA molecular weights, including nHA, which has not previously been accomplished due to the high viscosity of nHA. Effects of the hydrogels on NSCs and inflammation will be evaluated in a mouse model of acute SCI, whose outcome will be followed 4 weeks post injury. Thus, the project will provide a fundamental understanding of the molecular weight-dependent bioactivities of HA and guide the design of advanced HA-based therapeutics, in particular for spinal cord regeneration but with implications for a broad range of medical applications.

PI: Seidlits， stephanie提案#:1653730在美国有超过100万人患有脊髓损伤（SCI），目前没有临床治疗可以恢复其功能。脊髓再生的障碍包括功能性神经回路的丧失、广泛的细胞死亡、星形胶质细胞诱导的瘢痕形成和慢性炎症。透明质酸（HA）是一种粘性流体碳水化合物，是细胞外基质（ECM）的主要结构成分，在这些事件中都是重要的介质。在健康的脊髓中，透明质酸保持其天然的高分子量形式（nHA，分子量300 kDA），维持组织结构，防止氧化应激，促进星形胶质细胞和神经干细胞（NSCs）的静止。损伤后，nHA立即被降解成一系列较小的片段（fHA，分子量= 1-100 kDa），这些片段被认为对伤口愈合过程具有大小依赖性，包括对星形胶质细胞增殖、血管生成和NSC募集的直接影响。关于HA生物材料在减少瘢痕形成和促进NSC分化方面的作用的研究产生了相互矛盾的结果。PI认为，这些差异是由于未能通过实验控制HA分子量的差异造成的。因此，该项目的目标是通过研究：1)纳入交联水凝胶的透明质酸分子量如何影响细胞-生物材料的相互作用，以及2)如何利用这些分子量依赖效应来设计具有更好治疗效果的透明质酸生物材料，从而对如何利用透明质酸的各种生物效应来设计有效指导脊髓损伤后组织修复的生物材料提供一个基本的理解。综合研究和教育计划包括为高中，本科生和研究生提供指导实验室经验，旨在激发对医学科学和工程的热情，从而激发未来的职业目标，例如：1)荧光报告，使学生能够实时可视化亚细胞过程；2)脊髓修复的新临床治疗的前景。研究成果将整合到加州大学洛杉矶分校的两门本科生生物工程课程中，其中包括CAPSTONE设计课程，在该课程中，高年级学生与由学术和行业导师组成的跨学科团队密切合作，设计和构建针对重要生物医学问题的新解决方案。作为设计改进疗法以促进神经再生的长期目标的一部分，该项目的重点是提高对HA的分子量依赖性生物活性如何影响脊髓修复的理解。具体来说，该项目旨在确定HA对与脊髓损伤相关的人类细胞（NSCs和星形胶质细胞）的分子量依赖性作用，并将这些信息应用于设计HA释放生物材料，以指导脊髓再生。多项研究表明，nHA（脊髓损伤后降解为fHA）抑制星形胶质细胞增殖和反应性。相反，nHA基质的破坏促进星形胶质细胞增殖和活化，结果增加胶质瘢痕。一些研究报告了对NSCs的类似影响。尽管已知透明质酸的生物活性依赖于分子量，但在再生生物材料的开发中，透明质酸链的大小并不是一个重要的考虑因素。目的1将研究HA交联到水凝胶生物材料中的分子量如何影响CD44 （HA受体）介导的脊髓修复不可或缺的细胞（NSCs和星形胶质细胞）的生物活性。目的2将描述生物材料在生物降解过程中释放的HA片段的分子量特征，并评估其产物对NSCs和星形胶质细胞趋化性和增殖的影响。Aim 3将通过开发可注射的HA基水凝胶，支持稳健的细胞浸润，并能够对HA分子量进行时间控制，从而致力于临床翻译。这一目标包括可注射的大孔支架的新制造，具有明确的HA分子量，包括nHA，这是以前没有完成的，因为nHA的高粘度。水凝胶对神经干细胞和炎症的影响将在急性脊髓损伤小鼠模型中进行评估，其结果将在损伤后4周进行随访。因此，该项目将提供对透明质酸分子量依赖性生物活性的基本理解，并指导设计先进的基于透明质酸的治疗方法，特别是脊髓再生，但具有广泛的医学应用意义。