Engineering Bimodal Degrading Hydrogels

工程双峰降解水凝胶

• 批准号: 8093778
• 负责人: Stephanie J Bryant
• 金额: $ 19.37万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8093778
• 关键词: Behavior; Biocompatible Materials; Biological Models; Cartilage; Cells; Chondrocytes; Clinical; Coupled; Data; Defect; Deposition; Development; Diffusion; Engineering; Enzymes; Evolution; Experimental Designs; Extracellular Matrix; Extracellular Matrix Degradation; Foundations; Future; Gel; Glean; Glycols; Goals; Grant; Growth; Hydrogels; Hydrolysis; In Vitro; Indium; Kinetics; Liquid substance; Measurement; Mechanics; Mediating; Modeling; Natural regeneration; Outcome; Physics; Positioning Attribute; Production; Property; Qualifying; Research; Research Personnel; Scheme; Solutions; System; Testing; Tissue Engineering; Tissues; United States National Institutes of Health; Work; articular cartilage; base; cartilage regeneration; cell type; crosslink; density; design; experience; flexibility; in vivo; innovation; mathematical model; new growth; poly(lactic acid); prevent; research study; scaffold; skills; tool

DESCRIPTION (provided by applicant): Our long-term goal is to develop biodegradable synthetic hydrogels for regenerating articular cartilage, which are capable of supporting the normal forces in vivo while simultaneously permitting matrix deposition and new tissue growth. Current limitations in the development of such hydrogels can be summarized as follows: (a) highly cross-linked hydrogel can resist loads but restrict matrix diffusion, which prevents growth of new tissue (b) reversely, low cross-link density permits matrix diffusion but results in unacceptably weak bulk properties that cannot sustain normal forces. The objective of this work is thus to introduce a hydrogel system for which spatial and temporal degradation can be controlled to better match tissue development. Our global hypothesis is that a bimodal degrading hydrogels, incorporating localized and cell-mediated (enzymatic) and bulk (hydrolytic) degradation, maintains mechanical integrity while simultaneously allowing matrix development and that there exists an optimized design space to achieve the outcomes. To test our hypothesis, mathematical models will be developed in tandem with experiments in order to accurately describe the combined effects of gel degradation and matrix deposition. In particular, the specific aims of the project are to: 1. Develop, validate, and calibrate a mathematical model for bimodal degrading hydrogels. This aim will be decomposed in two parts. First, our existing model for matrix degradation will be validated against experimental measurement based on enzyme-loaded microparticles. Second, a model for ECM production and deposition, combined with hydrolytic degradation will be developed and validated against preliminary data. 2. Characterize degradation behavior and matrix evolution in single and dual mode degrading hydrogel. This aim will extend the mathematical model to the general case of a combination of bimodal degradation and ECM deposition in order to assess the effect of hydrogel parameters on the competition between gel degradation and ECM deposition. Two experimental strategies, testing both enzymatic and bimodal degradable gels, are then proposed to validate and calibrate the model. At the completion of this exploratory research, we expect to have developed a new class of bimodal degrading hydrogels based on crosslinked poly(ethyelene glycol) where the crosslinks can be degraded either through cell-mediated enzymatic degradation (i.e., aggrecanses secreted by entrapped chondrocytes) or hydrolytically (i.e., poly(lactic acid) segments). By merging experiments with modeling, we expect to clearly understand how a bimodal degradable gel can be used to maintain mechanical integrity while permitting macroscopic tissue evolution. In future work, this model system will enable us to develop superior degradable hydrogels, which will lay the foundation for seeking competitively a NIH R01 and to pursue their (pre)clinical utility. PUBLIC HEALTH RELEVANCE: This research aims to create a new class of biodegradable scaffolds that are in tune with new tissue development for treating damaged cartilage. New mathematical tools will be developed to elucidate scaffold design parameters that yield superior engineered tissues.

描述（由申请人提供）：我们的长期目标是开发可再生关节软骨的可生物降解的合成水凝胶，这些水凝胶能够在体内支撑正常力，同时允许矩阵沉积和新的组织生长。该水凝胶开发的当前局限性可以总结如下：（a）高度交联的水凝胶可以抵抗负载，但限制了矩阵扩散，这阻止了新组织的生长（b）反向相反，低的交联密度允许矩阵扩散，但无法接受的较弱的较弱的较弱的块状特性，无法维持正常力。因此，这项工作的目的是引入一个水凝胶系统，可以控制空间和时间降解以更好地匹配组织的发展。我们的全球假设是，融合了局部和细胞介导的（酶促）和大量（水解）降解的双峰降解水凝胶保持机械完整性，同时允许矩阵开发，并存在优化的设计空间以实现其远期结果。为了检验我们的假设，数学模型将与实验一起开发，以准确描述凝胶降解和基质沉积的综合作用。特别是，该项目的具体目的是：1。开发，验证和校准双峰降解水凝胶的数学模型。这个目标将分为两部分。首先，我们现有的矩阵降解模型将根据基于酶加载的微粒的实验测量进行验证。其次，将开发并根据初步数据来开发和验证ECM生产和沉积模型，并结合水解降解。 2。表征单个和双模式下降解水凝胶中的降解行为和基质演化。 该目标将将数学模型扩展到双峰降解和ECM沉积的一般情况，以评估水凝胶参数对凝胶降解与ECM沉积之间竞争的影响。然后提出了两种测试酶和双峰降解凝胶的实验策略，以验证和校准模型。这项探索性研究完成后，我们希望基于交联的聚乙二醇（乙烯乙二醇）开发出新的双峰降解水凝胶，在这些水凝胶中，可以通过细胞介导的酶降解来降解交联的交联链接（即，在围绕脑核心酸）（即含水液）（即含水液）（I. I. I. I.细分）。通过将实验与建模合并，我们希望清楚地了解如何使用双峰降解凝胶来维持机械完整性，同时允许宏观组织进化。在将来的工作中，该模型系统将使我们能够开发出卓越的可降解水凝胶，这将为寻求竞争性的NIH R01并追求其（前）临床实用程序奠定基础。 公共卫生相关性：这项研究旨在创建一类新的可生物降解脚手架，与新的组织开发相符，以治疗受损的软骨。将开发新的数学工具来阐明产生卓越的工程组织的支架设计参数。