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Hydrogels with Controlled Degradation and Stress Relaxation for Engineered Cartilage

用于工程软骨的具有受控降解和应力松弛的水凝胶

基本信息

批准号：
9770767
负责人：
Ovijit Chaudhuri
金额：
$ 17.27万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2020-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9770767
关键词：
3-Dimensional Address Alginates Animals Architecture Biochemical Biocompatible Materials Biological Assay Biopolymers Cartilage Cartilage Matrix Cells Chemistry Chondrocytes Chondrogenesis Clinic Clinical Trials Cues Defect Degenerative polyarthritis Deposition Development Disease Encapsulated Engineering Exhibits Exposure to Extracellular Matrix Future Gel Goals Harvest Health Care Costs Human Hyaluronic Acid Hydrogels Immunohistochemistry In Vitro Knowledge Lead Mechanics Medical Mesenchymal Differentiation Mesenchymal Stem Cells Mission Molecular Weight Morbidity - disease rate Nature Pain Patients Peptide Hydrolases Property Public Health Quality of life Relaxation Research Signal Transduction Site Source Stress System Testing Tissue Engineering Tissues Translating Trauma United States National Institutes of Health Work age related articular cartilage base cartilage degradation cartilage repair crosslink density design disability improved in vitro testing innovation mechanical properties novel strategies professor repaired scaffold success three dimensional cell culture viscoelasticity

项目摘要

Focal cartilage defects occur due to trauma, age-related degeneration and other causes, and can lead to progressive cartilage degeneration culminating in painful degenerative arthritis. These defects present a critical medical concern due to the limited capacity of cartilage to self-repair, and the limited success of current approaches in robustly repairing cartilage defects over the long term. One promising approach to repair defects is the use of tissue engineered cartilage-like equivalents formed in vitro to functionally replace damaged cartilage. Tissue engineered cartilage-like equivalents are formed by encapsulating cells within 3D hydrogels, and culturing the gels in media that contains the appropriate biochemical cues. While healthy chondrocytes encapsulated within hydrogels can form cartilage-like tissue equivalents, there is limited availability of healthy chondrocytes from patients with osteoarthritis and significant donor site morbidity during harvesting can occur. Mesenchymal stem cells (MSCs) present an attractive alternative cell source for forming tissue engineered cartilage equivalents. MSCs have been found to undergo chondrogenic differentiation when given the appropriate biochemical cues and encapsulated in hydrogels. However, MSC based tissue engineered constructs fail to mimic natural articular cartilage tissue in terms of their composition and mechanical properties. Here we propose to develop hydrogels that are viscoelastic, exhibiting fast stress relaxation, and engineered degradation for MSC-based tissue engineered cartilage. The specific hypothesis to be tested in this proposal is that fast stress relaxation combined with full degradability of hyaluronic acid (HA)-based hydrogels will direct chondrogenic differentiation of MSCs and promote formation of an interconnected cartilage matrix having mechanical properties, composition, and architecture approaching that of natural articular cartilage tissue. The proposed study will build on work by the PI’s group that have demonstrated the development of HA hydrogels with fast stress relaxation, and have shown that fast stress relaxation in alginate hydrogels promotes cartilage matrix formation by chondrocytes. This hypothesis will be tested in two specific aims: (1) materials design: develop hyaluronic acid based hydrogels in which degradation rate, stress relaxation, and stiffness can be independently modulated using a set of modular components; (2) in vitro testing: determine the optimal levels of degradation and stress relaxation for formation of engineered cartilage by human MSCs. This approach is innovative because the development of hyaluronic acid based hydrogels with both engineered degradation and stress relaxation represents an innovative strategy in biomaterials design, and presents a new type of biomaterial for cartilage tissue engineering. The proposed research is significant because of its potential to provide the critical advance for forming tissue engineered cartilage equivalents by MSCs, and in the ability of this approach to be translated into the clinic. A robust approach to repairing cartilage tissue defects will have a tremendous impact on the quality of life for patients, and reducing health care costs long-term.

局灶性软骨缺损的发生是由于创伤、年龄相关的退化和其他原因，并可导致进行性软骨退化，最终导致疼痛的退化性关节炎。这些缺陷是一个关键的由于软骨自我修复的能力有限，以及目前的治疗成功有限，长期稳健修复软骨缺损的方法。一种有前途的修复缺陷的方法是使用体外形成的组织工程软骨样等同物来功能性地替代受损的软骨组织工程软骨样等同物通过将细胞包封在3D水凝胶内形成，并在含有适当的生物化学信号的培养基中培养凝胶。健康的软骨细胞虽然封装在水凝胶内的胶原蛋白可以形成软骨样组织等同物，但健康的胶原蛋白的可用性有限。可能发生骨关节炎患者的软骨细胞和在收获期间显著的供体部位发病率。骨髓间充质干细胞（Mesenchymal stem cells，MSCs）是一种有吸引力的组织工程细胞来源软骨等同物。已经发现，当给予MSC时，MSC经历软骨形成分化。适当的生化线索并封装在水凝胶中。然而，基于MSC的组织工程就其组成和机械性能而言，构建体不能模拟天然关节软骨组织。在这里，我们建议开发粘弹性的水凝胶，表现出快速的应力松弛，用于基于MSC的组织工程软骨的降解。本提案中要检验的具体假设快速的应力松弛与透明质酸（HA）基水凝胶的完全降解性相结合， MSC的软骨形成分化，并促进互连软骨基质的形成，机械性能、组成和结构接近天然关节软骨组织。的拟议的研究将建立在PI小组的工作基础上，该小组已经证明了HA水凝胶的发展并且已经显示藻酸盐水凝胶中的快速应力松弛促进软骨软骨细胞形成基质。这一假设将在两个特定的目标进行测试：（1）材料设计：开发基于透明质酸的水凝胶，其中降解速率、应力松弛和刚度可以使用一组模块化组件独立调节;（2）体外测试：确定最佳水平的降解和应力松弛，以形成工程化软骨的人MSC。这种方法这是创新的，因为基于透明质酸的水凝胶的开发既具有工程降解，应力松弛是生物材料设计中的一种创新策略，软骨组织工程生物材料。这项研究之所以重要，是因为它有可能为利用MSC形成组织工程化软骨替代物提供了关键进展，这种方法将被转化为临床。修复软骨组织缺损的稳健方法将具有对患者的生活质量产生巨大影响，并长期降低医疗保健费用。