Hydrogels with Controlled Degradation and Stress Relaxation for Engineered Cartilage

局灶性软骨缺损是由于创伤、年龄相关性退变等原因而发生的，并可导致 进行性软骨退行性变，最终导致疼痛的退行性关节炎。这些缺陷构成了一种严重的 医疗关注由于软骨的自我修复能力有限，以及目前的成功有限 长期有力地修复软骨缺损的方法。一种很有希望的修复缺陷的方法 是否使用体外形成的组织工程软骨样的等价物来从功能上取代受损的软骨 软骨。通过将细胞包裹在3D水凝胶中形成组织工程化软骨样等效物， 并在含有适当生化线索的培养基中培养凝胶。而健康的软骨细胞 被包裹在水凝胶中可以形成软骨样组织的等价物，健康的可获得性有限 骨性关节炎患者的软骨细胞在采集过程中可能会出现供体部位的严重并发症。 间充质干细胞(MSCs)是形成组织工程化的一种有吸引力的替代细胞来源 软骨的等价物。已发现骨髓间充质干细胞在给予 适当的生化提示，并将其封装在水凝胶中。然而，基于MSC的组织工程化 在其组成和力学性能方面，构建物不能模拟自然的关节软骨组织。 在这里，我们建议开发粘弹性、表现出快速应力松弛和工程化的水凝胶。 以间充质干细胞为基质的组织工程软骨的降解。这项建议中要检验的具体假设 基于透明质酸(HA)的水凝胶的快速应力松弛和完全可降解性将直接 骨髓间充质干细胞向软骨细胞分化并促进形成相互连接的软骨基质 力学性能、成分和结构接近于天然关节软骨组织。这个 拟议的研究将建立在PI小组工作的基础上，这些小组已经展示了HA水凝胶的开发 快速应力松弛，并已表明海藻酸水凝胶中的快速应力松弛促进软骨 软骨细胞形成基质。这一假设将在两个具体目标中得到验证：(1)材料设计： 开发基于透明质酸的水凝胶，其中的降解率、应力松弛和硬度可以 使用一组模块化组件独立调节；(2)体外试验：确定最佳水平 人骨髓间充质干细胞形成工程化软骨的降解和应力松弛。这种方法是 创新是因为透明质酸基水凝胶的开发既具有工程降解性，又具有 应力松弛代表了生物材料设计中的一种创新策略，并提出了一种新型的应力松弛 用于软骨组织工程的生物材料。这项拟议的研究具有重要意义，因为它有可能 为骨髓间充质干细胞形成组织工程化软骨替代物提供关键进展，并在 这一方法将被转化为临床应用。一种修复软骨组织缺陷的强有力的方法将具有 对患者的生活质量影响巨大，并能长期降低医疗成本。

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.