Optimizing Nutrient Supply in Large Engineered Cartilage Tissue Constructs

优化大型工程软骨组织结构中的营养供应

• 批准号: 8025654
• 负责人: GERARD A. ATESHIAN
• 金额: $ 34.16万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-20 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8025654
• 关键词: Optimizing; Nutrient; Supply; Large; Engineered

DESCRIPTION (provided by applicant): Osteoarthritis (OA) is a debilitating degenerative disease that afflicts an estimated 27 million Americans age 25 and older. This disease leads to the progressive degradation of the articular layers of diarthrodial joints, significantly compromising the main function of cartilage as a load bearing material, leading to pain and limiting activities of daily living. Cartilage functional tissue engineering is a highly promising technology that aims to provide a biological replacement to worn articular layers, as a modality that considerably expands the limited options in the treatment of this disease. Though cartilage degeneration is occasionally limited to small focal areas within articular layers, OA generally becomes symptomatic when degradation has spread over much greater surface areas (such as greater than 25 percent of the articular layer). Unfortunately, functional tissue engineering of large cartilage constructs is significantly constrained by the balance of nutrient transport and consumption. Several studies have shown that matrix deposition and elaboration of functional properties preferentially occurs near the periphery of constructs, where nutrient supply from the surrounding culture medium is most abundant, whereas cells in the interior receive less nutrients and produce less matrix, with poorer functional properties. In this application, an engineering solution is proposed for the technical challenge of supplying plentiful nutrients for large engineered cartilage constructs by optimizing the number and spacing of narrow channels through the full thickness of construct layers, thus recapitulating the nutrient supply provided by cartilage canals during early development. The placement of channels in constructs of various dimensions must be optimized to balance competing needs: Increasing the channel density would logically increase the total nutrient supply, spreading it more evenly across the entire construct. However, an elevated channel density may effectively decrease the cell density and increase the pathways for loss of synthesized matrix products before they bind to the extracellular matrix. This type of optimization analysis, where competing needs must be balanced, is very well suited for an engineering approach that accounts for the dominant mechanisms regulating tissue growth. The development of this engineering technology will proceed through four specific aims: (1) Implement solute diffusion/binding/consumption and tissue growth equations from existing models into custom-written finite element software for the analysis of tissue engineered constructs. (2) Experimentally characterize the parameters needed for modeling nutrient supply and matrix growth in engineered cartilage. (3) Use these computational tools and experimental data to perform the optimization analysis for channel placement in large cylindrical and patella-shaped articular layer constructs. (4) Culture large constructs using theoretically optimal (N) and sub-optimal (N/2 and 2N) number of channels, as well as channel-free controls; compare matrix deposition and functional properties to test that N is the optimal value; refine model if necessary. PUBLIC HEALTH RELEVANCE: Osteoarthritis (OA) of the knee and hip is most often associated with loss of cartilage over relatively large regions of the articular layers. OA patients have limited treatment options: Early interventions mostly address pain management, whereas advanced stages of the disease are generally treated with joint replacement, a treatment constrained by the life expectancy of patients in relation to the survival rate of implants. Cartilage tissue engineering offers an opportunity to provide a biological implant as an intermediate treatment modality that follows conservative pain management but postpones (or possibly eliminates the need for) joint replacement. The technology proposed in this application will facilitate engineering of large cartilage tissue constructs needed to resurface defects in OA joints.

描述（由申请人提供）：骨关节炎（OA）是一种令人衰弱的退化性疾病，遭受估计25岁及25岁以上的美国人。这种疾病导致腹膜关节关节层的逐渐降解，严重损害了软骨作为负载轴承材料的主要功能，从而导致了日常生活的疼痛和限制活动。软骨功能组织工程是一项非常有前途的技术，旨在为磨损的关节层提供生物学替代品，作为一种大大扩展这种疾病治疗中有限选择的方式。尽管软骨变性偶尔仅限于关节层内的小焦点区域，但是当降解分布在更大的表面积（例如关节层的25％）上时，OA通常会成为症状。不幸的是，大软骨结构的功能组织工程受到养分运输和消耗的平衡的限制。多项研究表明，基质沉积和功能性能的阐述优先发生在构建体的周围附近，在构建体的外围，周围培养基的养分供应最丰富，而内部的细胞获得较少的营养，并且产生较少的基质，具有较差的功能性能。在此应用程序中，提出了一种工程解决方案，以通过通过构造层的全厚度优化狭窄的通道的数量和间距来为大型工程软骨结构提供丰富的营养，从而概括了早期开发过程中软骨运河提供的营养供应。必须优化通道在各个维度的构建体中的位置以平衡竞争需求：提高通道密度将在逻辑上增加总营养供应，从而在整个结构中更均匀地扩散。但是，升高的通道密度可以有效地降低细胞密度，并在合成基质产物与细胞外基质结合之前增加损失的途径。这种类型的优化分析，必须平衡竞争需求，非常适合一种工程方法，该方法解释了调节组织生长的主要机制。该工程技术的开发将通过四个具体目的进行：（1）从现有模型中实施溶质扩散/结合/消耗和组织生长方程，以分析组织工程结构的定制有限元软件。 （2）实验表征对工程软骨中营养供应和基质生长进行建模所需的参数。 （3）使用这些计算工具和实验数据来执行优化分析，以在大圆柱形和pat骨形的关节层构建体中放置通道的位置。 （4）使用理论上最佳（N）和亚最佳（N/2和2N）的通道数以及无通道控制的培养大型构造；比较矩阵沉积和功能属性，以测试n是最佳值；必要时提炼模型。 公共卫生相关性：膝盖和髋关节的骨关节炎（OA）最常见于关节层相对较大的软骨损失。 OA患者的治疗选择有限：早期干预措施主要解决疼痛管理，而疾病的晚期阶段通常是通过关节置换治疗的，这种治疗受患者与植入物存活率有关的预期寿命。软骨组织工程提供了一个机会，可以提供生物植入物作为中间治疗方式，遵循保守的疼痛管理，但推迟（或可能消除了需要的）关节置换。该应用程序中提出的技术将促进在OA关节中重新铺面缺陷所需的大软骨组织结构的工程。