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

基本信息

批准号：
8721343
负责人：
GERARD A. ATESHIAN
金额：
$ 33.4万
依托单位：
COLUMBIA UNIV NEW YORK MORNINGSIDE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-20 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8721343
关键词：
Accounting Activities of Daily Living Address Age American Area Binding Biological Biomedical Engineering Caliber Cartilage Cattle Cell Density Cells Chondrocytes Computer software Consumption Culture Media Custom Data Defect Degenerative Disorder Degenerative polyarthritis Deposition Development Diagnosis Diffusion Dimensions Disease Early Intervention Elements Engineering Equation Equilibrium Evolution Extracellular Matrix Gel Growth Health behavior Hip region structure Human Implant Joints Knee Osteoarthritis Knee bone Knowledge Laboratories Life Expectancy Location Measurement Methodology Methods Modality Modeling NIH Program Announcements Nutrient Pain Pain management Pathway interactions Patients Phase Process Property Replacement Arthroplasty Research Research Personnel Research Project Grants Sepharose Serum Shapes Solutions Source Staging Surface Survival Rate System Technology Testing Thick Tissue Engineering Tissues Weight-Bearing state Writing articular cartilage base computerized tools density design fetal improved prevent programs public health relevance scaffold solute tool

项目摘要

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.

描述（由申请人提供）：骨关节炎 (OA) 是一种使人衰弱的退行性疾病，估计有 2700 万 25 岁及以上的美国人深受其苦。这种疾病导致关节关节的关节层进行性退化，显着损害软骨作为承载材料的主要功能，导致疼痛并限制日常生活活动。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替代品，作为一种大大扩展了治疗这种疾病的有限选择的方式。尽管软骨退化有时仅限于关节层内的小局部区域，但当退化扩散到更大的表面积（例如大于关节层的 25%）时，OA 通常会出现症状。不幸的是，大型软骨结构的功能组织工程受到养分运输和消耗平衡的严重限制。多项研究表明，基质沉积和功能特性的形成优先发生在构建体的外围附近，周围培养基的营养供应最丰富，而内部的细胞接受的营养较少，产生的基质也较少，功能特性较差。在本申请中，提出了一种工程解决方案，通过优化整个结构层厚度的窄通道的数量和间距，从而概括早期软骨管提供的营养供应，以应对为大型工程软骨结构提供充足营养的技术挑战。发展。必须优化各种尺寸结构中通道的放置，以平衡相互竞争的需求：增加通道密度从逻辑上讲会增加总养分供应，使其更均匀地分布在整个结构中。然而，升高的通道密度可以有效地降低细胞密度并增加合成基质产物在与细胞外基质结合之前损失的途径。这种类型的优化分析必须平衡竞争需求，非常适合解释调节组织生长的主导机制的工程方法。该工程技术的开发将通过四个具体目标进行：（1）将现有模型中的溶质扩散/结合/消耗和组织生长方程实施到定制的有限元软件中，以分析组织工程结构。 (2) 通过实验表征工程软骨中营养供应和基质生长建模所需的参数。 (3) 使用这些计算工具和实验数据对大型圆柱形和髌骨形关节层结构中的通道放置进行优化分析。 (4) 使用理论上最佳 (N) 和次优 (N/2 和 2N) 数量的通道以及无通道对照培养大型构建体；比较基质沉积和功能特性，检验N是否为最优值；如有必要，完善模型。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Microbubbles as biocompatible porogens for hydrogel scaffolds.

微泡作为水凝胶支架的生物相容性致孔剂。

DOI：
10.1016/j.actbio.2012.07.007
发表时间：
2012
期刊：
Acta biomaterialia
影响因子：
9.7
作者：
Lima,EricG;Durney,KristaM;Sirsi,ShashankR;Nover,AdamB;Ateshian,GerardA;Borden,MarkA;Hung,ClarkT
通讯作者：
Hung,ClarkT

Fabrication of tissue engineered osteochondral grafts for restoring the articular surface of diarthrodial joints.

DOI：
10.1016/j.ymeth.2015.03.008
发表时间：
2015-08
期刊：
Methods (San Diego, Calif.)
影响因子：
0
作者：
Roach BL;Hung CT;Cook JL;Ateshian GA;Tan AR
通讯作者：
Tan AR

A puzzle assembly strategy for fabrication of large engineered cartilage tissue constructs.

用于制造大型工程软骨组织结构的拼图组装策略。

DOI：
10.1016/j.jbiomech.2016.01.023
发表时间：
2016
期刊：
Journal of biomechanics
影响因子：
2.4
作者：
Nover,AdamB;Jones,BrianK;Yu,WilliamT;Donovan,DanielS;Podolnick,JeremyD;Cook,JamesL;Ateshian,GerardA;Hung,ClarkT
通讯作者：
Hung,ClarkT

Biocompatibility of polysebacic anhydride microparticles with chondrocytes in engineered cartilage.

聚癸二酸酐微粒与工程软骨中软骨细胞的生物相容性。