High-Throughput Microenvironment Regulation for Chondrogenesis

软骨形成的高通量微环境调节

基本信息

批准号：
8914310
负责人：
Eben Alsberg
金额：
$ 42.1万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8914310
关键词：
Address Affect Animal Model Autologous Transplantation Biochemical Biocompatible Materials Biomechanics Bone Marrow Cartilage Cartilage injury Cell Proliferation Cells Cellularity Chondrogenesis Clinic Clinical Communities Cues Defect Development Engineering Ensure Extracellular Matrix Financial cost Future Goals Growth Factor Hip Osteoarthritis Histocompatibility Testing Hospitalization Human Hydrogels In Vitro Individual Injury Knee Osteoarthritis Knowledge Lead Mechanical Stimulation Mechanics Medical Mesenchymal Stem Cells Microfabrication Musculoskeletal Natural regeneration Nature New Zealand Operative Surgical Procedures Orthopedics Oryctolagus cuniculus Pathway interactions Patients Performance Play Population Procedures Production Property Regulation Research Research Personnel Research Proposals Role Safety Signal Transduction Source System Testing Time Tissue Engineering Tissues Variant aged articular cartilage base cartilage regeneration clinically relevant combinatorial design experience improved in vitro testing in vivo in vivo Model minimally invasive osteochondral tissue public health relevance repaired response stem cell differentiation

项目摘要

DESCRIPTION (provided by applicant): Musculoskeletal tissue injuries remain a significant challenge in orthopaedics research. For example, currently, millions of patients are suffering from cartilage injuries, with associated annual financial costs of more than $100 billion dollars. There are several viable clinical options to address these injuries. In this context, human mesenchymal stem cells (hMSCs) are a promising cell source for cartilage tissue engineering as they are capable of differentiating down the chondrogenic pathway, can be obtained from bone marrow in a minimally invasive manner, and are easily grown in culture. Although differentiation of hMSCs is regulated by soluble molecules, insoluble biochemical signals and mechanical cues, the combinatorial effects of mechanical loading and biomaterial signals are largely unknown. Our central hypothesis is that the use of high-throughput systems (HTSs) under mechanical stimulation can be used to elucidate single and synergistic microenvironmental factors for directing the chondrogenic differentiation of hMSCs, and thereby functional engineered cartilage formation in vitro and in a clinically relevant in vivo model. The information obtained from the HTS will help in the development of macroscale constructs with enhanced chondrogenesis, and the performance of these constructs will be validated in vivo by treating critical-sized articular cartilage defects. These goals will be accomplished by achieving the following specific Aims: (1) to develop three dimensional (3D) combinatorial HTS hydrogel-based microarrays, consisting of different extracellular matrix molecules and growth factors, which can be mechanically deformed to mimic the chondrogenic microenvironment of hMSCs, (2) to evaluate quantitatively the chondrogenic differentiation response of hMSCs in 3D combinatorial HTS microarrays and macroscale constructs selected from these microarrays, and (3) to determine the potential of hMSC-laden constructs with HTS-identified compositions and mechanical stimulation regimes to induce cartilage regeneration in vivo. The orthopedic community would benefit from a better understanding of these chondroinductive microenvironments that will ultimately induce neo-tissue formation and will represent a viable alternative to current clinical therapies. While the ultimate objective of this research is to engineer clinically relevant articular cartilage therapies, this HTS can also be applicable to test regeneration strategies for other tissues.

描述（由适用提供）：肌肉骨骼组织损伤仍然是正义研究中的重大挑战。例如，目前，数以百万计的患者患有软骨受伤，相关的年财务费用超过1000亿美元。有几种可行的临床选择来解决这些伤害。在这种情况下，人间充质干细胞（HMSC）是软骨组织工程的有望的细胞来源，因为它们能够以微不足道的方式从骨髓中获得降低软骨般的途径，并且很容易在培养中生长。尽管HMSC的分化受固体分子，不溶性生化信号和机械提示的调节，但是机械负载和生物材料信号的组合效应在很大程度上未知。我们的中心假设是，在机械刺激下使用高通量系统（HTSS）可用于阐明指导HMSC的软骨的单一和协同的微环境因素，从而在凝聚在Vivo Invivo Intivo模型中进行功能性工程性软骨形成。从HTS获得的信息将有助于以增强的软骨形成的宏观构建体的开发，并且这些构建体的性能将在体内通过治疗关键尺寸的关节软骨缺损来验证。这些目标将通过实现以下特定目的来实现：（1）开发三个维度（3D）组合HTS基于水凝胶的微阵列，包括不同的细胞外基质分子和生长因子和生长因子组成，它们可以机械地模仿HMSCS的响应，以评估HMSCS的范围，以评估HMSCS（2）基于HMSCS（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）（2）从这些微阵列中选择的3D组合HTS微阵列和宏观构建体，以及（3），以确定具有HTS识别的组合物和机械刺激方案的HMSC含量的潜力，以诱导体内的软骨再生。骨科群落将从对这些软骨诱导微环境的更好理解中受益，这些微环境最终将诱导新组织形成，并代表当前临床疗法的可行替代方案。虽然这项研究的最终目标是设计临床上相关的关节软骨疗法，但该HTS也适用于测试其他组织的再生策略。