Interface Tissue Engineering for Soft Tissue-to-Bone Integration

软组织与骨整合的界面组织工程

• 批准号: 7533812
• 负责人: HELEN H LU
• 金额: $ 30.65万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7533812
• 关键词: Anatomy; Anterior Cruciate Ligament; Articular ligaments; Arts; Biochemical; Biological; Biomimetics; Cells; Characteristics; Chondrocytes; Clinical; Coculture Techniques; Collaborations; Complex; Condition; Cultured Cells; Development; Devices; Environment; Fibroblasts; Fibrocartilages; Generations; Heterogeneity; Histocompatibility Testing; In Vitro; Knee; Lead; Ligaments; Maintenance; Mechanics; Mediating; Methods; Minerals; Modeling; Natural regeneration; Nature; Numbers; Operative Surgical Procedures; Osteoblasts; Osteogenesis; Personal Satisfaction; Phase; Phenotype; Physiological; Procedures; Property; Public Health; Qualifying; Research; Research Personnel; Site; Spatial Distribution; Stimulus; Stress; System; Technology; Tendon structure; Testing; Tissue Engineering; Tissues; Translations; Variant; Work; base; bone; calcium phosphate; cell type; design; experience; graft failure; implantation; in vivo; in vivo Model; injured; innovation; insight; mineralization; novel; reconstruction; sample fixation; scaffold; soft tissue; success

DESCRIPTION (provided by applicant): The anterior cruciate ligament (ACL) is the most frequently injured knee ligament, with over 100,000 reconstruction surgeries performed annually. Currently, the biological fixation of soft tissue-based grafts for ACL reconstruction poses a significant clinical challenge. Our approach to biological fixation centers on the regeneration of the anatomic insertion site between soft tissue and bone. Given the characteristic spatial variation in cell type, matrix composition and mineral content inherent at the enthesis, it is expected that interface regeneration will require multiple cell types and a stratified scaffold capable of supporting multi-tissue formation. Therefore, we have developed a biomimetic, multi-phased scaffold consisting of three distinct yet continuous phases, each designed for the formation of the ligament, fibrocartilage or bone regions found at the ACL-to-bone insertion. The objective of this proposal is to optimize multi-cell culture and scaffold design parameters for interface regeneration and multi-tissue formation. Aim 1 will test the hypothesis that osteoblast-fibroblast interactions can promote chondrocyte-mediated fibrocartilage formation on the scaffold. Aim 2 will optimize scaffold phase-specific mineral content and distribution. Aim 3 will focus on the formation of four distinct yet continuous tissue regions (ligament, non-mineralized fibrocartilage, mineralized fibrocartilage, and bone) through the tri-culture of fibroblasts, chondrocytes and osteoblasts on the stratified scaffold. Aim 4 will determine whether these biomimetic tissue regions formed in vitro can be maintained in vivo. Our effort to regenerate the anatomic fibrocartilage interface on ACL reconstruction grafts represents an innovative departure from the traditional focus on the non-physiologic fibrocartilage found within the bone tunnel. Moreover, the multi-phased scaffold design and tri-culture methods proposed here for multi-tissue formation are highly original. It is anticipated that the successful completion of our studies will facilitate the development of a new generation of integrative fixation devices, and our findings can be applied to many other conditions in which soft tissue-to-bone integration is also critical. PUBLIC HEALTH RELEVANCE: Biological fixation of soft tissue-based grafts for Anterior Cruciate Ligament (ACL) reconstruction poses a significant clinical challenge. We propose that the regeneration of the soft tissue-to-bone interface is a prerequisite for the functional integration of biological and synthetic grafts for ACL reconstruction. This project focuses on the design and optimization of a novel biomimetic scaffold for interface tissue engineering, using both in vitro and in vivo studies. Findings from the planned studies will have a significant impact on public health due to the large number of ACL reconstruction procedures performed nationally and worldwide. In addition, this project can have broad impact for the translation of tissue engineered grafts to the clinical setting, by enabling the formation of complex tissue systems through graft integration with each other as well as with the host environment.

描述（由申请人提供）：前十字韧带 (ACL) 是最常受伤的膝关节韧带，每年进行超过 100,000 例重建手术。目前，用于 ACL 重建的软组织移植物的生物固定提出了重大的临床挑战。我们的生物固定方法集中于软组织和骨骼之间的解剖插入部位的再生。考虑到附着点固有的细胞类型、基质组成和矿物质含量的特征空间变化，预计界面再生将需要多种细胞类型和能够支持多组织形成的分层支架。因此，我们开发了一种仿生多相支架，由三个不同但连续的相组成，每个相都设计用于形成 ACL 到骨插入处的韧带、纤维软骨或骨区域。该提案的目的是优化多细胞培养和支架设计参数，以实现界面再生和多组织形成。目标 1 将检验以下假设：成骨细胞-成纤维细胞相互作用可以促进支架上软骨细胞介导的纤维软骨形成。目标 2 将优化支架相特定的矿物质含量和分布。目标 3 将重点关注通过在分层支架上对成纤维细胞、软骨细胞和成骨细胞进行三重培养，形成四个不同但连续的组织区域（韧带、非矿化纤维软骨、矿化纤维软骨和骨）。目标4将确定这些体外形成的仿生组织区域是否可以在体内维持。我们在 ACL 重建移植物上再生解剖纤维软骨界面的努力代表了对骨隧道内发现的非生理性纤维软骨的传统关注的创新背离。此外，这里提出的用于多组织形成的多阶段支架设计和三培养方法是高度原创的。预计我们研究的成功完成将促进新一代一体化固定装置的开发，并且我们的研究结果可应用于软组织与骨骼整合也至关重要的许多其他情况。 公共卫生相关性：用于前十字韧带 (ACL) 重建的软组织移植物的生物固定提出了重大的临床挑战。我们认为软组织与骨界面的再生是用于 ACL 重建的生物和合成移植物功能整合的先决条件。该项目的重点是利用体外和体内研究设计和优化用于界面组织工程的新型仿生支架。由于国内外进行了大量的 ACL 重建手术，计划中的研究结果将对公众健康产生重大影响。此外，该项目可以通过移植物彼此以及与宿主环境的整合形成复杂的组织系统，从而对组织工程移植物向临床环境的转化产生广泛的影响。