In Situ Hardening Cell-Laden Constructs for Osteochondral Tissue Engineering

用于骨软骨组织工程的原位硬化细胞负载结构

基本信息

批准号：
9144318
负责人：
ANTONIOS G. MIKOS
金额：
$ 33.36万
依托单位：
RICE 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：
2015-09-15 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9144318
关键词：
Acrylates Address Aldehydes Amines Behavior Bone Regeneration Cartilage Cell Communication Cell Transplantation Cell-Matrix Junction Cells Characteristics Chemicals Chondrocytes Chondrogenesis Chondroitin Sulfates Coculture Techniques Coupled Crosslinker Custom Defect Development Diamines Dose Encapsulated Engineering Formulation Gel Glycolates Goals Hydrogels In Situ In Vitro Injectable Joints Kinetics Laboratories Lactones Lysine Mechanics Mesenchymal Stem Cells Modeling Modification N-isopropylacrylamide Natural regeneration Oryctolagus cuniculus Osteogenesis Patients Physical condensation Population Property Signal Pathway Signal Transduction Site Societies Stem cells Structure Swelling System Technology Time Tissue Adhesives Tissue Engineering Tissues Transplantation Vertebral column Work abstracting acrylic acid base bone butyrolactone cartilage regeneration cartilage repair chemical addition crosslink design dosage implantation improved in vivo innovation mechanical behavior novel osteochondral repair osteochondral tissue osteogenic poly-N-isopropylacrylamide repaired tissue regeneration tissue repair

Acrylates Address Aldehydes Amines Behavior Bone Regeneration Cartilage Cell Communication Cell Transplantation Cell-Matrix Junction Cells Characteristics Chemicals Chondrocytes Chondrogenesis Chondroitin Sulfates Coculture Techniques Coupled Crosslinker Custom Defect Development Diamines Dose Encapsulated Engineering Formulation Gel Glycolates Goals Hydrogels In Situ In Vitro Injectable Joints Kinetics Laboratories Lactones Lysine Mechanics Mesenchymal Stem Cells Modeling Modification N-isopropylacrylamide Natural regeneration Oryctolagus cuniculus Osteogenesis Patients Physical condensation Population Property Signal Pathway Signal Transduction Site Societies Stem cells Structure Swelling System Technology Time Tissue Adhesives Tissue Engineering Tissues Transplantation Vertebral column Work abstracting acrylic acid base bone butyrolactone cartilage regeneration cartilage repair chemical addition crosslink design dosage implantation improved in vivo innovation mechanical behavior novel osteochondral repair osteochondral tissue osteogenic poly-N-isopropylacrylamide repaired tissue regeneration tissue repair

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项目摘要

Project Summary/Abstract The ultimate goal of this proposal is to develop an innovative and modular technology for osteochondral tissue repair comprising injectable, thermally responsive, in situ forming, and biodegradable hydrogel constructs capable of sustaining the delivery of encapsulated chondrogenic and osteogenic cell populations in a spatially directed fashion to promote native tissue regeneration. We hypothesize that a cytocompatible hydrogel system consisting of non-shrinking, injectable hydrogels with fully soluble degradation products will be formed through the combination of custom poly(N-isopropylacrylamide)-based thermogelling macromers and lysine-based crosslinking macromers that also contain sites for covalent attachment of chondroitin sulfate (CS) to enhance the integration of resultant constructs. Additionally, we hypothesize that the incorporation of poly(L-lysine) (PLL) within the thermogelling hydrogel will enhance the chondrogenic capacity of co-encapsulated articular chondrocyte and mesenchymal stem cell (AC-MSC) cocultures via the induction of developmentally relevant condensation signals. Finally, we hypothesize that a bilayered construct combining the CS-modified chondrogenic hydrogel layer with an osteogenic hydrogel layer of designer mineralizing capability will be leveraged to promote effective osteochondral tissue repair. Three Specific Aims are proposed to address these hypotheses. First, a lysine-based polyesterurethane macromer comprising a biodegradable poly(DL-lactic-co- glycolic acid) mid-block and chemically crosslinkable diamine functionalities will be developed, covalently modified with CS, combined with the thermogelling macromer and thoroughly assessed to establish structure- property relationships. Second, PLL will be incorporated into the hydrogels and its effects on the chondrogenesis of encapsulated AC-MSC cocultures will be evaluated. Further, the combined effects of PLL presentation, AC-MSC coculture, and CS-modification of hydrogel constructs on cartilage tissue integration will be also evaluated ex vivo. Third, the hydrogels developed in Specific Aim 1 and optimized for chondrogenic potential in Specific Aim 2 will be merged with hydrogel formulations with high mineralizing capability to yield bilayered hydrogel constructs comprising chondrogenic and osteogenic layers for the effective repair of osteochondral defects. The potential synergistic effects of encapsulated cells in the osteogenic and chondrogenic layers with PLL delivery will be evaluated in vitro and in vivo to determine the most effective configuration for osteochondral tissue repair in a well-established rabbit osteochondral defect model. The proposed system will address persisting significant challenges associated with osteochondral defect repair by enabling stable integration of the construct with the surrounding native cartilage tissue through a highly modular two-component design, while promoting the chondrogenic and osteogenic differentiation of respective cell populations delivered to effect both cartilage and bone regeneration, respectively.