Injectable Cellular Composites for Cartilage Engineering

用于软骨工程的可注射细胞复合材料

• 批准号: 8688900
• 负责人: Fred Kurtis Kasper
• 金额: $ 31.44万
• 依托单位: RICE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8688900
• 关键词: Address; Adult; Autologous; Bone Regeneration; Cartilage; Cell Transplants; Cells; Chemicals; Clinical; Coupled; Culture Media; Defect; Degenerative polyarthritis; Dose; Drug Formulations; Encapsulated; Engineering; Environment; Foundations; Gelatin; Germ Cells; Goals; Growth Factor; Hydrogels; Implant; In Vitro; Injectable; Insulin-Like Growth Factor I; Kinetics; Mechanics; Mesenchymal Stem Cells; Modeling; Natural regeneration; Nature; Oryctolagus cuniculus; Pain; Population; Process; Progress Reports; Research Project Grants; Staging; Stem cell transplant; Stem cells; Testing; Time; Tissues; Transforming Growth Factors; Translations; Transplantation; articular cartilage; bone; cartilage regeneration; combinatorial; density; experience; implantation; in vivo; in vivo Model; novel; novel strategies; oligo(poly(ethylene glycol)fumarate); osteochondral tissue; osteogenic; repaired; scaffold; tissue regeneration

DESCRIPTION (provided by applicant): The ultimate goal of this research project is to develop a novel injectable, bilayered, biodegradable hydrogel composite for the co-delivery of chondrogenic growth factors and mesenchymal stem cells (MSCs) to influence the degree and quality of cartilage tissue regeneration within osteochondral defects. We hypothesize that controlled dual delivery of transforming growth factor-21 (TGF-21) and insulin-like growth factor-1 (IGF-1) using optimal release kinetics and doses will induce chondrogenic differentiation of progenitor cells within the recipient to influence the regeneration of cartilage tissue in an osteochondral defect. Additionally, we hypothesize that the duration of exposure of MSCs to TGF-21 and osteogenic medium supplements during in vitro expansion will modulate the chondrogenic and osteogenic differentiation stages of the cells, respectively, which will in turn influence the degree and quality of osteochondral tissue regeneration when the cells are encapsulated within and transplanted with a hydrogel construct. Finally, we hypothesize that the co-delivery of growth factor(s) from hydrogel composites, coupled with the transplantation of progenitor cells encapsulated within the hydrogels will act cooperatively to promote regeneration of cartilage tissue in an osteochondral defect, with the initial cell seeding density influencing the degree and quality of the cartilage regeneration. To address these hypotheses, three Specific Aims are proposed. First, TGF-21 and IGF-1 will be loaded into OPF hydrogel constructs at different doses and released with different kinetics to determine the effect of these parameters on tissue regeneration in a rabbit osteochondral defect. Second, MSCs will be exposed to TGF-21 as a chondrogenic culture medium supplement or osteogenic medium supplements for various durations to result in cells of different chondrogenic and osteogenic differentiation stages, respectively, then they will be encapsulated within and transplanted with OPF hydrogel scaffolds (without loaded growth factors) into a rabbit osteochondral defect model to assess the effect of the differentiation stages of the transplanted cells upon osteochondral tissue regeneration. Third, cells of the optimal differentiation stages will be encapsulated for transplantation within OPF scaffolds corresponding to the optimal growth factor delivery formulation and will be implanted into rabbit osteochondral defects to determine the optimal seeding density of the progenitor cells for osteochondral tissue regeneration, which will be assessed post-implantation through histomorphometric analysis and mechanical testing. This novel strategy for the concurrent and spatially defined delivery of chondrogenic growth factors and in vitro expanded autologous progenitor cells to osteochondral defects presents tremendous potential for clinical translation and osteochondral tissue regeneration.

描述（由申请人提供）：该研究项目的最终目标是开发一种可提供软骨生长因子和间质干细胞（MSC）共同传递的新型注射，双层，可生物降解的水凝胶复合材料（MSC），以影响骨软骨内部缺陷内部软骨组织再生的程度和质量。我们假设使用最佳释放动力学和剂量控制了转化生长因子21（TGF-21）和胰岛素样生长因子-1（IGF-1）的双重递送，将诱导受体中祖细胞的软骨分化，以影响骨软骨中软骨组织再生的祖细胞。此外，我们假设MSC在体外扩张期间对TGF-21的暴露持续时间和成骨的培养基补充剂将分别调节细胞的软骨成熟和成骨分化阶段，这又会影响细胞内部和转换构造的细胞的程度和质量。最后，我们假设水凝胶复合材料的生长因子的共同传递与封装在水凝胶内的祖细胞的移植将合作促进软骨组织在骨软骨缺陷中的再生，以及初始细胞播种密度的影响，影响了骨质和质量的初始细胞播种密度。为了解决这些假设，提出了三个具体目标。首先，将TGF-21和IGF-1以不同的剂量加载到OPF水凝胶构建体中，并使用不同的动力学释放，以确定这些参数对兔骨软骨缺陷中组织再生的影响。 Second, MSCs will be exposed to TGF-21 as a chondrogenic culture medium supplement or osteogenic medium supplements for various durations to result in cells of different chondrogenic and osteogenic differentiation stages, respectively, then they will be encapsulated within and transplanted with OPF hydrogel scaffolds (without loaded growth factors) into a rabbit osteochondral defect model to assess the effect of the differentiation stages of骨软骨组织再生的移植细胞。第三，最佳分化阶段的细胞将被封装，以在对应于最佳生长因子递送配方的OPF支架内移植，并将植入兔骨软骨缺陷中，以确定祖细胞的最佳接种密度，以确定骨质组织再生的术后骨化性组织再生，这将通过术后进行分析。这一新的策略是针对软骨生长因子的并发和空间定义的递送，并在体外扩展的自体祖细胞到骨软骨缺陷为临床翻译和骨软骨组织再生带来了巨大的潜力。

项目成果

Injectable biodegradable hydrogels for embryonic stem cell transplantation: improved cardiac remodelling and function of myocardial infarction.

用于胚胎干细胞移植的可注射生物降解水凝胶：改善心脏重塑和心肌梗塞功能。

• DOI: 10.1111/j.1582-4934.2011.01409.x
• 发表时间: 2012-06
• 期刊: Journal of cellular and molecular medicine
• 影响因子: 5.3
• 作者: Wang H;Liu Z;Li D;Guo X;Kasper FK;Duan C;Zhou J;Mikos AG;Wang C
• 通讯作者: Wang C

In vitro generation of an osteochondral construct using injectable hydrogel composites encapsulating rabbit marrow mesenchymal stem cells.

• DOI: 10.1016/j.biomaterials.2009.01.048
• 发表时间: 2009-05
• 期刊: BIOMATERIALS
• 影响因子: 14
• 作者: Guo, Xuan;Park, Hansoo;Liu, Guangpeng;Liu, Wei;Cao, Yilin;Tabata, Yasuhiko;Kasper, F. Kurtis;Mikos, Antonios G.
• 通讯作者: Mikos, Antonios G.

Effects of TGF-beta3 and preculture period of osteogenic cells on the chondrogenic differentiation of rabbit marrow mesenchymal stem cells encapsulated in a bilayered hydrogel composite.

• DOI: 10.1016/j.actbio.2010.02.046
• 发表时间: 2010-08
• 期刊: ACTA BIOMATERIALIA
• 影响因子: 9.7
• 作者: Guo, X.;Liao, J.;Park, H.;Saraf, A.;Raphael, R. M.;Tabata, Y.;Kasper, F. K.;Mikos, A. G.
• 通讯作者: Mikos, A. G.

Pre-clinical characterization of tissue engineering constructs for bone and cartilage regeneration.

用于骨和软骨再生的组织工程结构的临床前表征。

• DOI: 10.1007/s10439-014-1151-0
• 发表时间: 2015
• 期刊: Annals of biomedical engineering
• 影响因子: 3.8
• 作者: Trachtenberg,JordanE;Vo,TiffanyN;Mikos,AntoniosG
• 通讯作者: Mikos,AntoniosG

Synthetic biodegradable hydrogel delivery of demineralized bone matrix for bone augmentation in a rat model.

• DOI: 10.1016/j.actbio.2014.07.011
• 发表时间: 2014-11
• 期刊: ACTA BIOMATERIALIA
• 影响因子: 9.7
• 作者: Kinard, Lucas A.;Dahlin, Rebecca L.;Lam, Johnny;Lu, Steven;Lee, Esther J.;Kasper, F. Kurtis;Mikos, Antonios G.
• 通讯作者: Mikos, Antonios G.