A NOVEL STEM CELL BASED DELIVERY SYSTEM TO IMPROVE BONE TISSUE REGENERATION

一种基于干细胞的新型输送系统，可改善骨组织再生

• 批准号: 8764532
• 负责人: Alireza Moshaverinia
• 金额: $ 12.38万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8764532
• 关键词: Address; Adult; Affect; Alginates; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Aspirin; Autologous; Biocompatible Materials; Bone Marrow; Bone Regeneration; Bone Tissue; Bone Transplantation; Calvaria; Cell Communication; Cell Survival; Cells; Cephalic; Coculture Techniques; Collagen; Coupled; Data; Defect; Dental; Dentistry; Disadvantaged; Down-Regulation; Encapsulated; Foundations; Gene Expression Profiling; Goals; Gold; Health; Hydrogels; Immune; Immune system; Immunocompromised Host; Immunofluorescence Immunologic; In Vitro; Indomethacin; Inflammatory; Infusion procedures; Injectable; Interferons; Interleukin-17; Literature; Macrophage Colony-Stimulating Factor; Mediating; Mesenchymal Stem Cells; Modality; Modeling; Molecular; Mus; NF-kappa B; Natural regeneration; Nature; Neural Crest; Organ Transplantation; Orthopedics; Osteogenesis; Outcome; PTGS2 gene; Pathway interactions; Patients; Porifera; Procedures; Process; Property; Reaction; Regenerative Medicine; Regulatory T-Lymphocyte; Role; Signal Transduction; Skeletal bone; Staging; Staining method; Stains; Stem cells; System; T-Lymphocyte; Testing; Th1 Cells; Therapeutic; Tissue Engineering; Tissues; Transplantation; Tumor Necrosis Factor-alpha; Up-Regulation; Western Blotting; Wild Type Mouse; assault; base; bone; cell type; chemical genetics; craniofacial; cytokine; deciduous tooth; human stem cells; improved; in vivo; innovation; macrophage; maxillofacial; novel; novel therapeutics; orofacial; osteogenic; postnatal; regenerative therapy; repaired; scaffold; self-renewal; skeletal; subcutaneous; tissue regeneration

DESCRIPTION (provided by applicant): Regeneration of craniofacial and skeletal bone defects has widely been achieved with bone grafting procedures. The literature suggests that there are more than one million cases of skeletal defects per year that require bone-graft procedures. Autologous bone has been considered the gold standard for such procedures. However, there are several disadvantages associated with this modality of treatment. The ability of stem cells to give rise to multiple specialized cell types along with their extensive distributin in many adult tissues make them an attractive target for application in bone tissue engineering. Dental MSCs such as stem cells from human exfoliated deciduous teeth (SHED) are attractive postnatal stem cells because they possess self-renewal and multilineage differentiation capacity as well as superior osteogenic properties compared to bone marrow mesenchymal stem cells (BMMSCs). The central hypothesis of this proposal is that an RGD-coupled alginate hydrogel scaffold can protect the encapsulated dental MSCs (SHED) from immune cells and cytokines in the early stages of transplantation, providing an appropriate physiochemical microenvironment for enhanced MSC viability and osteo-differentiation. It is hypothesized that these interactions are crucial in the osteogenic lineage commitment of dental MSCs. This proposal addresses a very important unresolved question: what is the role of the microenvironment (biomaterial) in dental MSC-immune cell interplay, fate determination of MSCs and osteogenic differentiation of MSCs. The validity of the central hypothesis will be tested by 1) determining how RGD-coupled alginate hydrogel as an encapsulating scaffold can interfere with the interplay between immune cells and dental MSCs in bone regeneration; 2) investigating the detailed mechanism of immune cell-induced MSC apoptosis; 3) developing a 3D alginate-based delivery system with anti-inflammatory function in the presence of indomethacin and 4) evaluating the effects of this delivery system on the bone regeneration properties of encapsulated MSCs. Upon successful completion of the Specific Aims, this project will improve our understanding of dental MSC-host immune interactions and introduce a promising MSC-based treatment approach for maxillofacial and skeletal defects. The result will be a novel injectable and biodegradable scaffold, presenting an innovative treatment modality for bone regeneration with therapeutic properties to manage local inflammatory reactions.

描述（由申请人提供）：颅面骨和骨骼骨缺损的再生已通过骨移植手术广泛实现。文献表明，每年有超过一百万例骨骼缺陷需要骨移植手术。自体骨被认为是此类手术的黄金标准。然而，这种治疗方式存在一些缺点。干细胞产生多种专门细胞类型的能力及其在许多成体组织中的广泛分布使它们成为骨组织工程应用的有吸引力的目标。牙科间充质干细胞，例如来自人脱落乳牙（SHED）的干细胞，是有吸引力的产后干细胞，因为与骨髓间充质干细胞（BMMSC）相比，它们具有自我更新和多谱系分化能力以及优越的成骨特性。该提案的中心假设是，RGD耦合的藻酸盐水凝胶支架可以在移植早期保护封装的牙科MSC（SHED）免受免疫细胞和细胞因子的影响，为增强MSC活力和骨分化提供适当的理化微环境。据推测，这些相互作用对于牙科 MSC 的成骨谱系定向至关重要。该提案解决了一个非常重要的未解决问题：微环境（生物材料）在牙科 MSC 与免疫细胞相互作用、MSC 命运决定和 MSC 成骨分化中的作用是什么。中心假设的有效性将通过以下方式进行测试：1）确定RGD偶联的藻酸盐水凝胶作为封装支架如何干扰骨再生中免疫细胞和牙科MSC之间的相互作用； 2）研究免疫细胞诱导MSC凋亡的详细机制； 3) 开发一种在吲哚美辛存在下具有抗炎功能的基于 3D 藻酸盐的递送系统，4) 评估该递送系统对封装的 MSC 的骨再生特性的影响。成功完成具体目标后，该项目将提高我们对牙科 MSC 与宿主免疫相互作用的理解，并引入一种有前途的基于 MSC 的颌面和骨骼缺陷治疗方法。其结果将是一种新型的可注射和可生物降解的支架，为骨再生提供一种创新的治疗方式，具有控制局部炎症反应的治疗特性。