Functional Biointegration of Bioengineered Salivary Tissues in Irradiated Animal Models

生物工程唾液组织在辐射动物模型中的功能生物整合

• 批准号: 10569404
• 负责人: MARY C FARACH-CARSON
• 金额: $ 72.76万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10569404
• 关键词: 3-Dimensional; Achievement; Acinus organ component; Adult; Allografting; Amylases; Animal Model; Artificial Organs; Autologous Transplantation; Autonomic nervous system; Beds; Biology; Biomedical Engineering; Blood flow; Cell Differentiation process; Cell Polarity; Cell Survival; Cell Therapy; Cells; Chronic; Comparative Pathology; Complement; Data; Device Designs; Digestion; Duct (organ) structure; Enzymes; Epithelial; Excision; Family suidae; Feasibility Studies; Fostering; Gland; Goals; Growth; Head and Neck Cancer; Homologous Transplantation; Human; Hydrogels; Immunosuppression; Implant; Insulin-Dependent Diabetes Mellitus; Laboratories; Legal patent; Liquid substance; Luciferases; Lupus; Measurement; Measures; Methodology; Michigan; Miniature Swine; Modeling; Morphogenesis; Myoepithelial; Nerve; Nervous system structure; Nude Rats; Operative Surgical Procedures; Oral cavity; Oral health; Organ; Organoids; Patients; Peripheral Nerves; Phenotype; Population; Pre-Clinical Model; Production; Proteins; Protocols documentation; Radiation; Radiation therapy; Research; Research Personnel; Retrieval; Saliva; Salivary; Salivary Glands; Series; Site; Sjogren' s Syndrome; Source; Structure; Study models; System; Techniques; Testing; Therapeutic; Time; Tissue Engineering; Tissues; Translations; Transplantation; Water; Work; Xenograft Model; Xerostomia; alpha-amylase; aquaporin 5; base; cell replacement therapy; clinical translation; design; facial transplantation; genetic manipulation; head and neck cancer patient; immunosuppressed; implantation; improved; in vivo; islet; man; nerve supply; new technology; nutrition; porcine model; post-transplant; reparative capacity; replacement tissue; restoration; saliva secretion; salivary cell; side effect; stem; stem cells; success

The ultimate goal of this project is to develop a fully functional, implantable human salivary gland for patients suffering from xerostomia, or chronic dry mouth, subsequent to radiation therapy for head and neck cancer. Our team recently developed an immunosuppressed, irradiated human-in-miniswine animal model for preclinical translation of a patented tissue engineered salivary tissue replacement we call the 3D-ST. This large animal model is suitable for testing cell-based projects designed to restore salivary function that includes both water secretion and protein/enzyme production needed to initiate digestion and maintain health of the oral cavity. Complementing this, a radiated nude rat model we developed serves as a useful model for testing product designs purposed to maximize biointegration including both vasculature and nerve needed for longterm organ success. Our successful interdisciplinary team includes the Farach-Carson/Wu team at UTHealth, the Lombaert team in Michigan, and the Swegal surgical team in Pittsburgh. Functioning at three sites, we developed a demonstrated workflow for experimental success that takes advantage of the unique facilities at each site. This proposal builds on our exciting supporting data using irradiated models to demonstrate the ability of transplanted hS/PCs in the 3D-ST to restore salivary secretory function. While our work to date showed long term (3-4 months) viability of implanted human/stem progenitor cells (hS/PCs) in the 3D-ST construct in both immunosuppressed miniswine and nude rats, a significant hurdle remains to foster complete, permanent biointegration of the 3D-ST with the host implant bed. Biointegration of vasculature with salivary acini is needed to provide nutrition and to supply the fluid component of saliva. Stable innervation is critical for glandular morphogenesis, achievement of cell polarity for directional secretion, and restoration of autonomic stimulation of secretion. This proposal builds on our exciting supporting data to encourage transplanted human hS/PCs to reestablish salivary secretory function and moves our focus from design optimization and implant viability to successful functional biointegration using our two irradiated models. We hypothesize that both vasculature and peripheral nerve integration of the 3D-ST can be achieved to stabilize the differentiated salivary phenotype. The two aims will: 1) use a quantitative scoring system to evaluate biointegration of vasculature and autonomic nervous system into implanted 3D-STs in irradiated animal models and determine impact on salivary cell phenotype; and 2) evaluate the ability of the transplanted 3D-ST to restore salivary function. Successful achievement of these aims will improve existing xenotransplant models for testing a variety of adult stem/progenitor cell-based therapies to replace exocrine organs and open the door to first-inhuman trials for relief of xerostomia.

该项目的最终目标是为患者开发一个功能齐全的，可植入的人唾液腺 患有静脉癌的静态疗法后，患有静脉和颈部癌。 我们的团队最近开发了一种免疫抑制的，受辐照的人类在临床前的动物模型 我们称为3D-ST的专利组织工程唾液组织更换的翻译。这大 动物模型适合测试基于细胞的项目，旨在恢复包括唾液功能，包括 启动口服的消化和保持健康所需的水分分泌和蛋白质/酶产生 腔。补充这一点，我们开发的辐射裸大鼠模型是测试的有用模型 旨在最大化生物整合的产品设计，包括长期所需的脉管系统和神经 器官成功。我们成功的跨学科团队包括Uthealth的Farach-Carson/WU团队， 密歇根州的Lombaert团队和匹兹堡的Swegal手术队。在三个站点运行，我们 开发了一个展示的实验成功工作流程，利用了独特的设施 每个站点。该建议是建立在我们令人兴奋的支持数据的基础上的，以证明 3D-ST中移植的HS/PC恢复唾液分泌功能的能力。迄今为止我们的工作 在3D-ST中显示了长期（3-4个月）的人/茎祖细胞（HS/PC）的长期生存能力 在免疫抑制的Miniswine和裸鼠中建造，仍然有一个重大障碍可以促进促进 3D-ST与宿主植入床的永久生物整合。脉管系统与唾液的生物整合 需要acini来提供营养并提供唾液的液体成分。稳定的神经对 腺形态发生，实现定向分泌的细胞极性和自主神经的恢复 刺激分泌。该提案以我们令人兴奋的支持数据为基础，以鼓励移植人类 HS/PC可以重建唾液分泌功能，并将我们的重点从设计优化和植入物中移动 使用我们的两个辐照模型，可生存到成功的功能生物整合。我们假设这两个 可以实现3D-ST的脉管系统和周围神经整合以稳定分化 唾液表型。这两个目标将：1）使用定量评分系统评估生物整合 脉管系统和自主神经系统进入辐照动物模型中的植入3D-STS，并确定 对唾液细胞表型的影响； 2）评估移植的3D-ST恢复唾液的能力 功能。这些目标的成功实现将改善现有的Xenotlastrant模型来测试 成人茎/祖细胞基于细胞的种类替代外分泌器官并打开第一名的门 缓解静态的试验。