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: 10706557
• 负责人: MARY C FARACH-CARSON
• 金额: $ 68.03万
• 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/10706557
• 关键词: 3-Dimensional; Achievement; Acinus organ component; Animal Model; Autonomic nervous system; Beds; Biomedical Engineering; Blood flow; Cell Polarity; Cells; Chronic; Complement; Data; Digestion; Enzymes; Fostering; Gland; Goals; Head and Neck Cancer; Human; Implant; Laboratories; Legal patent; Liquid substance; Methodology; Michigan; Miniature Swine; Modeling; Morphogenesis; Nerve; Nervous System; Nude Rats; Operative Surgical Procedures; Oral cavity; Oral health; Organ; Patients; Peripheral Nerves; Phenotype; Pre-Clinical Model; Production; Proteins; Radiation; Radiation therapy; Saliva; Salivary; Salivary Glands; Site; System; Testing; Therapeutic; Tissue Engineering; Tissues; Translations; Transplantation; Water; Work; Xenograft Model; Xerostomia; adult stem cell; design; first-in-human; head and neck cancer patient; immunosuppressed; improved; nerve supply; nutrition; replacement tissue; restoration; saliva secretion; salivary cell; side effect; stem; stem cell therapy; 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功能齐全、可植入的人类唾液腺 头颈癌放射治疗后患有口干症或慢性口干症。 我们的团队最近开发了一种免疫抑制、辐射的人迷你猪动物模型，用于临床前研究 我们称之为 3D-ST 的专利组织工程唾液组织替代物的翻译。这个大 动物模型适合测试旨在恢复唾液功能的细胞项目，包括 启动消化和维持口腔健康所需的水分泌和蛋白质/酶产生 空腔。作为补充，我们开发的辐射裸鼠模型可作为有用的测试模型 产品设计旨在最大限度地提高生物整合度，包括长期所需的脉管系统和神经 器官的成功。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 外科团队。我们在三个地点开展工作 开发了一个实验成功的演示工作流程，该工作流程利用了独特的设施 每个站点。该提案建立在我们令人兴奋的支持数据的基础上，使用辐照模型来证明 3D-ST 中移植的 hS/PC 恢复唾液分泌功能的能力。虽然我们迄今为止的工作 显示 3D-ST 中植入的人类/干祖细胞 (hS/PC) 的长期（3-4 个月）活力 在免疫抑制的小型猪和裸鼠中构建，仍然存在一个重大障碍，以培养完整的、 3D-ST 与宿主种植床的永久生物整合。脉管系统与唾液的生物整合 需要腺泡来提供营养并提供唾液的液体成分。稳定的神经支配对于 腺体形态发生、定向分泌的细胞极性的实现以及自主神经的恢复 刺激分泌。该提案建立在我们令人兴奋的支持数据的基础上，以鼓励人类移植 hS/PC 重建唾液分泌功能，并将我们的重点从设计优化和植入转移 使用我们的两种辐照模型成功进行功能性生物整合的可行性。我们假设两者 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）使用定量评分系统来评估生物整合 将脉管系统和自主神经系统植入受辐射动物模型中的 3D-ST 中，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进现有的异种移植模型，用于测试 各种基于成体干细胞/祖细胞的疗法来替代外分泌器官并打开首个非人类的大门 缓解口干症的试验。