Functional Assembly of Salivary Cells to Relieve Xerostomia

描述（由申请人提供）：口干症或“口干”是头颈癌标准放射治疗的不可避免的后果，并导致严重的牙齿问题（龋齿、感染、腐烂）、吞咽、说话和进食困难， 体重逐渐减轻，全身不适。目前的治疗方法在长期应用中还没有被证明是有效的，并且很少有组织工程策略被应用于这个问题。在这个应用程序中，我们组装了三个PI与必要的工程，生物和临床专业知识，以解决唾液再生使用核心生物设计原则。在目标1中，Xinqiao Jia的实验室将开发透明质酸（HA）凝胶作为模块化细胞支架材料。HA是唾液腺再生医学的一种引人注目的材料，因为它是天然来源的，可生物降解的，并提供灵活的化学和机械性能调整，以匹配天然组织。微米级HA水凝胶颗粒（HGP）将用作生长因子库，以刺激唾液细胞组织化、腺体形态发生和新生组织的血管输入。在Aim 2中，Cindy Farach-Carson的实验室将在体外应用这些技术，利用它们可靠地分离和扩增人类组织样本中的腺泡，导管和肌上皮细胞的能力。将生物活性片段掺入HA基质中以促进腺泡/导管细胞组织化，并以逐步方式进行细胞重建， 确保适当的管腔形成、极性和功能。在目标3中，Robert Witt将在动物模型中进行HA基质的体内扩增，以确定宿主对HGP生长因子的反应，新唾液腺的活力，以及唾液产生，含量和质量的功能评估。这三个目标联合收割机结合了三个PI之间现有合作的新发现，并保持了最终转化应用的明确目标。 公共卫生相关性：头颈部癌症患者通常接受放射治疗作为其初始治疗的一部分。这种辐射的一个副作用是口腔中产生唾液的细胞萎缩，这导致口腔干燥症或“口干”。口干症明显降低生活质量。我们已经确定了在辐射前分离这些细胞的方法，在实验室中培养它们，并将它们接种在凝胶中，这可以帮助细胞改革为功能性唾液腺，然后可以将其送回原始患者。

DESCRIPTION (provided by applicant): Xerostomia, or 'dry mouth', is the inevitable consequence of the standard radiation treatment for head and neck cancers, and leads to severe dental issues (caries, infections, decay), difficulties in swallowing, speaking, and eating, gradual weight loss, and overall discomfort. Current therapies have not proven effective in long term application, and few tissue engineering strategies have been applied to this problem. In this application, we assemble three PIs with the necessary engineering, biological, and clinical expertise to address salivary regeneration using core biological design principles. In Aim 1, Xinqiao Jia's laboratory will develop hyaluronic acid (HA) gels as a modular cellular scaffolding material. HA is a compelling material for salivary gland regenerative medicine, as it is naturally derived, biodegradable, and offers flexible tuning of chemical and mechanical properties to match those of native tissue. Microscale HA hydrogel particles (HGP) will be used as growth factor depots to stimulate salivary cell organization, gland morphogenesis, and vascular input to the neotissue. In Aim 2, Cindy Farach-Carson's laboratory will apply these technologies in vitro, leveraging their ability to reliably isolate and expand acinar, ductal, and myoepithelial cells fro human tissue samples. Bioactive fragments will be incorporated into the HA matrix to facilitate acinar/ductal cell organization, and cell reconstitution will be conducted in a stepwise fashion to insure proper lumen formation, polarity, and function. In Aim 3, Robert Witt will conduct in vivo implantations of HA matrices in an animal model, to determine the host response to the HGP growth factors, the viability of the neo-salivary glands, and a functional assessment of saliva production, content, and quality. These three Aims combine fresh discoveries from an existing collaboration among the three PIs, and maintain a clear goal of eventual translational application. PUBLIC HEALTH RELEVANCE: Patients with cancers of the head and neck often undergo radiation therapy as a part of their initial treatment. One side-effect of this radiation is atroph of cells in the mouth that produce saliva, which leads to xerostomia or 'dry mouth'. Xerostomia markedly lowers quality of life. We have identified methods for isolating these cells prior to radiation, growing them in the lab, and seeding them within gels that could help the cells reform as functional salivary glands, which could then be returned to the original patient.