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结果，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。目前的疗法尚未证明在长期应用中有效，并且很少有组织工程策略已应用于该问题。在此应用中，我们汇集了三个具有必要的工程、生物学和临床专业知识的 PI，以利用核心生物设计原理解决唾液再生问题。在目标 1 中，贾新桥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 是一种引人注目的唾液腺再生医学材料，因为它是天然衍生的、可生物降解的，并且可以灵活调整化学和机械特性以匹配天然组织的特性。微型 HA 水凝胶颗粒 (HGP) 将用作生长因子库，以刺激唾液细胞组织、腺体形态发生和新组织的血管输入。在目标 2 中，Cindy Farach-Carson 的实验室将在体外应用这些技术，利用它们从人体组织样本中可靠地分离和扩增腺泡、导管和肌上皮细胞的能力。生物活性片段将被整合到HA基质中以促进腺泡/导管细胞组织，并且细胞重建将以逐步的方式进行 确保正确的管腔形成、极性和功能。在目标 3 中，Robert Witt 将在动物模型中进行 HA 基质的体内植入，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：头颈部癌症患者经常接受放射治疗作为初始治疗的一部分。这种辐射的副作用之一是口腔中产生唾液的细胞萎缩，从而导致口干症或“口干”。口干症显着降低生活质量。我们已经确定了在辐射前分离这些细胞、在实验室中培养它们并将它们接种到凝胶中的方法，这可以帮助细胞重新形成功能性唾液腺，然后将其返回到原来的患者体内。

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.