Functional Assembly of Salivary Cells to Relieve Xerostomia

描述(申请人提供)：口干，或口干，是头颈癌标准放射治疗的必然结果，并导致严重的牙齿问题(龋齿、感染、龋齿)，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并不被证明是有效的，而且很少有组织工程策略被应用于这个问题。在这一应用中，我们组装了三个具有必要的工程、生物和临床专业知识的PI，以使用核心生物设计原则解决唾液再生问题。在目标1中，新桥佳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，因为它是自然衍生的，可生物降解，并提供灵活的化学和机械性能调整，以匹配自然组织。微米级HA水凝胶颗粒(HGP)将被用作生长因子库，以刺激唾液细胞组织、腺体形态发生和血管进入肿瘤组织。在目标2中，Cindy Farach-Carson的实验室将在体外应用这些技术，利用它们可靠地分离和扩大人类组织样本中的腺泡、导管和肌上皮细胞的能力。生物活性片段将被结合到HA基质中，以促进腺泡/导管细胞的组织，并将逐步进行细胞重建，以 确保管腔的形成、极性和功能正确。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，新唾液腺的生存能力，以及唾液产量、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，并保持了最终翻译应用的明确目标。 公共卫生相关性：头颈部癌症患者通常在最初的治疗中接受放射治疗。这种辐射的一个副作用是口腔中产生唾液的细胞萎缩，这会导致口干或口干。口干症明显降低了生活质量。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，并将它们种植在凝胶中，帮助细胞重塑为功能性唾液腺，然后再返回给原始患者。

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.