人仿生唾液腺芯片的构建及其在放射损伤研究中的应用

The key function of salivary glands is to produce saliva. Patients with salivary gland hypofunction suffer from rampant dental caries, oral mucositis, and difficulties in eating, swallowing and speaking. Radiation-induced salivary gland damage is still a major problem after radiotherapy for head and neck cancer. There are presently no reliable and safe pharmacologic treatments for the resolution or prevention of radiation-induced salivary gland damage. In this application we propose to construct a microfluidic-based salivary-gland-on-a-chip that enable in vitro co-culture salivary gland parenchymal and mesenchymal cells, blood vessels, and nerved in extracellular matrix. It precisely mimics the salivary gland microenvironment, including molecules, cells, and mechanical forces. This biomimetic chip shows high physiological similarity to the human salivary glands from its histological structure to saliva-secreting function. Furthermore, radiation-induced damage will be developed on the salivary-gland-on-a-chip. The biomarker expression, cellular morphology, DNA damage, apoptosis and saliva-secreting function will be assessed to evaluate the similarity of the pathological chip model to in vivo models. The relationship between radiation-induced microenvironmental changes and hypofunction in salivary glands will be revealed. Then therapeutic strategies aiming at the whole salivary gland microenvironment will be determined. Stem cell therapy and therapies against damages to blood vessels and nerves will be evaluated on the biomimic chip. We hope the salivary-gland-on-a-chip would provide a rapid alternative to animal models and could be used in preclinical tests to assess the radioprotective and regenerative strategies for the treatment of salivary gland diseases.

唾液腺是以分泌唾液为核心功能的腺体。唾液减少可致严重龋齿、口腔黏膜炎、进食困难、语言障碍等。头颈部肿瘤放疗导致的唾液腺放射损伤是唾液分泌减少的重要原因。本项目拟基于微流控技术构建人功能性唾液腺芯片，精准仿生唾液腺微环境（分子、细胞、细胞外基质和机械力等），实现唾液腺实质和间质细胞、血管、神经在细胞外基质中共培养，使该仿生芯片从组织结构到核心功能均与人唾液腺高度相似。进而，基于生理模型建立放射损伤唾液腺芯片病理模型，并验证芯片病理模型的细胞标志物表达、DNA损伤、凋亡、唾液分泌功能等变化与人唾液腺放射损伤的仿生相似性，揭示放射损伤导致唾液腺微环境各要素改变与唾液分泌功能下降的相关性，针对唾液腺微环境制定预防和治疗放射损伤的策略，在芯片病理模型上对干细胞移植、保护血管和神经等疗法进行评估。人仿生唾液腺芯片可望实现替代动物模型进行相关评估的有效尝试，成为唾液腺疾病临床前治疗研究的实用型评价系统。

唾液腺是以分泌唾液为核心功能的腺体。唾液减少可致严重龋齿、口腔黏膜炎、进食困难、语言障碍等。头颈部肿瘤放疗导致的唾液腺放射损伤是唾液分泌减少的重要原因。本项目拟基于微流控技术构建人功能性唾液腺芯片。我们采用大鼠原代唾液腺细胞、优化细胞外基质（ECM）成分和比例构建了唾液腺类器官，并从形态结构和标志物表达等方面进行表征。此外，我们构建了一个微流控芯片，在该芯片上体外重构了包括唾液腺癌细胞、间质细胞和细胞外基质的微环境，考察细胞间的相互作用。人仿生唾液腺芯片可望实现替代动物模型进行相关评估的有效尝试，成为唾液腺疾病临床前治疗研究的实用型评价系统。