Tissue engineering an artificial salivary gland device

为什么会有人想要建造一个人工唾液腺(SG)？答案在于满足每年被诊断患有头颈癌的4000名加拿大人的临床需求。在世界范围内，这相当于每年新增64万名患者。这些患者接受治疗性放射治疗，以治疗他们的癌症。辐射领域中的SGs受到严重破坏，导致唾液腺泡细胞的丧失，唾液腺泡细胞是液体分泌的主要部位(即唾液)。这些患者经历了相当大的发病率和不适，如口干、吞咽困难、龋齿、对食物失去味道以及口咽感染/溃疡。对于许多患者来说，目前还没有可用的适当治疗。他们不能利用现有的药理工具(如刺激唾液的药物)，因为这些工具需要一些存活的上皮组织的存在。因此，我们有动力开发一种口腔植入性液体分泌装置来治疗此类患者。到目前为止，我们设备制造中的一个主要障碍是找到一种合适的移植细胞，这种细胞可以分泌水(唾液)，并且可以很容易地扩展以整合到设备中。我们这项建议的目标是：1)建立一个三维(3D)人工SG原型并测试其是否能够单向移动液体；2)对人唾液分泌细胞进行工程设计，并评估其在3D凝胶环境(如纤维连接蛋白凝胶、基底膜提取凝胶、硫酸软骨素和聚乙二醇水凝胶)中的组织组装能力；3)评估两种将基因工程的人唾液分泌细胞输送到因辐射受损的SGS小鼠体内的方法：a)直接注入腺体组织，或b)导管内插管并在压力下输注细胞。对于许多口干患者来说，重新设计上皮细胞以在人工SG设备或3D凝胶中具有液体分泌功能的影响将是一个关键突破。它可以为全球数百万唾液产量减少或没有唾液输出的患者提供有效的治疗选择。这些包括成人腺体唾液腺细胞再生和修复的潜力，以及这些细胞用于植入型人工SG装置的潜力。

Why should anyone wish to construct an artificial salivary gland (SG)? The answer lies in filling a clinical need for the 4,000 Canadians diagnosed each year with cancer of the head and neck. Worldwide, this amounts to 640,000 new patients yearly. These patients receive therapeutic irradiation as a treatment for their cancer. SGs in the field of radiation are severely damaged, resulting in a loss of salivary acinar cells, the principal site of fluid secretion (i.e. saliva). These patients experience considerable morbidity and discomfort such as dry mouth, difficulty swallowing, tooth decay, loss of taste to foods, and oro-pharyngeal infections/ ulcers. For many patients, there is currently no available adequate treatment. They cannot utilize existing pharmacological tools (such as saliva-stimulating drugs), which require the presence of some surviving epithelial tissue. Accordingly, we have been motivated to develop an orally implantable fluid secretory device for treating such patients. To date, a major hurdle in the fabrication of our device has been finding a suitable graft cells that can secrete water (saliva) and can be expanded readily for incorporation in the device. Our objectives for this proposal are to: 1) Build a three-dimensional (3-D) artificial SG prototype and test if it can move fluid unidirectionally; 2) Engineer human saliva-secreting cells and assess their capability to tissue assembly in 3-D gel environments (such as fibronectin gel, basement membrane extract gel, chondroitin sulfate and polyethylene glycol hydrogel); 3) Assess two methods to deliver engineered human saliva-secreting cells into mice with SGs damaged by irradiation: a) by direct injection into the glandular tissue, or b) by intra-ductal cannulation and infusing the cells under pressure. The impact of re-engineering epithelial cells to possess a fluid secretory function in the artificial SG device or in 3-D gels would be a key breakthrough for the many patients affected with dry mouth. It could offer to millions of patients worldwide, having reduced or no saliva output, effective treatment option. These include the potential for regeneration and repair of salivary acinar cells in adult glands, and the potential for these cells to be used in an implantable artificial SG device.