Tissue engineering an artificial salivary gland device

为什么会有人希望构建人工唾液腺（SG）？答案在于满足每年被诊断患有头颈癌的4,000名加拿大人的临床需求。在世界范围内，这相当于每年640 000名新患者。这些患者接受治疗性放射作为其癌症的治疗。辐射场中的SG严重受损，导致唾液腺泡细胞（即唾液）的损失，唾液腺泡细胞是液体分泌的主要部位。这些患者经历相当大的发病率和不适，例如口干、吞咽困难、蛀牙、对食物失去味觉和口咽感染/溃疡。对于许多患者来说，目前没有足够的治疗方法。他们不能利用现有的药理学工具（如唾液刺激药物），这需要一些幸存的上皮组织的存在。因此，我们一直致力于开发一种用于治疗此类患者的口腔可植入液体分泌装置。迄今为止，制造我们的装置的主要障碍是找到合适的移植细胞，其可以分泌水（唾液）并且可以容易地扩增以并入装置中。我们的目标是：1）建立一个三维（3-D）人工SG原型，并测试它是否可以单向移动流体; 2）工程化人类唾液分泌细胞，并评估它们在3-D凝胶环境中组织组装的能力（如纤连蛋白凝胶、基底膜提取物凝胶、硫酸软骨素和聚乙二醇水凝胶）; 3）评估将工程化的人唾液分泌细胞递送到具有被辐射损伤的SG的小鼠中的两种方法：a）通过直接注射到腺组织中，或B）通过导管内插管并在压力下输注细胞。 在人工SG装置或3-D凝胶中重新设计上皮细胞以具有液体分泌功能的影响将是许多受口干影响的患者的关键突破。它可以为全球数百万唾液分泌减少或没有唾液分泌的患者提供有效的治疗选择。这些包括再生和修复成人腺体中的唾液腺泡细胞的潜力，以及这些细胞用于可植入人工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.