Tissue engineering an artificial salivary gland device

为什么会有人想要构建一个人工唾液腺？答案在于满足每年4000名被诊断患有头颈部癌症的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。这些病人接受放射治疗作为癌症的一种治疗方法。放射领域的SGs严重受损，导致唾液腺泡细胞的损失，这是液体分泌的主要部位（即唾液）。这些患者会出现相当高的发病率和不适，如口干、吞咽困难、蛀牙、食物失去味道和口咽感染/溃疡。对于许多患者，目前没有可用的适当治疗方法。他们不能利用现有的药理学工具（如唾液刺激药物），这需要一些存活的上皮组织的存在。因此，我们一直致力于开发一种用于治疗此类患者的可口服植入式分泌液装置。到目前为止，我们设备制造的一个主要障碍是找到一种合适的移植物细胞，这种细胞可以分泌水（唾液），并且可以很容易地膨胀以纳入设备。我们这个提案的目标是：1)建立一个三维（3-D）人造SG原型，并测试它是否可以单向移动流体；2)对人类唾液分泌细胞进行工程化，并评估其在三维凝胶环境（如纤维连接蛋白凝胶、基底膜提取物凝胶、硫酸软骨素和聚乙二醇水凝胶）中组织组装的能力；3)评估两种将工程人唾液分泌细胞注入辐照致SGs损伤小鼠体内的方法：a)直接注射到腺组织中，或b)导管内插管并加压灌注细胞。改造上皮细胞使其在人工SG装置或三维凝胶中具有液体分泌功能的影响将是许多口干患者的关键突破。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。其中包括成人腺体中唾液腺泡细胞再生和修复的潜力，以及这些细胞用于植入式人工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.