Engineering intestinal mucosal tissue grafts as a novel treatment for inflammatory bowel disease.

炎症性肠病是一种影响许多成年人的终身疾病，并且可以在5岁的儿童中开始。这种疾病涉及形成溃疡和疤痕的肠道，导致疼痛，出血和腹泻。常见的治疗方法包括强效药物，这些药物并不总是有效的，而且有明显的副作用。如果患者对药物没有反应，那么手术往往是唯一的选择。手术涉及切除肠道的患病部分，在严重的情况下可能需要结肠造口术，其中肠道被转移到体外，内容物从外部排入造口袋。虽然手术可以在短期内帮助减轻疾病症状，但它可能导致患者出现营养不良和保持水分的问题。此外，手术并不能治愈，一半的患者在首次手术后的10年内需要进一步手术。炎症性肠病患者的生活质量可能非常差，因为目前的治疗通常不完全有效，可能只能提供暂时的缓解。因此，开发炎症性肠病的新疗法是迫切而重要的。该项目的目的是利用干细胞技术与先进材料和3D打印技术，在实验室中开发替代肠组织，该组织可以安全地插入大肠（结肠）作为移植物，从而避免造口并可能恢复肠功能。最近的研究已经使人们有可能采取皮肤细胞，并把它们变成干细胞，可以形成任何组织在体内。由此可见，替代组织可以从患者自己的细胞中产生，这避免了器官排斥的风险。要做到这一点，我需要建立条件，使干细胞形成细胞，结肠内衬。在概念验证研究中，我已经成功地在实验室中培养干细胞形成早期结肠细胞。通过尖端的3D打印技术，我将非常精确地设计材料的表面，这将进一步提高我们可以生产的肠细胞的质量。因此，我的目标是建立最佳条件，使诱导多能干细胞生长成结肠细胞。在确定了如何在实验室中小规模地制造功能性肠组织之后，我将制造更大的材料片，这些材料片将适合插入肠中。最后，我打算通过将实验室生长的组织移植物植入动物宿主的结肠来测试它们。这将使我能够确保他们按预期运作，安全并保持健康。这将提供一个原理性的证据，证明这些细胞可以被植入人类的肠道，作为一种潜在的治疗方法。干细胞研究与尖端材料工程的结合是一种新的方法。如果成功的话，它可能会导致炎症性肠病和其他需要手术的肠道疾病的新治疗方法的发展。该项目还将帮助我们了解驱动肠道发育的机制。特别是，我将研究细胞生长的材料特性如何影响它们的行为（这与患者特异性组织移植物的发展高度相关）。这种组织也可以作为肠道疾病的实验室模型，用于研究疾病的发展和测试其他治疗方法。

Inflammatory bowel disease is a life-long condition which affects many adults and which can begin in children as young as 5. This disease involves the formation of ulcers and scarring in the bowel which causes pain, bleeding and diarrhoea. Common treatment involves powerful drugs that do not always prove effective and have significant side effects. If patients do not respond to drugs then surgery is often the only option. Surgery involves removing diseased parts of bowel and in severe cases may require a colostomy where the intestines are diverted to the outside of the body and contents draining externally into a stoma bag. Whilst operations can help reduce disease symptoms in the short term, it may result in patients having problems with malnutrition and maintaining hydration. Additionally, surgery is not a cure and half of all patients require further surgery within 10 years of the first procedure.The quality of life for people with inflammatory bowel disease can be very poor as current treatments are often not completely effective and may only offer temporary respite. Developing new treatments for inflammatory bowel disease is thus urgent and important.The aim of this project is to utilise stem cells technology with advanced materials and 3D printing to develop replacement bowel tissue in the laboratory which can be safely inserted into the large bowel (colon) as a graft thereby avoiding a stoma and possibly restoring bowel function. Recent research has made it possible to take skin cells and turn them into stem cells which can form any tissue in the body. It follows from this that replacement tissue can be created from a patient's own cells which avoids the risk of organ rejection. To do this, I need to establish the conditions which make stem cells form the cells which line the colon. Already in proof of concept studies I have successfully grown stem cells in the laboratory to form early colon cells. Incorporating this with cutting-edge 3D printing technology, I will design materials very precisely with surfaces which will further enhance the quality of intestinal cells we can produce. I will therefore aim to establish the optimal conditions to make induced pluripotent stem cells to grow into colon cells. Having established how to create functional bowel tissue in the laboratory on a small scale, I will manufacture larger sheets of material which would be suitable for inserting into the bowel. Finally, I intend to test the laboratory grown tissue grafts by implanting them into the colon of an animal host. This will allow me to ensure they function as expected, are safe and remain healthy. This would provide proof-of-principle that these could be inserted into the bowel of humans as a potential treatment.The combination of stem cell research with cutting-edge materials engineering is a novel approach. If successful, it could lead to the development of a novel treatment in inflammatory bowel disease and in other bowel diseases where surgery is necessary. This project will also help us to understand the mechanisms driving bowel development. In particular, I will investigate how the characteristics of material on which cells grow influence their behaviour (which is highly relevant to the development of patient-specific tissue grafts). The tissue would also be valuable as a laboratory model of bowel disease to research disease development and to test other treatments.