Drug-eluting in vivo probe to monitor age-related lower bowel dysfunction

随着年龄的增长，由于肠道排空困难、不频繁和不完全（慢性便秘）以及肠内容物渗漏（大便失禁），大肠中的粪便堆积经常相关。这些被称为与年龄相关的肠道疾病。社区中超过三分之一的65岁以上的奥尔兹和超过一半的养老院老年人将患有这些与年龄相关的肠道疾病。对患者来说，这些症状可能会导致严重的尴尬，失去尊严和生活质量。2010年，医疗服务部门治疗此类疾病的费用达到10亿英镑。预计这一年龄段的人口数量将会增加，其中65岁及以上的人口数量将在20年内增加40%以上，成为一个重大的社会和经济问题。因此，需要一种方法，允许早期检测与年龄相关的肠道疾病的预测标志物，以便在早期阶段开始有效的治疗，延迟/预防疾病的发作并延长健康寿命。粪便通过大肠的运动需要控制该区域的神经和肌肉的协调活动。肠的最外层称为粘膜，具有可以检测我们肠道内存在的内容物的细胞，它们释放化学物质与神经沟通以协调肌肉收缩。我们已经证明，这种沟通过程随着年龄的增长而改变，因为这些化学物质的释放会发生变化。这反过来又会损害肌肉的功能，导致粪便运动的损失。因此，如果我们能够测量肌肉的化学物质和功能随时间的变化，我们将能够在患者出现症状之前很早就发现这些变化，并开始治疗以延迟/预防这些疾病的发作。为了应对这些挑战，第一步是制作一种电化学探针，可以插入到下肠中，以跟踪粘膜和肌肉释放的化学物质的变化。活动这将需要优化设计和电子设备，以允许我们进行所需的测量，此外，我们希望我们的探头能够将药物局部释放到肠道中，因此该设备将在探头内构造一个管，以实现这一点。为了制造这些探针，我们将利用3D打印，这为探针部件的高效制造提供了一个平台。此外，这种方法将使我们能够扩展这种设备，从作为啮齿动物研究的一部分开发的小型探针到用于未来人类研究的更大探针。一旦这些探针已经作出，我们将探讨如何修改用于构建探针的材料和探针的形状影响其性能。最好的原型将用于动物模型的研究。最初，我们的探针将插入麻醉小鼠的下肠道。这些研究将使我们能够绘制出化学物质如何在小肠中释放以及肌肉活动如何在测量区域中变化。此外，我们可以探索不同药物在下肠道中的作用。这些重要的研究将使我们能够为我们的衰老研究建立关键协议。使用小鼠模型，其具有与人类经历的相似的年龄相关的肠功能障碍，并且其中肠由人类使用的许多相同的化学物质调节，为我们提供了一个理想的模型，以进行纵向探索粘膜化学物质和肌肉活动在个体动物的寿命期间如何变化，同时监测其粪便输出作为功能障碍的标志。这将使我们能够展示我们的探针如何成为跟踪和预测与年龄相关的肠道疾病可能性的有吸引力的工具。这些发现将使我们能够快速地在人体中进行我们的设备的临床试验。

Increasing age is frequently associated with a build-up of faeces in the large bowel due to difficult, infrequent and incomplete emptying of the bowel (chronic constipation) as well as leaking of bowel contents (feacal incontinence). These are known as age-related bowel disorders. Over one third of the over 65-year olds in the community and more than half of those in care homes will suffer these age-related bowel disorders. To the sufferer the symptoms can cause significant embarrassment, loss of dignity and quality of life. To the health service the cost of treating such conditions reached £1 billion in 2010. This age group is predicted to increase, where the number of people aged 65 and over will increase by more than 40 % within 20 years, making this a major social and economic problem. Therefore, there needs to be an approach that allows for the early detection of predictive markers of age-related bowel disorders so that effective treatment can commence at an early stage, delaying/preventing the onset of the disorder and extending healthspan.The movement of faeces through the large bowel requires the coordinated activity of the nerves and muscles that control this region. The outer most layer of the bowel known as the mucosa, has cells that can detect the contents present within our bowels and they release chemicals to communicate to the nerves to coordinate muscle contractions. We have shown that this communication process is altered with age as there are changes in the release of these chemicals. This in turn impairs the function of the muscles and results in a loss in the movement of faecal matter. Therefore, if we can measure the chemicals and the function of the muscle over time, we will be able to detect these changes very early before the patient gets symptoms and start treatments to delay/prevent the onset of these disorders.To meet these challenges, the first step will make an electrochemical probe that can be inserted into the lower bowel to track the changes in the chemicals released from the mucosa and the muscle activity. This will require optimising the design and the electronics to allow us to conduct the required measurements, Additionally, we would like our probe to be able to release drugs locally into the bowel so the device will be constructed with a tube within the probe to allow for this. To make these probes we will utilise 3D printing, which provides a platform for the efficient manufacturing of the parts of the probe. Additionally, this approach will allow us to scale this device, from the small probe developed as part of this study in rodents to a larger probe for use in future human studies. Once these probes have been made, we will explore how modifications to the materials used to construct the probe and the shape of the probe affect its performance. The best prototype will be used for investigations in animal models.Initially our probe will be inserted into the lower bowel of an anaesthetised mouse. These studies will allow us to map how chemicals are released in the lower bowel and how muscle activity varies in the regions measured. Additionally, we can explore the effects of different drugs in the lower bowel. These important studies will allow us to establish key protocols for our ageing studies. Using a mouse model which has similar age-related bowel dysfunction to that experienced in humans and where the bowel is regulated by many of the same chemicals used by humans provides us with an ideal model to carry out a longitudinal exploration of how mucosal chemicals and muscle activity change during the lifespan of an individual animal whilst simultaneously monitoring its faecal output as a marker of dysfunction. This will allow us to showcase how our probe can be an attractive tool for tracking and predicting the likelihood of age-related bowel disorders. Such findings will allow us to rapidly conduct clinical trials of our device in humans.