Title: Drug-eluting in vivo probe to monitor age-related lower bowel dysfunction
Funder: Engineering and Physical Sciences Research Council

Abstract: 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.

Lay abstract: Age-related bowel disorders such as chronic constipation and faecal incontinence can have a significant impact on quality of life and provide a significant economic burden to the NHS. Currently, treatments for both conditions are limited and for many treatments fails. Therefore, a new radical approach is needed to provide early prediction and detection of age-related bowel dysfunction so that interventions to delay/prevent the onset can be commenced. To resolve these challenges, we will develop a novel in vivo electrochemical probe to monitor, understand and track age-related changes in the lower bowel function. The longer-term goal is to utilise the probe as a theranostic device for the early detection of age-related lower bowel dysfunction. This will be achieved by the following objectives: 1. Convert the ex vivo electrochemical sensor into a drug-eluting in vivo probe. 2. Enhance the sensitivity and linear range of the in vivo probe to monitor contractions and mucosal signalling markers. 3. Monitor in vivo age-related changes in lower bowel signaling and function The priority is to establish a novel approach for manufacturing a drug-eluting probe, which can be inserted into the lower bowel for in vivo monitoring. To achieve this, the probe will need to encompass all electrodes needed to complete an electrochemical cell (working, reference and counter electrode). This developed prototype will be established using 3D printing to provide robust reproducible probes that can be generated at mass. A variation of this device will be established, where a cannula can be inserted within the probe to allow for localized delivery of therapeutic agents within the lumen of the bowel. Performance testing of the device will be conducted in an animal model system; however, the device is aimed in the future for measurements in humans. Therefore, the strategies utilised for fabrication of these device are completely scalable from measurements in animal models to humans and therefore successful measurements to highlight the theranostic potential of the probe will provide us with the necessary preliminary data to conduct human trials. Probe evaluation studies will be conducted to ensure the linear range and sensitivity of the probe for monitoring luminal signalling and contractility. To achieve this, we will vary the conductive carbon materials and the geometry of the electrode to make the 3D printed sensors to enhance the scope to monitor a wider linear range of muscle contractions. The most successful prototype will be used for spatial mapping of signalling and contractions in the lower bowel and how these are altered following the application of pharmacological agents through the integrated cannula. Together, these experiments will establish protocols for our ageing studies. Lastly, we will use the developed probe and established measurement protocols to conduct a longitudinal study where we will track male and female mice from 3 months (20 years human equivalent) to 24 months (80 years human equivalent) to identify the changes that occur during ageing and use this to develop predictive models on how to identify the onset of age-related bowel disorders. This will be the first ever in-depth study to track and identify changes in bowel signalling and muscle contractility across the life course of individual animals. Our findings from the completion of this proposal will provide the template for the establishment of a probe which can be fabricated for in vivo measurement in humans and a methodology for in vivo measurement of luminal signalling and muscle contractions from the anorectum. The results from this study will provide a series of markers that can inform on future bowel dysfunction allowing early treatment interventions to reduce the burden on the healthcare services and improve quality of life for older people.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.3 MEDICAL DEVICES
Health categories: GENERIC HEALTH RELEVANCE;ORAL AND GASTROINTESTINAL