Organ on chip gut mucosa with integrated electronic monitoring for drug discovery

The gastrointestinal (GI) tract is an attractive route for therapeutic delivery. However, targeting across the mucosal barrier is highly challenging, and evidence shows that therapeutics may be metabolised in the GI tract altering bioavailability[1] or even inducing toxicity.[2] The standard for assessing efficacy and safety of novel therapeutics has been a combination of (2D) in vitro cell assays followed by animal testing, and human clinical trials. However, the drug discovery pipeline is inefficient (~90% attrition[3]), expensive (£2Bn++)[4] and lengthy (10-12 years). There are strong economic and humanitarian arguments for improving the efficiency of therapeutic screening. Animal models can provide useful information on therapeutic effectiveness, however, many late-stage failures in pre-clinical testing are related to species differences between rodents and humans. Recent awareness of the power of in vitro models to answer specific questions in drug discovery, has prompted a new wave of interest in Organ on chip technologies, with new legislation encouraging the use of alternatives to animal testing in the USA. This aligns with the NC3Rs work on new approach methodologies, recently debated in parliament.[7] Some failure points have been identified, including the inability of current in vitro testing to predict how physicochemical interactions of compounds of interest with specific tissues will impact human health. The consensus is that 2D models do not recapitulate the in vivo situation, as gene/protein expression and cell function is inherently different.[5] In addition, failure to consider the microbiota resident in the gut, is increasingly being identified as problematic, as it is now known to significantly alter therapeutic bioavailability and function.[1,6] 3D, engineered in vitro models of human tissues represent a solution to more accurately recapitulate in vivo biology, overcoming these challenges. We propose to develop tissue-scale, human, multicellular 3D models of the GI tract with embedded electronics, using dynamic in situ monitoring to evaluate the health of the tissue with subsequent monitoring of the effects of model therapeutics, taking into account the additional parameter of host-microbiota interplay. Advanced materials engineering will ensure accurate mimicry of the tissue, crucial to understanding initial interactions with tissues, and barriers to entry or effectiveness. The goal is to provide a medium-high throughput method to screen for therapeutics. The team’s expertise ranges from engineering biology (the PI is a leader in Organ-on-chips (OoC) with integrated electronic monitoring, a disruptive sensing technology), metabolomics of the gut microbiome (Patil), and clinical expertise on gastrointestinal disorders and derivation of human intestinal organoids from tissue biopsies (Zilbauer). This multi-disciplinary scientific expertise is complemented by the team at AZ, leaders in development and testing of therapeutics. The success of this proposal will result in faster, more accurate early screening of promising drug candidates, and enhanced understanding of host microbe interactions in the gastrointestinal tract. This work will not only solidify the strength of the UK in therapeutics development (particularly gut-directed biologics together with our partner AZ), but it will also contribute to our understanding of the basic biology behind gut disease. Our team’s combined expertise will complement existing knowhow, injecting increased strength and breadth, bringing in engineers and physical scientists to enhance the technology component, e.g. by incorporation of highly sensitive bioelectronic devices for efficient and accurate readouts in complex biological models. This project will contribute to strengthening engineering biology capabilities, applying engineering principles to the development of advanced tools for therapeutic screening.