Impedance toxicology monitoring of biomimetic barrier tissue models with flexible electronics.

Barrier systems exist within the body as a line of defence against harmful substances and contribute to normal homeostatic mechanisms via cell secretion, selective transport and immunological signalling. Dysfunctional barrier systems are the origin of many chronic and critical illnesses. A prime example is a maladaptive Pulmonary epithelial Barrier (PEB) which can lead myriad of lung conditions including asthma, cystic fibrosis, Chronic Obstructive Pulmonary Disease (COPD) and acute lung injury, with 1 in 5 UK citizens reporting a history of longstanding respiratory illnesses. Thus, pulmonary drug delivery research is aimed at understanding how the PEB is dynamically regulated and how the cellular and non-cellular components of the barrier can be overcome or repaired. In the pharmaceutical industry, current gold-standards for modelling barrier systems and assessing barrier integrity rely on 2D cell cultures and electrical monitoring via Transepithelial/Transendothelial Electrical Resistance (TEER). However, with high drug attrition rates, high lead times and a call for a reduction in animal testing, there is an increasing demand for novel, biomimetic and 3D in vitro human tissue models as well as sensors for monitoring their growth, functionality and toxicology. Although model systems have undergone a surge in development, there remains a need for sensor technology to be adapted for these 3D architectures. To this end, the Organic electrochemical Transistor (OECT) offers a promising solution. Compared to rigid and invasive materials traditionally used in electronic devices, OECT's are made with semiconducting, flexible and biocompatible polymers. Furthermore, OECT's show mixed ionic/electric conductivity, chemical tuneability and optical transparency, which are desirable traits to achieve multi-modal characterisation of complex cell cultures. This project aims to adapt OECT technology to be conformable with flexible electrode devices. These devices will be used to monitor 3D barrier models or tissues at the air-liquid interface and will represent the first instance of a flexible sensing platform that is non-invasive to the biological system under study. The project's objectives include the design and fabrication of a novel microelectronic device, to achieve multimodal device operation including optical, electrical and metabolite sensing, and the integration of said devices at the interface of complex 3D barrier models including the PEB. This will not only improve understanding of barrier biology, pathology and toxicology mechanisms, but aims to help reduce the cost and attrition rates associated with the pharmacological screening and testing process.

The research methodology includes device design using AutoCad and ClenWin software and device fabrication using photolithographic and microfabrication techniques. Methods involved in the functionality of the device include Electrical Impedance Spectroscopy (EIS), optical microscopy and biofunctionalization via the immobilisation of enzyme/mediator complexes. Once integrated with the cellular model, any device-induced mechanical damage will be assessed via comparison against assays such as the scratch would healing assay, ciliary beating frequency and pathoimmunological staining. Device performance will also be validated against existing state-of-the-art TEER measurements and the commercialised version, CellZscope. This project is in alignment with the EPRSC's strategies and research areas of microelectronic device technology and biomaterials and tissue engineering and will be carried in out in collaboration with industrial partners at AstraZeneca and academic partners in Prof. Maliaras' bioelectronics group.

Outputs from the CDT will include both research outputs and the training of cohorts of highly qualified, interdisciplinary postgraduates, expert in a wide range of sensing activities.
WHO WILL BENEFIT: Immediate beneficiaries of the research outputs will be industrial consortium partners in the CDT (currently Alphasense, Rolls Royce, Shell, Cambridge Display Technologies, Nokia, NPL and others). They will help steer the training and research programmes of the PhD students and CDT outputs will feed directly into their research programmes and future strategy. Other interested UK companies will also be able to benefit via outreach activities of the CDT (workshops etc) and recruitment from the CDT's student pool. It is anticipated that both national and international policy makers and regulators, e.g. in the area of environmental monitoring, medical diagnostics, etc. will also benefit from the research output of the CDT in terms of setting regulations commensurate with state-of-the-art sensor technologies emanating from the CDT consortium. Potential public-sector beneficiaries include the NHS (sensing advances for medical diagnostics, patient monitoring etc), Museums and Galleries (new sensing techniques applied to conservation of artworks), Armed and Security Services (new sensing techniques and approaches for threat detection and mitigation, contraband and drugs-of-abuse detection - direct beneficiaries will be the Home office and other government agencies, with whom discussions are taking place), Transport (sensor networks for traffic management, pollution control). Beneficiaries of the sensor-training aspect of the CDT will be the afore-mentioned companies, both in the UK and abroad (e.g. EU), who will be able to employ the highly-trained, interdisciplinary postgraduates produced by the CDT, who will be skilled and experienced in a wide range of sensing aspects and technologies. It is anticipated that some of this postgraduate cohort will also remain in academia and hence will implant their sensor knowledge and expertise in Universities outside Cambridge, to the overall benefit of the UK higher-education sector.
HOW WILL THEY BENEFIT: Sensing technologies contribute to an estimated £200bn global market. Thus, there is a very significant opportunity for increasing the UK competitiveness and share in this large market as a result of the new technologies and research outputs emanating from the CDT, coupled with the uniquely qualified and trained researchers emerging from the CDT who will be able to develop new products and forge new markets in this area, both via SME and large corporations in the UK. Thus, there is a very considerable potential economic upside to this activity, in terms of wealth generation and employment in this sector. In addition, there are appreciable potential societal health and well-being benefits from this Sensors CDT. Sensing is central to medical diagnostics and patient monitoring. Future developments in personalized healthcare monitoring, e.g. networked home-monitoring of patients with chronic illnesses will improve patient outcomes and quality of life, and concomitant cost savings for the NHS. There is exciting potential in combining health care sensing (and indeed many other types of sensing) with mobile phone and wireless technology improving coverage, cost, and speed of response. Better and novel sensors will reduce downtime of transport infrastructure due to targeted preventive maintenance; novel sensors will be less intrusive, but more robust, in security measures for public places, etc. The postgraduate cohorts emerging from the CDT will have been trained in a wide range of activities in addition to sensor science and engineering. They will have been exposed to courses in entrepreneurship, and so will be equipped to start up new ventures. Students will also have greater awareness and experience at teamwork, both through activities in the CDT itself, and during secondment to industry.