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

Lead Research Organisation: University of Cambridge
Department Name: Chemical Engineering and Biotechnology

Abstract

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.

Publications

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Boys AJ (2020) Building Scaffolds for Tubular Tissue Engineering. in Frontiers in bioengineering and biotechnology