Dementia-on-a-chip: Trevor Bushell and Michele Zagnoni on microfluidics, collaboration and the future of dementia research

Written by Lauren Pulling, Editor

The use of on-a-chip technologies has seen enormous growth across the biomedical sciences in recent years, but how can this approach be harnessed to further understand dementia and its contributing diseases, and develop new therapies? We spoke to Trevor Bushell and Michele Zagnoni (both University of Strathclyde, UK) about how they’ve brought together their respective expertise in neuroscience and bioengineering to develop “dementia-on-a-chip” microfluidic technologies. In this interview, they discuss their joint projects, including how they’re enabling predictions on the efficacy and pharmacological effects of agents targeting tau in Alzheimer’s disease; the importance of collaboration; and their forecast for the future of dementia research.
Can you talk us through your current collaborative projects?

Michele and I are currently collaborating on a number of projects funded by the NC3Rs (National Centre for the Replacement, Refinement and Reduction of Animals in Research) and the University of Strathclyde. Our overarching aim is to develop microfluidic technologies that will enable novel neuroscience research. With respect to Dementia-on-a-chip, this is undertaken as part of a consortium led by Selina Wray from the UCL Institute of Neurology (London, UK) that was successful in obtaining NC3Rs funding via their Crack It Challenge 12 called UnTangle. The aim of this challenge was to develop a physiologically relevant human stem cell-derived neuronal assay to predict the efficacy and unexpected pharmacological effects of new chemical entities and biologics targeting tau in Alzheimer’s disease. To this end, we have been utilizing patient-derived neurons using induced pluripotent stem cell (iPSC) technologies to investigate the consequence of tau mutations on neuronal development, function and maturity.

How do you anticipate this on-a-chip technology could be used to facilitate dementia research  and where do you see its biggest uses being?

“The benefits obtained from the microfluidic approach for these studies are numerous.”

The benefits obtained from the microfluidic approach for these studies are numerous. These include: the enhanced capabilities of controlling the fluid environmental parameters surrounding the cells; the higher control over the neuronal network patterning; the reduction of cell number (90% reduction) needed per assay; the ability to perfuse compounds of interest in an automated manner and with a throughput exceeding current capabilities; and the ability to monitor tau spread between co-cultures recreating pathological conditions found in vivo. Hence, utilizing this on-a-chip technology will allow us to provide an improved understanding of the mechanisms implicated in tau phenotypic variability and expression. Furthermore, we hope that this work will result in the development of an innovative and robust platform for patient-derived neuronal culture and drug screening that has the potential to be applied in other biological scenarios as well.

Do you think on-a-chip technologies are likely to become more commonplace in the dementia research field? If so, when are we likely to see this?

“Given the explosion of interest in the use of patient-derived neurons or stem cell-derived neurons with CRISPR-induced mutations, we envisage that on-a-chip technologies will become more commonplace…”

The use of microfluidic technologies for research of brain disorders has increased dramatically in recent years. Given the explosion of interest in the use of patient-derived neurons or stem cell-derived neurons with CRISPR-induced mutations, we envisage that on-a-chip technologies will become more commonplace, especially given the small cell number required for each device (a significant advantage when using precious patient-derived neurons) and novel experimental protocols that could not be performed with conventional culture plates. The use of these cells is not trivial both from sourcing the relevant cells through to the known intrinsic variability between cultures from the same patient in addition to inter-patient variability. However, we feel we now have the experience to fully reap the benefits from combining these technologies. For on-a-chip technologies to become a commonplace in the dementia research field, interdisciplinary research must be facilitated by more flexible funding schemes that allow engineering and neuroscience disciplines to come together.

How could on-a-chip technologies impact patient treatment?

Given the recent failures of clinical trials of β-amyloid-targeted antibodies and the acceptance that current animal models of dementia do not truly reflect human pathology, development of these devices utilizing human neurons will increase our understanding of the mechanisms underlying the pathology associated with the various forms of dementia. On-a-chip technologies will also facilitate the upscaling of compound screening to be achieved with cost-effective resources and physiologically relevant in vitro models. This in turn will allow novel treatments, be they targeted at β-amyloid, tau mutations or any other potential targets, to be used in drug screening with the long term goal being that these will identify both novel entities that will help in treating these devastating diseases and improve our understanding of the disease mechanisms.

Do you envisage that this technology could one day facilitate a personalized medicine approach to treating dementia?

“…the use of patient-derived neurons is still in its relative infancy and given the time and variability associated with producing neurons, more work is required to create a robust personalized approach.”

Whilst we hope these miniaturized technologies will aid in increasing our understanding of the processes and mechanisms involved in dementia, it is unlikely that they will facilitate a personalized medicine approach to treating dementia any time soon. Unlike other fields, such as oncology with the use of patient-derived biopsy samples, the use of patient-derived neurons is still in its relative infancy and given the time and variability associated with producing neurons, more work is required to create a robust personalized approach. That said, the area is developing rapidly and these technologies, in combination with powerful imaging techniques, will definitely help in facilitating dementia research.

You come from quite varied research backgrounds – how did you come to collaborate? How do your differing backgrounds influence your work?

We first met when Michele was appointed to the Centre for Microsystems and Photonics in the Department of Electrical and Electronic Engineering at the University of Strathclyde. He had an interest in utilizing microfluidic devices for biomedical research and contacted me regarding using them for neuroscience research. We met for coffee, got on well and so we applied for a PhD studentship via the EPSRC-funded Medical Devices Doctoral Training Centre held at Strathclyde. We were fortunate to be successful in this and (now Dr) Graham Robertson joined the group and he was instrumental in developing the initial microfluidic technologies using rodent cultures. He is currently the PDRA on the NC3Rs-funded Crack It grant. We also obtained EPSRC Bridging the gap funding as Strathclyde strongly promotes interdisciplinary research. This allowed us to boost our experimental capabilities with novel microfluidic protocols to a stage that when the Crack It call was announced, we were in a position to support Selina Wray (who we knew was an expert in patient-derived neurons) with novel microfluidic technologies and from there the successful consortium was put together.

We believe our collaboration has worked well as we have both committed to and believed in every project. We do come from varied research backgrounds but we have made a constant effort in the past 5 years to “educate” each other more and more in the unknown discipline (Trevor in microfluidics and Michele in neuroscience). In addition to getting on at a personal level and with the right work environment, we believe this to be the fundamental aspect required to produce truly interdisciplinary research.

What’s next for your groups?

We have a 2-fold aim. One is to use and keep developing these technologies for providing new experimental capabilities for neuroscience research. For instance, we have recently validated microfluidic perfusion systems to develop novel approaches to repeatedly stimulate and monitor neuronal activity. The other is to create novel screening technologies based on on-chip technologies that can improve the yield of pharmacological research.

More generally, where do you hope the field of dementia research will be in 10 years’ time?

“With the aging population, the economic and social burden of dementia is only going to grow, but it seems that finally there is some acceptance of this and we need to take action now.”

With the aging population, the economic and social burden of dementia is only going to grow, but it seems that finally there is some acceptance of this and we need to take action now. Given the advances made in other disease areas, for example cancer, on the back of significant research funding, this now needs to happen in dementia. If it does and researchers – both within academia and the pharmaceutical industry – work in a collaborative way, we can significantly increase our understanding of the underlying mechanisms and development of the various forms of dementia that should lead to better treatments. We are hopefully at a turning point regarding dementia research but we, and importantly the public at large, should be under no illusions that there is going to be a quick fix to this ever-increasing problem.

 

Biographies

Trevor Bushell undertook his PhD at the University of Bristol (UK) under the supervision of Graham Collingridge. He was then awarded a Wellcome Trust International Travel Fellowship to examine receptor modulation of neuronal function at the University of Chicago (IL, USA) with Richard Miller. He then returned to Imperial College London (UK), where he investigated the neuronal function of two-pore potassium channels and molecular targets for anesthetics with Brian Robertson and Nick Franks, respectively. He then obtained a lectureship at the University of Strathclyde (UK) where he is now a Senior Lecturer. His current research focusses on the modulation of astrocytic and neuronal function under physiological and pathophysiological conditions.

Michele Zagnoni is an Electronic Engineer with a Masters in Biongineering. He undertook his PhD at the University of Bologna (Italy) developing electromechanical sensors for airplane wings. Following his experience as a visiting researcher at the University of Southampton (UK) (supervised by Hywel Morgan) and the University of Oxford (UK) (supervised by Richard Berry), he switched his research interest towards engineering for the biological sciences. He investigated artificial cell membranes and single-cell omics using lab-on-a-chip technologies at the Universities of Southampton and Glasgow (UK), respectively, before taking up an academic position at the University of Strathclyde where he is now a Senior Lecturer. His current research focusses on the development of microfluidics and lab-on-a-chip technologies for fundamental biological investigation, compound screening, in vitro diagnostics and treatment of disease.