Printable Micro-rockets for Rapid Medical Diagnosis and Biomarker Detection

Lead Research Organisation: University of Sheffield
Department Name: Chemical & Biological Engineering

Abstract

Medical diagnostic tests performed in high throughput, time critical NHS hospital laboratories are key to ensuring that clinicians can deliver high quality patient care. An important type of test, providing diagnosis for a wide range of diseases and illnesses, including cancer and heart problems, are immunoassays. These assays are based on nature's exquisite recognition apparatus: anti-bodies. Immunoassays involve attaching anti-bodies to a detector surface, waiting for the analyte (e.g. protein biomarkers or specific cells) of interest to become bound at the surface, and finally using electrical or optical methods to read-out the test result. However, due to the low concentration of many diagnostic analytes, the time spent waiting for sufficient amounts of analyte to diffuse to the detector to enable read-out can be significant. The consequence of these long incubation times is severe: for example automated hospital instruments that can handle thousands of samples per hour are rate limited by up to twenty minute waits for the immunoassay process to complete. As well as reducing throughput for routine analysis, these delays hamper the task of returning time critical diagnostic information to clinicians, such as screening for heart problems in patients with chest pain. Slow accumulation of analyte at an anti-body detector also limits developing methods that rely on isolating rare cells, such as circulating tumour cells to indicate the progression of cancer and enable personalised medicine.

In this context, it is clear that the challenge of speeding up the rate at which analytes reach the detector is great, and that successfully achieving this can have significant Healthcare impact.

Here we propose to develop a new approach to achieve rapid analyte detection, by exploiting micro-rockets; small scale devices that can generate rapid motion within fluids. Micro-rockets are powered by the asymmetrical release of bubbles from their surface. These bubbles are generated by enzymes decomposing fuel molecules in the surrounding solution. Micro-rockets will be used to speed up immunoassays in two ways. Firstly, micro-rockets' rapid motion and bubble generation stirs solutions, which is otherwise hard to achieve at small scales. This will be used to reduce the incubation times for immunoassays where anti-bodies are attached to the inside surfaces of a "micro-well" containing the analytical solution. By agitating the solution with micro-rockets, analytes will contact the well surfaces more frequently, speeding up detection. In the second method, the micro-rockets themselves will be covered with anti-bodies and used as a mobile detector, rapidly moving throughout the analytical sample. The fast motion will allow dilute quantities of analyte to be rapidly located. Analyte binding rate to anti-bodies and selectivity will also be improved by using a rapidly moving detector surface. At the end of the incubation period, magnets will be used to retrieve the dispersed rockets to enable analyte concentration to be determined using existing optical or electrical methods. Efficiently developing new micro-rockets with the required functions of analyte recognition and magnetic control will be aided by using ink-jet printing to allow micro-rocket composition, size, shape to be easily controlled and optimised.

To demonstrate the utility of micro-rockets, experiments will be conducted to compare the speed at which micro-rockets can acquire analytes, compared to the existing diagnostic methods used by hospitals. Two diagnostic tests will be considered: one for protein molecules called "Troponins" that signal recent cardiac damage, and the second for circulating tumour cells. Establishing proof of micro-rocket effectiveness in this way will be a key step to attract interest from industrial partners who can assist the development of this technology to allow eventual deployment in hospitals.

Planned Impact

The project has been chiefly designed to develop technology to address challenges experienced in deploying diagnostic tests within NHS hospitals, and so has significant potential for societal and economic impact. The new catalytic micro-rocket based methods targeted here can considerably reduce the duration of the incubation stage during immunoassays. The improvement to healthcare provision that this can produce is clear: e.g. patients presenting with symptoms that may require critical interventions, such as chest pain, will benefit from a reduction in time for their clinicians to access diagnostic test results. Beyond this emergency care scenario, in automated hospital analysis suites, long immunoassay incubation periods currently dramatically reduce sample throughput rate. Higher sample throughput will therefore enable immunoassays to be deployed more widely and responsively: e.g. to stratify hospital admissions, producing both health and economic benefits via cost savings by reducing admissions and preventing unnecessary clinical interventions.

An additional healthcare impact for micro-rockets targeted here is to provide a new method for retrieving rare cells, such as Circulating Tumour Cells (CTCs). CTCs indicate prognosis for cancer patients, and provide a route for personalised medicine: by culturing cells clinicians can determine details of an individual's tumour allowing the best drugs to be selected. Current methods to enrich CTCs from blood require processing stages which damage cells. Micro-rockets can potentially provide both faster and less destructive retrieval method, enabling improved care for cancer patients.

Beyond these specific targeted goals, developing the proposed technology can produce ancillary far reaching impacts. Micro-rockets have the potential to produce significant speed enhancements for any current immunoassay, and so can lead to future advances in diagnosis for a vast range of disease and illness. In addition, microrockets can be enablers for future efforts to translate laboratory based diagnosis into Point-of-care (POC) implementations. Key features for POC technology are simplicity, speed and autonomy: it is clear that micro-rocket based immunoassays meet these criteria. This is in contrast to other new immunoassay technology which requires sophisticated external control to generate fluid flows or agitate magnetic components. POC tests will deliver considerable societal and economic benefits, for example by allowing patients to monitor their own conditions, thereby reducing burden on clinical infrastructure.

The technology envisaged can also produce longer term societal benefits, by providing new tools for medical research, and improving existing standard methods. Immunoassays, and related standard methods such as immunoprecipitation, together with rare cell analysis are widely used in current medical research programs, and so speeding up these methods will assist researchers in these fields, providing a route to improved treatments.

The process of developing micro-rocket technology to achieve these Healthcare benefits also provides routes to additional economic benefits. The proposed pathway to translate the new diagnostic technology to clinical end users will heavily exploit industrial expertise. The UK has significant numbers of SMEs involved in the development, manufacture and distribution of immunoassay devices, and so collaboration with these companies to translate the research planned here will open up new opportunities for wealth generation, and additionally improve UK competiveness in the world healthcare market. In addition, licensing and the formation of new companies provide further routes for economic benefit.

Finally, the proposal provides a chance for public engagement on acceptance for autonomous small scale devices for healthcare applications, an issue that is likely to become increasingly significant in the future.

Publications

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Kumar P (2022) 3D inkjet printed self-propelled motors for micro-stirring. in Journal of colloid and interface science

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Ebbens SJ (2018) Catalytic Janus Colloids: Controlling Trajectories of Chemical Microswimmers. in Accounts of chemical research

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Campbell AI (2019) Experimental observation of flow fields around active Janus spheres. in Nature communications

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Gregory DA (2019) Reactive Inkjet Printing and Propulsion Analysis of Silk-based Self-propelled Micro-stirrers. in Journal of visualized experiments : JoVE

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Gregory DA (2016) Reactive Inkjet Printing of Biocompatible Enzyme Powered Silk Micro-Rockets. in Small (Weinheim an der Bergstrasse, Germany)

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Zhang Y (2019) Reactive Inkjet Printing of Functional Silk Stirrers for Enhanced Mixing and Sensing. in Small (Weinheim an der Bergstrasse, Germany)

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Gregory DA (2018) Symmetrical Catalytically Active Colloids Collectively Induce Convective Flow. in Langmuir : the ACS journal of surfaces and colloids

 
Description This grant has developed autonomous miniature stirring devices that are capable of enhancing mixing within microwell plates.

The mixing has the potential to enhance the performance of medical diagnosis assays, and also be used as motion detectors for solution properties and composition.
Exploitation Route The stirring devices can potentially have application in medical diagnosis and a range of sensing applications. We are actively pursuing these ideas for deployment for water quality testing, and increasing throughput of immunoassays. Promising results reflecting the ability for micro-rockets to capture cells, as envisaged in the orginal project aims are also emerging.
Sectors Aerospace

Defence and Marine

Agriculture

Food and Drink

Environment

Healthcare

Pharmaceuticals and Medical Biotechnology