Laser-based engineering of paper for manufacturing fluidic sensors: (Lab-flo)

Lead Research Organisation: University of Southampton

Abstract

In 2013 we started work on an 18-month EPSRC feasibility grant entitled 'Laser-printable point-of-care sensors for low-cost medical diagnosis and disease monitoring', which explored laser-based printing of biological materials for applications in the healthcare sector. Our results have attracted the attention of several major international healthcare manufacturers who see the potential of laser-patterning of porous materials like paper for their future product range and who want to work with us to further develop this technology. We are submitting this follow-on proposal to (1) develop a laboratory-standard process for laser-based paper-patterning for fluidic devices, (2) use our technology in trials for a point-of-care diagnostics demonstrator sensor that allows detection of specific diseases such as tuberculosis, as well as dramatically reducing detection limits, (3) extend the technique to incorporate methodologies for fluid delay, multiplexing, and patterning of 3-D devices, and (4) explore applications beyond planar devices in paper, including 'Light-Up Paper' and functionalised fabrics for 'Smart Plasters'.

Planned Impact

With the continuously increasing strains on already over-burdened public health systems of a developed nation such as U.K, and developing countries with the low-resource settings, the role of diagnostics is proving to be crucial. On-site detection and point-of-care (POC) diagnostic testing is a trend that is emerging as one of the popular choices for such non-invasive clinical diagnostics. The reason central to the increasing approval of POC diagnostic testing at a patient's bed-side in a near-patient environment of a hospital emergency ward, or an intensive care or simply in a general practitioners clinic, is because it presents an effective modus-operandi which eliminates unnecessary communication delays between the clinical care team and external testing laboratories.

Economic Impact:
In common with most other countries, the U.K. continues to experience an economic downturn, where austerity cuts on the one hand and ever-increasing demands for increased provision in the healthcare sector on the other make for a very unhappy and unbalanced scenario. One favourable and hence a much preferred route that will enable crucial savings to the NHS (in terms of costs and staff) is the need to enable early-stage testing for disease/condition at the POC (homes, care-homes, nursing home and GP practices) thus reducing the burden on the NHS-hospitals via reduced patient trips to A&E units, emergency call outs and hospital admissions that then improves hospital bed-shortages and unnecessary occupation of these beds - all of this translates into huge financial savings for UK public health system and the economy .
The total POC diagnostics market, which comprises products outside the laboratory, used by healthcare professionals in hospital emergency, critical care, out-patient and GP surgeries, as well as consumers, to test for disease, infection, fertility, drug and alcohol abuse, was worth $13.8 billion in 2011 and is predicted to grow due to increasing interest in the adoption of these technologies to $16.5 billion in 2016. Currently, the United States accounts for almost 50% of the total POC market, however, this is followed by regions, that include Europe and Japan.
The motivation of the proposed research is the underpinning need to enable such potentially life-saving diagnostics, and hence the end-goal is to develop a methodology that will truly make possible the fabrication of such POC diagnostics devices on a paper-platform on a large-scale, which most importantly will make such devices affordable in cost, and thus allow for their wide-scale use at the POC. The UK stands to make considerable gains therefore from the economic benefits that would ensue.

Societal Impact:
POC diagnostics also facilitate prompt exchange of invaluable clinical information between healthcare professionals and their patients from the convenient comforts of their homes, which in some probabilities could be in inaccessible locations. Since a timely exchange of clinical data could potentially be very useful in early detection and prevention of life-threatening infectious diseases (such as TB, which is the focus of this research) diseases or conditions, the wide societal benefits would be not just be in the form of saving lives and but also improving the quality of life for a patient suffering from terminal illness.
For the aging population, incapacitated patients or for those suffering from illnesses such as AIDS or cancer, the possibility to remotely test themselves and send their information to the doctor, could help them from contracting possible life-threating infections from trips to the hospitals. Furthermore, the applicability of low-cost, disposable paper-based testing, the technology developed through this project, could also be extended to include testing for screening of food pathogens and environmental toxins, all of which unarguably have massive societal benefits.
 
Description We have been able to demonstrate new concepts in paper-based diagnostic performance. This work is highly relevant to new point-of-care diagnostic capability, and we are in discussion with several industries in the UK and beyond who want to use this technology for their own products.

We have been pitching to a range of investors, VCs and angels during the past 2-3 years and are now on the point of receiving funding from a major US corporate for year 1 investment. we aim to close the investment during Q1-Q2 or 2020.

We have used IAA funding to establish a spinout, Highfield Diagnostics, (http://highfielddiagnostics.co.uk/) and have exhibited at tradeshows in the UK and abroad. we should be able to report a successful spinout, funded and operational in a subsequent researchfish submission in 2021.
Exploitation Route The results will be taken forward by the healthcare and diagnostics industry in the near future, and we are actively pursing funding for formation of a spinout via the University of Southampton
Sectors Environment,Healthcare,Pharmaceuticals and Medical Biotechnology

URL http://highfielddiagnostics.co.uk/
 
Description We are working with a range of companies in the UK and internationally to prove that our concept for rapid point-of-care paper-based diagnostics will lead to significant benefits in the global healthcare sector. it is still early days, but we are now actively engaged with several investors and likely VCs. We have been pitching to a range of investors, VCs and angels during the past 2-3 years and are now on the point of receiving funding from a major US corporate for year 1 investment. we aim to close the investment during Q1-Q2 or 2020. We have used IAA funding to establish a spinout, Highfield Diagnostics, (http://highfielddiagnostics.co.uk/) and have exhibited at tradeshows in the UK and abroad. In 2021 we were invested for a pre-seed round from a healthtech fund in Singapore which has allowed us to employ 2 staff from April 2021, (one more from March 2022) who are focussing on raising funds via a seed round. our aim is to close this round by Q2-Q3 2022.
First Year Of Impact 2021
Sector Healthcare
Impact Types Societal,Economic

 
Description EPSRC call
Amount £1,768,136 (GBP)
Funding ID EP/P027644/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 06/2017 
End 06/2022
 
Description EPSRC standard grant
Amount £720,997 (GBP)
Funding ID EP/S003398/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 12/2018 
End 06/2021
 
Description HIPS 2017
Amount £773,734 (GBP)
Funding ID EP/P025757/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 03/2017 
End 03/2020
 
Description BBI 
Organisation BBI Solutions
Country United Kingdom 
Sector Private 
PI Contribution We worked on samples and products that they provided to try out our methodology for their applications
Collaborator Contribution They engaged in dialogue with our group in the context of commercial needs associated with out printing technique.
Impact from our contacts with BBI, we have since won further funding from EPSRC in area that directly relate to their current product lines. Having access to such internal 'knowledge' for this market sector is invaluable.
Start Year 2015
 
Description DSTL 
Organisation Defence Science & Technology Laboratory (DSTL)
Country United Kingdom 
Sector Public 
PI Contribution We are now working with DSTL to use our technique which has shown enhanced sensitivity for detection of harmful disease pathogens.
Collaborator Contribution They have provided access to their labs and facilities, and we are currently in the middle of negotiating a research contract with them.
Impact A soon-to-be submitted joint proposal for further development of our novel lateral flow technology.
Start Year 2016
 
Description GE Healthcare 
Organisation GE Healthcare Limited
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaborative discussions and soon agreements to sponsor the work and results that are coming out of this work. We intend to work with GE healthcare to benefit from their extensice experience in manufacturing the membranes we use in our laser-based patterning process.
Collaborator Contribution Time, visits, and soon entering into formal agreements and a partnership.
Impact No outputs yet, but hopefully by the end of the project
Start Year 2016
 
Description Myron 
Organisation University of Southampton
Department Faculty of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution We have analysed samples that he has collected from Brazil for diagnosis of Leischmania disease
Collaborator Contribution Extensive interaction and collaboration in providing human samples for us to trial our lab-flo technique.
Impact A joint paper is about to be submitted on the results of this work and collaboration
Start Year 2016
 
Title FLUID FLOW DEVICE AND METHOD FOR MAKING THE SAME 
Description Techniques for making fluid flow devices are described. The technique is based on radiation-induced conversion of a radiation-sensitive substance from a first state to a second state. With adjustment of the radiation parameters such as power and scan speed we can control the depths of barriers that are formed within a substrate which can produce 3D flow paths. We have used this depth-variable patterning protocol for stacking and sealing of multilayer substrates, for assembly of backing layers for two-dimensional (2D) lateral flow devices and for fabrication of 3D devices. Since the 3D flow paths can be formed via a single laser- writing process by controlling the patterning parameters, this is a distinct improvement over other methods that require multiple complicated and repetitive assembly procedures. 
IP Reference WO2017207958 
Protection Patent application published
Year Protection Granted 2017
Licensed No
Impact We are intending to form a spinout based on this technology and this patent, which is first of a series of three filed
 
Title FLUID FLOW DEVICE ON A POROUS SUBSTRATE AND METHOD FOR MAKING THE SAME 
Description A method of making a fluid flow device comprises providing a substrate of porous material, depositing a radiation-sensitive substance onto the substrate in a pattern defining one or more regions intended to receive and contain fluid during use of the device or occupying an area within such a region, such that the radiation-sensitive substance extends at least partly through the thickness of the substrate below the pattern, and exposing radiation onto the substrate thereby delivering energy to the radiation-sensitive substance in at least part of the pattern to change the radiation-sensitive substance from a first state to a second state through at least part of the thickness of the substrate. One of the first state and the second state may be less permeable than the other. 
IP Reference US2018120312 
Protection Patent application published
Year Protection Granted 2018
Licensed No
Impact This patent is one of a family that supports the spinout of Highfield Diagnostics
 
Title FLUID FLOW DEVICE WITH FLOW CONTROL AND METHOD FOR MAKING THE SAME 
Description A method of making a fluid flow device comprises: providing a substrate of porous material (2) impregnated with a light-sensitive substance (5) in a first state and which is configured to change from the first state to a second state when exposed to light (3), the second state being a solid state that is resistant to a solvent and the first being removable with the solvent; the substrate having a fluid flow channel (7) defined therein, the channel having a depth; exposing a beam of light (3) onto an area of the substrate surface within the fluid flow channel to deliver energy to a volume of the substrate below the area to change the light-sensitive substance to the second state; during exposure, creating a partial barrier to flow of fluid along the channel by controlling the amount of energy delivered to the volume below at least part of the area to change the light-sensitive substance to the second state in a volume of the substrate within the fluid flow channel that has a depth less than the depth of the fluid flow channel; and developing the substrate in the solvent to leave the light-sensitive substance which is in the solid state and remove the light-sensitive substance which is in the other state. The device may be a medical diagnostic device, and the substrate may be a paper substrate or may be a nitrocellulose substrate. 
IP Reference WO2015173543 
Protection Patent application published
Year Protection Granted 2015
Licensed No
Impact We will be using this patent as part of the basket of IP that will back up our imminent spin-out in healthcare diagnostics
 
Title FLUID FLOW DEVICE WITH FLOW CONTROL AND METHOD FOR MAKING THE SAME 
Description A method of making a fluid flow device comprises: providing a substrate of porous material (2) impregnated with a light-sensitive substance (5) in a first state and which is configured to change from the first state to a second state when exposed to light (3), the second state being a solid state that is resistant to a solvent and the first being removable with the solvent; the substrate having a fluid flow channel (7) defined therein, the channel having a depth; exposing a beam of light (3) onto an area of the substrate surface within the fluid flow channel to deliver energy to a volume of the substrate below the area to change the light-sensitive substance to the second state; during exposure, creating a partial barrier to flow of fluid along the channel by controlling the amount of energy delivered to the volume below at least part of the area to change the light-sensitive substance to the second state in a volume of the substrate within the fluid flow channel that has a depth less than the depth of the fluid flow channel; and developing the substrate in the solvent to leave the light-sensitive substance which is in the solid state and remove the light-sensitive substance which is in the other state. The device may be a medical diagnostic device, and the substrate may be a paper substrate or may be a nitrocellulose substrate. 
IP Reference US2017106367 
Protection Patent granted
Year Protection Granted 2017
Licensed No
Impact This patent is one of a family that supports the spinout of Highfield Diagnostics
 
Title Fluid flow device and method for making the same 
Description Techniques for making fluid flow devices are described. The technique is based on radiation-induced conversion of a radiation-sensitive substance from a first state to a second state. With adjustment of the radiation parameters such as power and scan speed we can control the depths of barriers that are formed within a substrate which can produce 3D flow paths. We have used this depth-variable patterning protocol for stacking and sealing of multilayer substrates, for assembly of backing layers for two-dimensional (2D) lateral flow devices and for fabrication of 3D devices. Since the 3D flow paths can be formed via a single laser-writing process by controlling the patterning parameters, this is a distinct improvement over other methods that require multiple complicated and repetitive assembly procedures. 
IP Reference US11185857 
Protection Patent application published
Year Protection Granted 2021
Licensed No
Impact This patent is one of a family that supports the spinout of Highfield Diagnostics
 
Title LATERAL FLOW DIAGNOSTIC DEVICE 
Description A lateral flow diagnostic device (4) comprises a substrate (5) of porous material; channel boundaries (11) defining a fluid flow channel (6) within the substrate (5); and a test site (10) disposed at a predetermined location along the fluid flow channel (6), the test site (10) comprising an analyte detection substance for detecting presence of a target analyte in fluid flowing along the fluid flow channel. The fluid flow channel (6) has a constricted portion with a smaller cross-sectional area than another portion of the fluid flow channel. The test site (10) is disposed within the constricted portion of the fluid flow channel. 
IP Reference US2021055295 
Protection Patent application published
Year Protection Granted 2021
Licensed No
Impact this patent is one of a family that supports the spinout of Highfield Diagnostics
 
Company Name Highfield Diagnostics ltd 
Description The company was registered in 2017, but since 2021 we have been trading, have received our first pre-seed investment and have secured access to University labs. We now have 3 employees and are building our pitch, capability and revenue to secure seed stage investment, likely by the end of Q2 2021. Highfield Diagnostics, HDx, is a spinout from the University of Southampton, focussed on developing rapid tests for a range of diseases and conditions using their patented technology for smart diagnostic sensing. The HDx mission is to bring to market a range of point-of-care, single use, 'here and now' rapid tests where patients can be diagnosed in a matter of minutes, for diseases such as TB and sepsis and monitored over the longer term for conditions such as dementia. Our philosophy is to keep the testing simple, local, available, reliable and cost-effective. During 2020/2021 the company focussed their attention on Covid-19 and developed a solution to implement rapid antigen-detection testing. Of critical importance, unlike other current rapid tests that look for the presence of antibodies produced in response to the virus, our test detected the presence of the virus itself. Antibodies will only be present in blood samples 7-14 days after infection, and there is a lack of consensus about the reliability or utility of such antibody testing for tracking, tracing and containing the pandemic. Our tests detected the presence of a virus-specific protein in swabs taken from the patient, and this is key to determining if the person is infected now, not some weeks ago. The test format is similar to that of the commonly available pregnancy test and the testing provides an answer within a short time of 10-15 minutes directly at the testing site (at the hospital, primary care, or patient's home): if the test shows a red line, the person is infected. The current testing regime, which also looks for the virus and is considered as the gold-standard, is the laboratory-based RT-PCR test. This multistep test requires first taking a swab at a designated test centre, its transport to a central testing facility, followed by a long testing procedure that might take more than one day. Furthermore, it is costly (£12-15 per test) and requires an expensive testing system (costing ~£20-30k), amounts well beyond the budgets in most developing nations, and skilled technical staff to perform the testing procedure. We trialled out tests using human samples and the results were very impressive, matching (and out-performing on occasions) existing commercial tests. We then decided to enter our test for the XPrize foundation, a charity that sponsors work in areas of clear humanitarian need. HDx made it through all the stages to the final, where we were one of five finalists, 1 in the UK and 4 in the US https: //www.xprize.org/prizes/covidtesting since 2021, when we received our pre-seed funding, we have been co-developing a range of other tests with the clear goal to bring our innovative solutions in multiplexed, high-sensitivity and semi-quantitative testing solutions to the market. : 
Year Established 2017 
Impact during the last year of 2021, the company has been trading and secured contracts from a large EU-based company to use our proprietary printing process to manufacture test devices to validate their ongoing products. This is generating ongoing revenues, and is likely to remain a useful source of income for the next year. Our COVID test that was developed and trialled in 2020/21 was featured on local TV. while we were not able to go into production, and have no regulation or validation of these tests (yet), the news item was valuable for promoting our ongoing R&D in the area of rapid diagnostics development. We entered our test for the XPrize foundation, a charity that sponsors work in areas of clear humanitarian need. HDx made it through all the stages to the final, where we were one of five finalists, 1 in the UK and 4 in the US. more info at https: //www.xprize.org/prizes/covidtesting
Website http://www.highfielddiagnostics.co.uk
 
Description CES tradeshow, Las Vegas, 2019 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact We presented at the CES tradeshow in Las Vegas, where we showcased the results and capabilities of our diagnostic platform. many interested parties, including a follow up US company who will be visiting us in March 2019.
Year(s) Of Engagement Activity 2019
URL http://highfielddiagnostics.co.uk/
 
Description Medica Tradeshow, Germany 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact We promoted the outputs from the research at an international tradeshow for Med Tech in Dusseldorf, Germany, where we showcased the results and new capabilities of our research, with the intention of commercialisation.
Year(s) Of Engagement Activity 2018
URL http://highfielddiagnostics.co.uk/
 
Description Medlab tradeshow, Dubai, 2019 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talking directly to a range of sponsors and commercial enterprises, advertising the capabilities of our research outputs.
Year(s) Of Engagement Activity 2019
URL http://highfielddiagnostics.co.uk/