Flexible Raman biosensing platform for low-cost health diagnostics

Lead Research Organisation: University of Southampton
Department Name: Optoelectronics Research Centre (ORC)


Highly specific, sensitive sensors interfaced with portable, easy-to use, low-cost instruments are needed for rapid point-of-care infection diagnostics, and will lead to better targeted therapy, shorter time to treatment and reduced morbidity. In this project, we propose to realise a generic, flexible, compact sensing platform with high sensitivity and selectivity. The system will comprise a low-cost instrument employing cheap, disposable generic sensor chips that can be readily committed to specific analytes, from small molecules to proteins and DNA, by using conventional surface modification techniques. Paper-based fluidics will be used to deliver analytes straightforwardly from a drop to the sensor surface or, where required, fluidic microsystems may be easily integrated. The sensing system will be demonstrated with clinical samples from patients who have been exposed to controlled infection to whooping cough and for the analysis of priority pathogens such as ebola and plague. This proposal builds upon our recent work on waveguide-enhanced Raman spectroscopy (WERS) to realise a sensor chip which shows surface enhancements comparable to those of surface enhanced Raman spectroscopy (SERS) with improved application flexibility and manufacturability, and upon joint work between Dstl and Chemistry on surface enhanced Raman approaches to bioanalyte detection. The proposed biosensing platform will have widespread application at the point of care for patients, in the detection of infection and the diagnosis of disease, and for broader applications such as environmental monitoring and security, and will be flexibly configurable for specific settings and analytical challenges. The desktop instrument, employing plug-in disposable sensor chips with simple operation will be appropriate for use in the GP's surgery, the ward, or in remote communities.

Planned Impact

The creation of an innovative generic biochemical sensing system for application to healthcare diagnosis will provide significant benefits by allowing rapid in-situ decision making and optimised care for infectious diseases. The cheap, disposable sensing platform will be flexibly configurable for multiple assay types, including immunoassays and DNA-based approaches, allowing greater impact for low investment. This capability will be demonstrated for whooping cough and ebolavirus, for example, the first addressing a public health problem which is re-emerging due to reducing efficacy of vaccines and the second representing pathogens that pose the highest risk to national security and public health worldwide. The ability to diagnose these infections locally, rapidly and cheaply has clear societal benefits, but this sensing platform will be applicable to a much wider range of infectious diseases and in several other fields of application. The users and beneficiaries of this research would include primary care healthcare organisations such as hospitals and general practice clinics, government agencies such as Dstl protecting overseas MoD bases and responding to security threats, government departments such as the Home Office monitoring at airports and ports and for illicit drug detection (for example in roadside testing for "drug driving"), and environmental monitoring authorities for water pollution.

Economic benefits will accrue through new opportunities in a worldwide market for manufacturing industry in sensing, instrumentation and photonic devices to commercialise a high-yield platform technology which is cheap to manufacture. Our approach does not suffer from the "niche" market problems faced by many chemical sensing systems, as the analytes to be measured may be post-selected by reconfiguring the chip surface chemistry, without changing the chip itself or the instrument. A multi-use platform like this would have great disruptive potential to overcome current limitations of mobile health and environmental monitoring systems, in particular in low-resource environments where sophisticated laboratory tools are not available. The long term economic and societal impact of this platform is potentially significant worldwide, particularly in remote areas where healthcare needs are most immediate and challenging to address.
Description New materials and processes for biosensor chip fabrication as a platform for a wide range of biochemical assays have been generated and new highly efficient input grating coupler designs established, fabricated and experimentally verified to operate as designed. This has allowed for high-sensitivity Raman chips to be routinely and repeatably fabricated, and the grating excitation approach allows for simple replacement of disposable chips in the compact instrument for use by a non-specialised user. Waveguide Raman measurements of a wide range of bulk analytes have been made with high sensitivity and directly compared with both molecular simulations (DFT) and measurements using a conventional Raman microscope. Benzyl alcohol has been identified as providing an improved standard for sensor assessment and calibration, and enabling system performance to be verified against theoretical models. Two compact instruments for use in clinical settings which use these disposable chips have been designed and constructed and include newly specified miniature lasers and compact spectrometers, and software using a new approach for spectral denoising for improved sensitivity has been realised. One instrument has been transferred to users, who have found the interchanging of chips and using the instrument easy to do without specialist skills. Theoretical work has shown how Raman signals can be further enhanced in waveguides with unavoidable nanometre scale roughness which causes loss, by redesign of the layered structure of the optical waveguide. Waveguide enhanced Raman Spectrometer (WERS) measurements of self-assembled chemical monolayers of controlled orientation have been successful. Surface chemistries developed for surface assays on tantalum pentoxide waveguides for both viral and bacterial infections have been established and bacterial assays validated with University Hospital Southampton with templated SERS chips for transfer to WERS chips.
Exploitation Route These findings may be used by academia and industry to realise compact highly sensitive Raman sensor chips for chemical and biochemical analysis. The instrument and chips may be used by clinical researchers in studying point-of-care diagnostics and ultimately by clinicians in hospitals, GP surgeries and remote settings for rapid low-cost point-of-care diagnosis of infectious diseases. In particular, our approach to the system design, including chips and instruments, has ensured that mass-production is simple and that instrument operation is extremely easy for operators, with minimal instrument training. More broadly, the sensing platform can be applied to a much wider range of diseases and for environmental and safety monitoring, the findings on optical losses in waveguides with nanoscale roughness are expected to be widely applicable to integrated photonics, and the denoising algorithms are well-suited for a wide range of spectroscopies, including conventional Raman spectroscopy, SERS and absorption spectroscopy. The chip materials selected are proving to be candidates for the lowest noise operation, leading to improved spectra, and have been taken up by others.
Sectors Agriculture, Food and Drink,Digital/Communication/Information Technologies (including Software),Environment,Healthcare,Pharmaceuticals and Medical Biotechnology,Security and Diplomacy

Description Combining the Strengths of Mid-IR and Raman Spectroscopies on Single Chip for Rapid Bedside Biomarker Diagnostics
Amount £805,209 (GBP)
Funding ID EP/S03109X/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 12/2019 
End 06/2023
Description EPSRC ICase Award
Amount £103,200 (GBP)
Funding ID EPSRC ICase 18000060 
Organisation Defence Science & Technology Laboratory (DSTL) 
Sector Public
Country United Kingdom
Start 09/2018 
End 09/2022
Description MISSION (Mid- Infrared Silicon Photonic Sensors for Healthcare and Environmental Monitoring)
Amount £5,757,814 (GBP)
Funding ID EP/V047663/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 06/2021 
End 06/2026
Description Southampton AMR Clinical Research Laboratory
Amount £2,859,673 (GBP)
Funding ID NIHR200638 
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 08/2019 
End 03/2022
Description Collaboration on materials for waveguide-enhanced Raman spectroscopy 
Organisation University of Ghent
Country Belgium 
Sector Academic/University 
PI Contribution Samples were compared across several laboratories to evaluate the suitability of various waveguide materials or waveguide-enhanced Raman spectroscopy, showing our preferred material pf tantalum pentoxide to be optimum. We supplied waveguides to UGhent's specification for ready comparison.
Collaborator Contribution Samples were compared across several laboratories to evaluate the suitability of various waveguide materials or waveguide-enhanced Raman spectroscopy. UGhent made optical measurements to characterise devices.
Impact "High index contrast photonic platforms for on-chip Raman spectroscopy" Raza, Ali; Clemmen, Stéphane; Wuytens, Pieter; de Goede, Michiel; Tong, Amy S. K.; Le Thomas, Nicolas; Liu, Chengyu; Suntivich, Jin; Skirtach, Andre G.; Garcia-Blanco, Sonia M.; Blumenthal, Daniel J.; Wilkinson, James S.; Baets, Roel, Optics Express 27(16) 23067-23079 (2019).
Start Year 2018
Description Surface chemistry and protocols for viral infection detection 
Organisation Defence Science & Technology Laboratory (DSTL)
Country United Kingdom 
Sector Public 
PI Contribution Collaborating with partner to realise specific surface chemistry and protocols for detection of viral infection using WERS chips including PhD student focussed on this aspect.
Collaborator Contribution Expertise on biochemical detection, supervision, attending meetings, provision of samples
Impact Biochemistry, chemistry, optoelectronics.
Start Year 2018