Flexible Raman biosensing platform for low-cost health diagnostics
Lead Research Organisation:
University of Southampton
Department Name: Optoelectronics Research Centre (ORC)
Abstract
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.
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.
Publications
Coucheron DA
(2021)
Study of waveguide background at visible wavelengths for on-chip nanoscopy.
in Optics express
Ettabib M
(2024)
Waveguide-enhanced Raman spectroscopy
in Nature Reviews Methods Primers
Ettabib MA
(2021)
Waveguide Enhanced Raman Spectroscopy for Biosensing: A Review.
in ACS sensors
Ettabib MA
(2020)
Optimized design for grating-coupled waveguide-enhanced Raman spectroscopy.
in Optics express
Ettabib MA
(2023)
Grating-incoupled waveguide-enhanced Raman sensor.
in PloS one
Klokkou N
(2022)
Structured surface wetting of a PTFE flow-cell for terahertz spectroscopy of proteins
in Sensors and Actuators B: Chemical
Liu Z
(2024)
Multiframe-based non-local means denoising for Raman spectra
in Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy
Liu Z
(2023)
Accurate dipole radiation model for waveguide grating couplers
in Results in Physics
Liu Z
(2024)
Effect of scattering loss on optimization of waveguide enhanced Raman spectroscopy
in Journal of Lightwave Technology
Marti A
(2020)
Monitoring the efficient bioconjugation of small molecules
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. A new theoretical model for deep gratings in thin-film waveguides has been established and validated against experimental measurements, allowing for correction of designs for multilayer interference and thus improved efficiency of coupling of light into these waveguides, of significance in multiple applications. 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 due to its low toxicity and low volatility. The use of benzyl alcohol allows system performance to be verified against theoretical models in a safe and efficient manner. 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 set of new approaches for spectral post-processing 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 photonics 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. We have demonstrated that the unavoidable scattering loss can be mitigated by adding additional layers to the waveguide substrates. A new generation of chips capable of higher efficiencies and improved light throughput has been designed, fabricated and experimentally tested without compromising the cost or ease of use. Additionally, we have developed an accurate analytical theoretical model for waveguide grating couplers providing greater physical insight and serving as an alternative design tool to common, but time-consuming, numerical methods. A more elaborate grating coupler design capable of significantly increasing the coupling efficiencies has also been studied, showing the potential of driving the efficiency of these WERS chips even further. New insights on using quick and cheap post-processing fabrication steps to reduce chip losses and improve throughput have been gained and demonstrated to be highly effective. 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 researchers internationally. |
Sectors | Agriculture Food and Drink Digital/Communication/Information Technologies (including Software) Environment Healthcare Pharmaceuticals and Medical Biotechnology Security and Diplomacy |
Description | Growing interest in the emerging field of waveguide-enhanced Raman spectroscopy, and our contribution to it, has been demonstrated by the publication of two recent review articles (DOI10.3390/s22239058 and DOI10.1002/jrs.6628). In addition, the Investigators were invited to write a Nature Reviews Methods Primer based on their work in this field, and this was published in January 2024 (DOI10.1038/s43586-023-00281-4), underpinning the nucleation of a new research area. |
First Year Of Impact | 2022 |
Sector | Healthcare |
Impact Types | Societal |
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 | 06/2024 |
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 |
Title | Data supporting the publication "Accurate dipole radiation model for waveguide grating couplers". |
Description | This dataset supports the publication: Zhen Liu, Mohamed A. Ettabib, James S. Wilkinson, Michalis N. Zervas. (2023) "Accurate dipole radiation model for waveguide grating couplers" . The excel file contains all experimental data used for generating Fig.2 to Fig.4 : Fig. 2: CE and WGC parameters for different core indices, with core thickness selected to maximize the surface intensity; (a) CE on the left y-axis in blue and joint loss on the right y-axis (b) WGC etch depth (left axis) and grating period (right axis). Dots: numerical [from [2]), solid line: theoretical, dashed line: theoretical without joint loss. Fig. 3: Total CE and WGC parameters for different Si core thickness; (a) WGC etch depth (left axis-red) and grating period (right axis-blue), (b) CE (left axis C blue) and joint loss (right axis-red). Solid lines: theoretical result; dots: numerical results from [2]. Fig. 4: (a) Normalized attenuation coefficient _tot (left axis - solid lines), and joint loss (right axis - dashed lines) as a function of etch depth; (b) total CE as a function of grating depth, for different core thicknesses. Related projects: Engineering and Physical Sciences Research Council (EP/R011230/1). Dataset available under a CC BY 4.0 licence |
Type Of Material | Database/Collection of data |
Year Produced | 2023 |
Provided To Others? | Yes |
Impact | Data to support novel high-efficiency grating designs for coupling into thin-film waveguides. |
URL | https://eprints.soton.ac.uk/id/eprint/477182 |
Title | Dataset for the journal article 'Effect of scattering loss on optimization of waveguide enhanced Raman spectroscopy' |
Description | The excel file contains all experimental and theoretical data used for generating Fig.2 to Fig.8 The figures are as follows: Fig 2. Excitation and waveguide coupling for a dipole on the cladding-core interface; (a) Normalized squared electric field at the core-cladding surface. (b) Signal capture efficiency in different modes for horizontal dipole. (c) Signal capture efficiency in different modes for vertical dipole. Fig 3. The propagation loss coefficient is plotted as a function of core thickness and correlation length for (a) TE0 mode and (b) TM0 mode. The surface roughness RMS amplitude is 1nm. The red lines mark the thickness that maximizes the surface modal field. (c) loss coefficient for the first three modes as a function of thickness with correlation length fixed at 180nm. The dot-dash line corresponding to the right y-axis is calculated by the widely used Payne's model. (d) The scattering loss from the film on S_i substrate with a 'm oxidized layer in between. Fig 4. Measured loss coefficient and comparison with the theoretical value for different modes. The Theoretical value is calculated by assuming the RMS, , is 1nm. The measured experimental loss coefficient is normalized to the mean square of the RMS amplitude, ^2. Fig 5. FOM calculations for forward collection as a function of core thickness and waveguide length for TE_0 pumping and signal collected as (a) TE_0, (b) TE_1, (c) TE_2 and (d) TM_0, (e) TM_1, (f) TM_2. Fig 6. FOM calculations for forward collection as a function of core thickness and waveguide length for TM_0 pumping and signal collected as (a) TE_0, (b) TE_1, (c) TE_2 and (d) TM_0, (e) TM_1, (f) TM_2. Fig 7. Total forward-collection FOM for different pumping polarization and modes. The pumping is in (a) TE_0, (b) TE_1, (c) TE_2 and (d) TM_0, (e) TM_1, (f) TM_2 polarization, for forward collection. Fig 8. Total backward-collection FOM for different pumping polarization and modes. The pumping is in (a) TE_0, (b) TE_1, (c) TE_2 and (d) TM_0, (e) TM_1, (f) TM_2 polarization, for backward collection. |
Type Of Material | Database/Collection of data |
Year Produced | 2024 |
Provided To Others? | Yes |
Impact | Improved technique for the design of optimised waveguide-enhanced Raman chips |
URL | https://eprints.soton.ac.uk/id/eprint/486667 |
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 |