Developing non-invasive and accurate diagnostics that are easily manufactured, robust and reusable will provide monitoring of high-risk individuals in any clinical or point-of-care environment, particularly in the developing world. Our research involves the development of medical and environmental diagnostics in three main areas: (i) optical sensors, (ii) smartphone applications and (iii) microfluidics.
Optical Sensors for Monitoring Metabolic Disorders
Our research consists of the development and optimisation of optical colorimetric sensors for applications in point-of-care diagnostics. The sensing devices consist of metal or dielectric nanostructures periodically organised in a 10 μm thick functionalised hydrogel film. Such hydrogels may be selected from poly(2-hydroxyethyl methacrylate), polyacrylamide or gelatin, and they can be functionalised to be sensitive to a wide range of analytes such as pH, glucose, metal ions and antibodies. These hydrogels can be transformed into colorimetric devices by integrating periodically organised nanoparticles or highly crosslinked density regions within the matrix. We record diffraction gratings in these functionalised polymers by nanosecond pulsed laser writing. The gratings can be formed by photochemistry, laser ablation or photopolymerisation in Denisyuk reflection mode using a pulsed laser (6 ns, 532 nm, 350 mJ). The formed grating has a periodicity of half the wavelength of the laser light used since the grating is an image of the periodicity of the standing wave created during laser exposure. The image and periodicity can be controlled by changing the object and exposure conditions. When the fabricated sensor is illuminated with a white-light source, the grating produces visible-light diffraction and displays a monochromatic colour. This diffraction is governed by Bragg's law:
λpeak = 2 n d sin(θ)
where λpeak is the wavelength of the first order diffracted light at the maximum intensity in vacuo, n is the effective index of refraction of the recording medium, d is the spacing between the two consecutive recorded nanoparticle (or highly crosslinked regions) layers (constant parameter), and θ is the Bragg angle which is determined by the recording geometry.
The mode of action of these sensors involves the modulation of Bragg diffraction gratings and localised refractive index changes. When a target analyte is introduced to the sensor in an aqueous solution, the target analyte binds to a receptor in the polymer matrix, and the binding process produces a change in Donnan osmotic pressure. This change in the osmotic pressure swells or shrinks the polymer matrix, which allows the diffraction grating to change periodicity and/or index of refraction, hence report on the concentration of the target analyte by fine changes in λpeak. Such sensors exhibit reversible wavelength shifts, and diffract the spectrum of narrow-band light over the wavelength range λpeak ≈ 300-1100 nm. λpeak measurements can be obtained by fully-quantitative readouts through spectrophotometry, and semi-quantitative results through visual readouts.
The optical sensor represents a simple and label-free analytical platform for the quantification of clinical and environmental analytes, while showing potential scalability. We anticipate that our sensing platform will lead to many novel applications from printable devices to low-cost colorimetric biosensors.
Diabetes Screening through Nanotechnology
Diabetes is one of the most challenging health problems of the 21st century. Today, 382 million people live with diabetes. This epidemic on the rise all over the world and countries are struggling to keep pace in controlling this disease. The number of people with the disease is estimated to reach 592 million in less than 25 years. In 2035, one in ten people will have diabetes. The number of people with diabetes is rapidly increasing in the Middle East, Western Pacific, sub-Saharan Africa and South-East Asia where economic development has transformed lifestyles. These rapid transitions are bringing high rates of obesity and diabetes; developing countries are facing a healthcare challenge coupled with inadequate resources to protect their population. The new estimates show an increasing trend towards younger people developing diabetes.
Diabetes has been known to be ‘a disease of the wealthy’. But studies showed that this was not the case. 80% of people with diabetes live in low- and middle- income countries, and the socially disadvantaged in any country are the most vulnerable to the disease. The financial burden of diabetes is taking up 548 billion dollars in health spending, which is 11% of the global healthcare expenditure. Yet, it is estimated that 175 million people are undiagnosed today. This is because there are few symptoms during the early years of type 2 diabetes, or those symptoms may not be recognised as being related to diabetes. Type 2 diabetes can go unnoticed and undiagnosed for years. In such cases, those affected are unaware of the long-term damage being caused by this disease. Population-based diabetes studies consistently show that 40% diagnosed people live in low income countries. According to International Diabetes Federation, in sub-Saharan Africa, where resources lack and governments may not prioritise screening for diabetes, this proportion is as high as 90% in some countries.
We can screen for diabetes using glucose meters and urine dipsticks. These technologies might look low cost, but considering that 1 billion people live on less than $1.25 a day, they are not affordable. For example, glucometers, a lancing device, lancets and tests costs up to $115 for testing 100 people in the rural village. On the other hand, a urine dipstick test, which costs about $0.5, have low sensitivity and often provide erroneous results due to subjective reading. If we develop diagnostic tools that are low cost, reusable, user friendly, non-invasive and reliable, we can help deprived communities. We design and develop medical diagnostics that intend to satisfy these criteria.
The principle of operation of these sensors is based on swelling and shrinking of the holographic films, which in turn diffracts light at different wavelengths. These wavelengths are colours that can be read by naked eye. In this case, the smart material is made out of a polymer and boronic acid derivative that can reversibly bind to glucose so that we can see the colour change in the presence or absence of glucose. These sensors can be tuned to diffract light in the entire visible spectrum. It is also possible to pattern these devices to give written messages.
We can use a single sensor for about 100 times by washing with water and it costs 20¢. We recently completed clinical trials of this sensor by testing urine samples of diabetic patients. It has comparable performance with the commercial tests while also showing higher cost effectiveness. These sensors can be read by eye or quantitatively using spectrometers. However, alternative solutions such as generic smartphone applications we developed in our research group can also be used to read sensors semi-quantitatively. Such applications offer connectivity for global diagnostic data management. Such technologies can make a difference for monitoring disease where early diagnosis and the treatment are needed the most.
Medical Smartphone Applications and Telemedicine
The high mobile phone penetration and rapidly growing telecommunications infrastructure in the world represents an unprecedented opportunity for reading and transferring point-of-care diagnostic data. Global mobile-cellular subscriptions have grown 70% over the last 5 years, reaching 7 billion as of 2014. Hence, exploiting the existing mobile phone infrastructure to monitor health conditions and the environment will accelerate the efforts toward connected and readily available diagnostics, as well as low-cost healthcare for existing and emerging diseases.
Our research involves development and testing of smartphone apps that allow quantification of colorimetric tests at both Android and iOS operating systems. The app transforms the smartphone into a reader to quantify commercial colorimetric tests with high accuracy and reproducibility in measuring pH, protein, and glucose. Our further efforts in this area include research in the regulations of mobile medical applications. These studies evaluate the impact on academia, industry and other key stakeholders, such as patients and clinicians.
The Regulation of Mobile Medical Applications
Mobile medical apps have the potential to revolutionise healthcare systems around the world. They will influence the healthcare systems globally – empowering patients and clinicians, and potentially reducing healthcare burden worldwide. Mobile medical apps are expanding rapidly and they hold a potential to transform the patient-healthcare provider relationship through saving time and reducing costs. Commercial examples include health management applications, bedside monitors, heart rate monitors and point-of-care diagnostics. However, the effectiveness of the regulatory agencies will be crucial in overseeing this process. In 2013, the U.S. Food and Drug Administration (FDA) released its guidelines on the regulations of mobile medical apps. Although strategies to regulate these mobile medical applications are clear, their effect on the quality of healthcare delivery and patient safety has not been investigated thoroughly. For example, they may malfunction or their unintended use may harm patients. As the public continues to embrace mobile apps for the management of their healthcare, the providers must act in accordance with the regulations to ensure patient safety. We assess the implications of the mobile medical applications on healthcare systems and evaluate their regulatory oversight from various perspectives: patients, clinicians, entrepreneurs, academics and researchers. We also work with the Cabinet Office of the United Kingdom to support policy making in healthcare.
Dipstick and lateral-flow formats have dominated rapid diagnostics over the last three decades. These formats gained popularity in the consumer markets due to their compactness, portability and facile interpretation without external instrumentation. However, lack of quantitation in measurements has challenged the demand of existing assay formats in consumer markets. Recently, paper-based microfluidics has emerged as a multiplexable point-of-care platform which might transcend the capabilities of existing assays in resource-limited settings. Paper-based microfluidics can enable fluid handling and quantitative analysis for potential applications in healthcare, veterinary medicine, environmental monitoring and food safety. Currently, in its early development stages, paper-based microfluidics is considered a low-cost, lightweight, and disposable technology. Our research focuses on (i) fabrication of paper-based microfluidic devices, (ii) functionalisation of microfluidic components to increase the capabilities and the performance, (iii) introduction of existing detection techniques to the paper platform and (iv) exploration of extracting quantitative readouts via handheld devices and camera phones. Additionally, we study challenges to scaling up, commercialisation and regulatory issues.
Contact Lens Sensors
Contact lenses as a minimally-invasive platform for diagnostics and drug delivery have emerged in recent years. Contact lens sensors have been developed for analysing the glucose composition of tears as a surrogate for blood glucose monitoring, and for the diagnosis of glaucoma by measuring intraocular pressure. However, the eye offers a wider diagnostic potential as a sensing site, and therefore contact lens sensors have the potential to improve the diagnosis and treatment of many diseases and conditions. With advances in polymer synthesis, electronics and micro/nanofabrication, contact lens sensors can be produced to quantify the concentrations of many biomolecules in ocular fluids. Non- or minimally-invasive contact lens sensors can be used directly in a clinical or point-of-care setting to monitor a disease state continuously. We develop new approaches for the fabrication, sensing, wireless powering, and readout mechanisms in contact lens sensors. We also explore the possibilities to integrate the contact lens sensors with wearable devices and smartphones.
Patent Protection and Commercialisation of Lab-on-a-Chip Devices
Microfluidic devices offer automation and high-throughput screening, and operate at low volumes of consumables. Although microfluidics has the potential to reduce turnaround times and costs for analytical devices, particularly in medical, veterinary, and environmental sciences, this enabling technology has had limited diffusion into consumer products. Their efficient commercialisation has implications for biomedical sciences, veterinary medicine, environmental monitoring and industrial applications. In particular, market diffusion of microfluidic laboratory and point-of-care diagnostic devices can contribute to the improvement of global health. In their commercialisation, consultancy and patent protection are essential elements that complement academic publishing. Additionally, the awareness of patent law can enable researchers to pursue patent protection efficiently. Our research is directed to the analysis of microfluidics market, identification of issues, and evaluation of commercialisation strategies. We also study patent law in the US, EU, Japan and internationally. Understanding of the patent law allows obtaining optimised, valid and valuable patents, while accelerating implementation to market route. Understanding of commercialisation strategies and patent law will benefit not only the inventors, industrial partners and investors but will also increase the economic growth and social impact of microfluidics.
Printable Holograms for Data Storage
We develop surface holograms that can be printed anywhere to store information, which allows personalised security, sensing and optical devices. We create 2D and 3D holograms made out of printed ink via nanosecond pulsed laser patterning. The printable holograms can be formed on a variety of surfaces, including transparent and opaque materials. This approach allows printing personalised holograms at low-cost. The printable holograms display visible-light Bragg diffraction and monochromatic colour corresponding to angle of view, and they diffract light in the entire visible spectrum. Surface holograms can be read and viewed under normal ambient light conditions or through the use of smartphones and other mobile devices. These surface holograms can be printed on a variety of material surfaces to produce holographic QR codes, logos, barcodes, personalised signatures and 3D images. For example, holographic QR codes can be used to identify counterfeit medicine, pharmaceuticals, biologics and other high-value products. The printable holograms represent a simple technology for the personalised printed of custom holograms and signatures in a scalable and facile way. We are now developing a prototype test suitable for a security feature on the packages of pharmaceuticals and biologics, including blister packs and vials. Security tests and integration with smartphones and other mobile devices algorithms are also in progress. We envision that this technology can be integrated in desktop printers for easy-to-fabricate holograms for applications in data storage and optical displays.
1. Yetisen, A.K., Naydenova, I., Vasconcellos, F.C, Blyth, J., Lowe,C.R. Holographic Sensors: Three-Dimensional Analyte-Sensitive Nanostructures and their Applications. Chemical Reviews. 114 (20), 10654-10696 (2014) link
* Featured on the front cover link
2. Yetisen, A.K, Montelongo, Y., Vasconcellos, F.C., Martinez-Hurtado, J.L., Neupane, S., Butt, H., Qasim, M.M., Blyth, J., Burling, K., Carmody, J.B., Evans, M., Wilkinson, T.D., Kubota, L.T., Monteiro, M.J., Lowe, C.R. Reusable, Robust, and Accurate Laser-Generated Photonic Nanosensor. Nano Letters, 14 (6), 3587-3593 (2014) link
* Sensors: Photonic sugar detector. Nature Photonics, 8 (8), 585 (2014) link
* This manuscript is thought as course material in the undergraduate curriculum in diagnostic design class, Innovations in International Health, Massachusetts Institute of Technology (MIT),
17. Yetisen, A.K., Montelongo, Y., Qasim, M.M., Butt, H., Wilkinson, T.D.,and Lowe, C.R. Nanocrystal Bragg Grating Sensor for Colorimetric Detection of Metal Ions (under review) (2014)
18. Kong, X.T., Khan, A.A., Kidambi, P.R., Deng, S., Yetisen, A.K., Dlubak, B., Hiralal, P., Montelongo, Y., Bowen, J., Xavier, S., Jiang, K., Amaratunga, G.A.J., Hofmann, S., Wilkinson, T.D., Dai, Q., Butt, H. Graphene based Ultra-Thin Flat Lenses (under review) (2014)
19. Yetisen, A.K., Holographic Sensors, Springer, ISBN 978-3-319-13583-0 (in press) (2015) link
20. Akram, M.S., Daly, R., Vasconcellos, F.C., Yetisen, A.K., Hutchings, I., Hall, E.A.H. Applications of Paper-Based Diagnostics. Lab-on-a-Chip Devices and Micro-Total Analysis Systems. Eds. Castillo-Leon, J., Svendsen, W. E. Springer. ISBN 978-3-319-08686-6 (2014) link
* This device was commercialised by Diagnostics Division of Hoffmann-La Roche
Wired Magazine: Low-cost 'smart' holograms can monitor diabetes, Gizmag: Smart holograms can test for and monitor diseases, Chemistry World: Cheap and colourful holographic sensors, El Pais: El futuro es holográfico, Extremetech: A new hydrogel uses holograms to warn you about your health, Science 2.0: Holographic Diagnostics, Med device: Holographic Diagnostics, Futuristech: Color changing holograms developed for portable medical tests from infections to diabetes, Co.exist: Colorful Nanotechnology Holograms Make Cheap Medical Testing In The Field, Impresive Magazine: Smart Holograms Monitor Health Conditions, University of Cambridge Research: Holographic Diagnostics, Business Weekly: 10p medtech sensor could lead to smartphone testNews Medical: , Electronics Weekly: Cambridge uses holograms on your smartphone to monitor diabetes, Genetic Engineering & Biotechnology news, Cambridge Enterprise: Holographic Diagnostics, ScienceDaily: Holographic Diagnostics in Medicine, PhysOrg: Holographic diagnostics, World Health: Holograms for Health, Liberty: Color-changing holograms may be used to monitor glucose levels, UPI: Colorful, smart holograms could be used to monitor health conditions, my science: Holographic Diagnostics, Medilink UK: Smart Holograms can Test for and Monitor Diseases, body1: Diseases Diagnosed by 'Smart' Holograms, eurekalert: Holographic diagnostics, Cambridge Network: Researchers develop holographic diagnostics, Product Design and Development: Responsive Holograms Change Color, Laboratory Equipment: Holograms Can Monitor Disease, tcetoday: Holographic sensors change colour, Technology.org: Holographic diagnostics, e! Science News: Holographic Diagnostics, Hispanic Business: Holographic diagnostics, Medical Design Technology: Holographic Diagnostics, Azonano: Responsive Holograms, My Biologica: Holographic diagnostics in medicine, Health Medicine Network: Holographic diagnostics, iMedicalApps: Researchers starting clinical trials of low cost holographic test that monitors diabetes, The Watchers: Researchers develop holograms that change colour, diabetes1: Diabetes Diagnosis by 'Smart' Holograms, CEB: Responsive holograms act as sensors for medical diagnostic applications
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Mobile Medical Applications
The Daily Beast: New Camera-Centric Smartphone App Puts Healthcare in Your Pocket, Yahoo news: Diagnostics On the Go, The Times of India: Cambridge University scientists develop diagnostic app, University of Cambridge Research News: Pocket diagnosis, Smartphone app to change the status quo in point-of-care diagnostics, Business Standard: Now, app that turns smartphone into portable medical diagnostic device, Phys.org: Pocket Diagnosis, my Science: Pocket Diagnosis, Colorimetrix test reader, USANews: Pocket Diagnosis, Medical Daily: ‘Mobile Healthcare’ Can Help Stop Spread Of Pandemics: New Phone App, ‘Colorimetrix,’ To Monitor Diabetes And Kidney Disease, Science Daily: Pocket diagnosis: App turns any smartphone into a portable medical diagnostic device, R&D Magazine: New app delivers pocket diagnosis, Public Health at Cambridge: Smartphone diagnostics, Qmed: Colorimetrix App Turns Smartphones into Lab Test Readers, Cambridge Network: New app enables pocket diagnosis, Wireless Design Magazine: Pocket Diagnosis, Hindustan Times, ANI News, Z News, ECN Magazine: Pocket Diagnosis, Fast Company: This App Turns Your Smartphone Into A Medical Diagnostic Device, Green Technology World: QMED -Colorimetrix App Turns Smartphones into Lab Test Readers, Fierce Mobile Healthcare: Smartphone app aims for faster, more accurate, body fluid testing, Tree Hugger: New app turns smartphone into portable medical diagnosis device, Lab Manager: Pocket Diagnosis, Ghana Health Nest: This new app turns any smartphone into a portable diagnostic device, Hispanic Business: Now, app that turns smartphone into portable medical diagnostic device, Science and Enterprise: Smartphone App for Point-of-Care Diagnostics in Development, Innovation Toronto: App turns a smartphone into a portable medical diagnostic device, Hispanic Business: Colorimetrix App Turns Smartphones into Lab Test Readers, Fierce Diagnostics: Mobile app could offer inexpensive Dx in developing world, Medical News Today: New app turns any smartphone into a portable medical diagnostic device, Press News: Pocket Diagnosis, Bio-Medicine: Pocket Diagnosis, The Outbreak: Colorimetrix: New App provides Pocket diagnosis, Eurekalert!: Pocket Diagnosis, Science Codex: Pocket diagnosis, Global Biodefence: Cambridge Researchers Develop Pocket Diagnosis App, TMC News: University of Cambridge - Pocket diagnosis, The Siasat Daily: Now, app that turns smartphone into portable medical diagnostic device, Smashits, Kurzweil: Fabrication of pH-Sensitive Holograms, Thisisreallyinteresting: Pocket Diagnosis, NDTV: Colorimetrix smartphone app to help diagnose diseases, The Health Site: Now a smartphone app which can diagnose diseases!, Business Standard: New smartphone app to diagnose diseases, TechMagnifier: Colorimetrix app for Smartphone reads Colorimetric Test Strips Accurately, Art of Healthy Living: Colorimetrix - the smartphone app for disease diagnosis, CSR Journal: New app turns smartphone into portable medical diagnosis device, Post: New smartphone app to diagnose diseases including HIV, Deccan Herald: New smartphone app to diagnose diseases, Electronics Bulletin: Pocket Diagnosis, medGadget: New App from University of Cambridge Accurately Reads Colorimetric Test Strips, Tech and Gadget News: Android Beta App ‘Colorimetrix’ May be the First Medical Tricorder, Wireless Design Magazine: New App Provides Pocket Medical Diagnosis, Lab Manager: Pocket Diagnosis, Clinical Innovation and Technology: New app aims to simplify colorimetric tests, , : Stickly ColourInternet Medicine: A DIY medical diagnosis app, SnapMD: Test for Kidney Disease On Your Smart-Phone, Idea Connection: Smartphone App Reads Colorimetric Test Strips
Patent Protection and Licensing in Microfluidics
GenomeWeb: Q&A: University of Cambridge Researchers on a Roadmap for Patenting Microfluidic Devices link
The Regulations of Mobile Medical Applications
Printable holograms offer security and data storage solutions link
Department of Chemical Engineering and Biotechnology
Biotechnology CET I - Lent Term 2014
Entrepreneurship - ETECH Projects - Lent Term 2014
Fellow,, Department of Medicine
Affiliate Member, Royal Society of Chemistry
Alumnus, Roche Continents
Member, Tau Beta Pi and Phi Kappa Phi
Yunuen Montelongo, Department of Engineering, University of Cambridge
Michael Monteiro, Australian Institute for Bioengineering & Nanotechnology, The University of Queensland, Australia
Izabela Naydenova, Dublin Institute of Technology, Ireland
Jeff Blyth, Department of Chemical Engineering and Biotechnology, University of Cambridge
Malik Qasim, Department of Engineering, University of Cambridge
Haider Butt, School of Mechanical Engineering, University of Birmingham
Tim Wilkinson, Department of Engineering, University of Cambridge
Lisa Volpatti, Department of Chemistry, University of Cambridge
J. Bryan Carmody, The Children's Hospital of the King's Daughters, Norfolk, VA, USA
Mark Evans, Institute of Metabolic Science, Addenbrooke's Hospital
Sankalpa Neupane, Institute of Metabolic Science, Addenbrooke's Hospital
Keith Burling, The Core Biochemical Assay Laboratory, NHS, Addenbrooke's Hospital
Ateeq Suria, XLab, Stanford University
Karl Gerhardt, Bioengineering, Rice University
Juan L. Martinez-Hurtado, Technical University of Munich, Germany
Lukas Chvatal, Institute of Scientific Instruments of the ASCR, Czech Republic
Pavel Zemanek, Institute of Scientific Instruments of the ASCR, Czech Republic
Silvia Vignolini, Department of Chemistry, University of Cambridge
Jeremy Baumberg, Cavendish Laboratory, University of Cambridge
Caterina Ducati, Department of Materials Science and Metallurgy, University of Cambridge
Ullrich Steiner, Cavendish Laboratory, University of Cambridge