Meta-fibres: Optical fibres with meta-surfaces for advanced optical biopsy through needles

Cancers that occur deep within the body are difficult to detect and treat due to their inaccessibility via natural orifices. For example, ovarian cancer has a 50% 5-year survival rate while for pancreatic cancer this is just 1%. Early detection of these cancers could allow surgeons to treat or remove them before they spread, dramatically improving survival. However, early cancer is only subtly different to healthy tissue so accurate detection requires very high resolution imaging to reveal these subtle differences, much higher than MRI or X-rays. Imaging using light can achieve the necessary resolution but requires the camera to be very close to the tissue being examined, which is difficult for internal organs like the pancreas. I propose to overcome this limitation by developing a new generation of endoscopes that take images through optical fibres: hair-thin pieces of glass that fit inside tiny needles, which can be harmlessly inserted deep into the body. Imaging through optical fibres requires using holography, which provides a further advantage over conventional endoscopy: holography enables state-of-the-art optical microscopy techniques to be performed at the tip of the fibre. These techniques not only provide unprecedented resolution (100nm) but also measure additional optical information that dramatically improves their ability to see subtle changes in tissue microstructure and chemical composition indicating early cancer. However, this additional functionality has not been fully exploited because optical fibres bend during use, distorting images. I propose to overcome this limitation by using nanotechnology to fabricate a special type of optical element, called a 'meta-surfaces', on the tips of fibres. Meta-surfaces are made from tiny metal structures, smaller than the wavelength of light (<50nm), which produce optical behaviours that can be tailored to a particular application: for example, we can create flat lenses (<100nm thick) that only focus red light. When fabricated on the tips of optical fibres, the resulting 'meta-fibres' will enable advanced imaging robust to realistic clinical use. There will be two key meta-fibre designs. The first design is an ultra-thin meta-surface lens (a 'meta-lens') on the tip of the fibre that will dramatically improve power-collection efficiency and depth resolution for several state-of-the-art microscopy techniques. The second design is a multilayered structure comprising meta-surfaces sandwiched between colour filters. In a recent publication and patent I demonstrated that in principle this design can enable dynamic correction of bending-induced distortions, which is they key to enabling a wide range of cutting-edge microscopy techniques to be implemented through optical fibre. During this fellowship I will build the first full experimental prototype of this optical fibre endoscope, thus overcoming a major hurdle to clinical translation. Once fabricated, I will test the two meta-fibres in two key clinical applications. The first is examining the ovaries for early signs of cancer, which requires access via the narrow fallopian tubes and a needle-thin rod traversing the vaginal wall. This will be tested using an imaging technique called multi-photon imaging on ex vivo ovarian tissue. The second application is imaging inside pancreatic cysts to identify early pancreatic cancer. Here, multi-layer meta-fibre designs will be trialled using a technique called quantitative phase imaging on excised pancreatic cysts. Clinical translation will be accelerated by the Centre for Healthcare Equipment and Technology Adoption (CHEATA) and our project partner, a manufacturer of ultra-thin medical endoscopes, ultimately improving patient survival for these two challenging cancers. Longer term, I envision creating a versatile endoscopy platform: wherever a need can reach, there will be an opportunity to perform a smart 'optical biopsy', offering unprecedented vision deep in the body.

Ovarian cancer causes 4000 deaths in the UK each year while pancreatic cancer causes nearly 9000. Improved early detection of these cancers could lead to dramatic reductions in mortality. The ultra-thin optical fibre endoscopes I will develop in this fellowship will enable easier access for imaging the ovaries and pancreas and, when combined with optical metasurfaces, will enable improved imaging contrast for detecting cancer earlier, thus enabling earlier intervention and therefore improving prognosis and ultimately survival rates for these cancers.

Stakeholders standing to benefit from this research include:
- Cancer patients, through: earlier diagnosis resulting in less invasive and fewer interventions, improved outcomes (reduced mortality); improved quality of life (fewer invasive interventions); reduced anxiety (better informed at point of test). Impact time-frame: 10-15 years.
- Clinicians (gynaecologists, hepatologists and endoscopists), through: better imaging contrast that improves interpretation; ability to perform multi-modality imaging in inaccessible areas of the body (e.g. brain, kidney, liver, bone); improved clinical workflows such as biopsy and treatment in a single session or real-time decisions during laparoscopic procedures; and improvements in patient management.
- Endoscope manufacturers: initially smaller companies involved as project partners and then in the medium to long term major international manufacturers (impact time-frame: 10 years). Manufacturers will benefit from the IP we generate by being able to create endoscopes that are thinner, can access more areas of the body, and offer improved contrast for disease. The new technologies involved, including optical metasurfaces, advanced image processing techniques, machine learning algorithms and visualisation, will create new highly-skilled jobs in the endoscopy industry.
- Industrial inspection industry: ultra-thin endoscopes also have many other potential commercial applications as borescopes for industrial inspection because they are suitable for very confined spaces, are robust against harsh chemicals and can perform advanced imaging modalities enabling, for example, strain mapping and quantification of chemical reactants. Impact time-frame: 5 years.
- Fundamental biological research: advanced microscopy techniques are enabling some of the key breakthroughs in biology (e.g. super-resolution microscopy), but cannot penetrate deep inside 3D samples which represent much more realistic biological models than conventional 2D cell cultures. Advanced microscopy using ultra-thin fibres could be used to see inside 3D structures such as lab-grown organoids to enable new perspectives into biological processes and applications such as testing how new drugs affect tissue. Achieved at Nottingham, this would help maintain the UK's place as a world leader in biomedical research. Impact time-frame 5 years.
- Public service providers, primarily the NHS, through: cost reductions via early minimally-invasive treatment of cancer (compared to costly chemotherapy/radiotherapy at later stages), better and faster triage of patients for more efficient clinical workflow, improved patient survival. The fabricated meta-fibres should be highly robust so could also reduce service costs.