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

发生在身体深处的癌症很难检测和治疗，因为它们无法通过自然孔口进入。例如，卵巢癌有50%的5年生存率，而胰腺癌只有1%。这些癌症的早期发现可以让外科医生在它们扩散之前治疗或切除它们，从而大大提高生存率。然而，早期癌症与健康组织只有细微的不同，因此准确的检测需要非常高的分辨率成像来揭示这些细微的差异，远远高于MRI或X射线。使用光成像可以达到必要的分辨率，但需要相机非常接近被检查的组织，这对于胰腺等内脏器官来说是困难的。我建议通过开发新一代的内窥镜来克服这一局限性，这种内窥镜通过光纤拍摄图像：头发丝般细的玻璃片，可以装在微小的针头中，可以无害地插入身体深处。通过光纤成像需要使用全息术，这提供了比传统内窥镜更大的优势：全息术使最先进的光学显微镜技术能够在光纤尖端进行。这些技术不仅提供了前所未有的分辨率（100 nm），而且还测量了额外的光学信息，大大提高了他们看到组织微观结构和化学成分的细微变化的能力，从而表明早期癌症。然而，由于光纤在使用过程中会发生弯曲，使图像失真，因此这种附加功能尚未得到充分利用。我建议通过使用纳米技术在纤维的尖端制造一种特殊类型的光学元件，称为“元表面”来克服这种限制。超表面由微小的金属结构制成，小于光波长（<50 nm），产生的光学行为可以根据特定的应用进行定制：例如，我们可以创建仅聚焦红光的平面透镜（<100 nm厚）。当在光纤的尖端上制造时，所产生的“元纤维”将使先进的成像对现实的临床使用具有鲁棒性。将有两个关键的元纤维设计。第一种设计是在光纤的尖端上的超薄元表面透镜（“元透镜”），其将显著地提高若干最先进的显微镜技术的功率收集效率和深度分辨率。第二种设计是多层结构，包括夹在滤色器之间的元表面。在最近的出版物和专利中，我证明了原则上这种设计可以动态校正弯曲引起的失真，这是通过光纤实现广泛的尖端显微技术的关键。在此期间，我将建立这种光纤内窥镜的第一个完整的实验原型，从而克服临床转化的主要障碍。一旦制造出来，我将在两个关键的临床应用中测试这两种超纤维。第一种是检查卵巢是否有癌症的早期迹象，这需要通过狭窄的输卵管和穿过阴道壁的针细杆进入。这将使用称为多光子成像的成像技术在离体卵巢组织上进行测试。第二个应用是在胰腺囊肿内成像以识别早期胰腺癌。在这里，将使用一种称为定量相位成像的技术对切除的胰腺囊肿进行多层超纤维设计的试验。医疗设备和技术采用中心（CHEATA）和我们的项目合作伙伴（超薄医用内窥镜制造商）将加速临床翻译，最终提高这两种具有挑战性的癌症患者的生存率。从长远来看，我设想创建一个多功能的内窥镜平台：无论需要到达哪里，都有机会进行智能“光学活检”，在身体深处提供前所未有的视野。

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.