Biophotonic Imaging

Lay description

Today the timely detection of pancreatic cancer prohibits adequate treatment. Currently, the life expectancy at diagnosis is currently less than five months; hence new strategies need to be developed and implemented. In Zee-Zoom-Zap, we develop a highly specific probe, which targets pancreatic cancer, optical imaging systems and catheters, deployed via endoscopes, powered by AI to detect the cancerous lesions as early as stage 1a. In other words, lesions are detected before spreading. Moreover, the probe can be activated for therapeutic purposes (‘zap’), essentially targeting and effectively eliminating the cancerous cells without damaging the surrounding tissue. Once fully developed, the concept can provide a huge improvement in the survival rate from pancreatic cancer. And the concept can be extended to other types of cancers.

Detailed description

We develop a disruptive concept overcoming the fundamental limit of concurrently achieving specific, high-resolution imaging at depth in tissue. The Zee-Zoom-Zap concept will serve as a one-stop-shop by combining early detection of cancer through small lumens (‘zee’), non-invasive “biopsies” (‘zoom’), and local therapy (‘zap’).

The main challenge in realising early, effective detection of cancer is to overcome the fundamental limitation in concurrently achieving specific, high-resolution imaging at the cellular scale at depth in tissue. A radical departure from conventional optical biopsy concepts, our project employs a holistic approach to optical theranostics, with each research pillar constructed as an integral part of a unified concept. Four research fields, represented by four collaborating PIs, form its basis: 

• cancer-specific phototheranostic probes, 
• monolithically 3D-printed micro-optical catheters, 
• complementary optical imaging methods for unprecedented range and sensitivity, lasers at wavelengths for both imaging and therapy, and 
• novel physics-enhanced deep learning AI models for imaging, detection, decision support, and treatment guidance.

In Zee-Zoom-Zap, we target pancreatic cancer, based on an unmet clinical need. For decades, there has been little improvement in detecting and treating this cancer form: the life expectancy at diagnosis is currently less than five months. The long-term perspective for the Zee-Zoom-Zap is translation into the clinical setting as part of a combined population - and imaging-based screening workflow for early detection of pancreatic cancer and in situ treatment. The concept will be applicable to other cancers reachable through small lumens. The societal and economic impact, in terms of return on investment and increased survival rates, are envisaged to be significant. Furthermore, the project’s innovations, interdisciplinary character, and synergy are expected to lead to new ideas being conceived and the emergence and growth of new fields of research. The development of the Zee-Zoom-Zap concept is only the first step. 

ERC-SyG: 2026-2032

Read more here (ORBIT)

Lay project description
Optical imaging can help doctors examine tissue in a way like conventional biopsies, but without needing to remove tissue from the body. Optical methods capture detailed and accurate images, though they cannot see very deep into tissue. Optical coherence tomography (OCT) is well established, and it captures detailed, real-time images of tissues without needing any labels or dyes. Still, OCT has a limitation: it cannot see deep into tissue. To overcome this, we propose a new technique called Spatial Offset OCT (SO-OCT). Our method allows us to see deeper into tissues — 5 mm or even more; five times deeper than what was previously possible. And it provides new information to help doctors distinguish between different types of tissues. Our goal is to show how SO-OCT can provide high-quality images deep inside living tissue. The target is cancer surgery, where doctors need to get detailed images during surgery before cutting tissue, allowing for better decision-making in real time.

Detailed description
Optical imaging offers opportunity for realising so-called optical biopsy providing equivalent information obtained via conventional excisional biopsy, except the optical biopsy can be performed in vivo. Optical imaging techniques offer sensitivity, specificity, and spatial resolution unparalleled by any other modality. However, imaging depth penetration is limited.

Optical coherence tomography (OCT) is well established in achieving label-free high-resolution volumetric morphology in vivo and in real time. We propose a disruptive concept overcoming the barrier of achieving high-resolution imaging at depth in tissue. By introducing so-called spatial offset OCT (SO-OCT), the depth penetration barrier can be overcome. Moreover, by optimising the detector integrating time, imaging penetration can be increased five-fold. For example, it implies OCT imaging depth is extended from 1mm to 5mm or more in tissue, ultimately depending on tissue properties. 

The project aims to first demonstrate the depth penetration advantage, achieving label-free high-resolution, volumetric morphological information in vivo. Our aim is to realise a prototype system. The targeted clinical application is image-guided cancer surgery. It requires high-resolution imaging, without excising tissue, for real-time assessment.

Read more here: (ORBIT)

 

Lay description
Oral cancer is a significant healthcare burden with an estimated 62,000 new cases and 24,000 deaths annually in Europe alone. The main treatment is surgical removal, but small, isolated tumors can develop away from the main tumor site and can be missed during surgery. Incomplete removal of the tumor can have dire consequences for patients due to high risk of recurrence; on the other hand, surgeons want to remove as little tissue as possible to preserve the patient’s ability to eat and speak normally. Surgeons urgently need better guidance to improve the precision of these surgeries. In this project we aim to develop a groundbreaking new imaging platform which uses light to map out tumor margins with very high precision over a large depth range. Our platform aims to triple the imaging depth that can be achieved using existing methods. The result will be a new paradigm in image guided cancer surgery that will significantly improve the long-term quality of life for oral cancer patients.

Project description
Our overall aim is to investigate a new paradigm for image-guided cancer surgery in the oral cavity.
Cancer detection and tumor margin mapping in the oral cavity faces unique challenges in terms of accessing the tissue of interest, managing patient movement, and imaging sufficiently deep in the tissue to map out the margins with high spatial resolution and specificity. We aim to overcome these challenges using a new imaging paradigm based on a dual frequency comb light source and coherent optical receiver techniques combined with a breakthrough new imaging modality, spatial offset optical coherence tomography (SO-OCT). Through our synergistic approach, we aim to image >5mm deep in tissue with sub-cellular resolution, providing a 3-fold increase in imaging depth compared with existing methods and providing improved contrast between tumor and healthy tissue at depth. Additionally, our imaging platform will achieve at least a 10-fold increase in imaging speed compared with the fastest existing OCT systems, thereby overcoming another fundamental bottleneck. We will demonstrate the opportunities for future development of the platform by imaging ex vivo samples from human oral cancer patients. This platform will be unique for its ability to address all outstanding challenges for image guided cancer surgery in the oral cavity. This project requires a close collaboration between Technical University of Denmark, University College London, UK, and Rigshospitalet, Copenhagen (DK).

Read more here (ORBIT)

Lay project description
Diabetic peripheral neuropathy (DPN) is a serious complication affecting up to half the population with diabetes. Currently, there is no available treatment, and the current screening methods are either unspecific, insensitive or require invasive procedures. The present study aims to unite researchers from basic research from three Danish Universities with clinicians from three Steno Diabetes centres, to develop and clinically validate a novel method for objective, non-invasive assessment of small nerve fibres in the skin, with the overarching aim of providing a future method for early assessment of DPN.

The optical imaging method deployed in this multi-center study is optical coherence tomography, and we use it to image changes in the skin under activation by different stimuli and thereby assess the function of small peripheral nerves.

Project description
This project aims to develop new optical methods to non-invasively assess nerve and microvascular damage in the skin and thereby meet an unmet need for an easy, quick, and painless method of diagnosing these damages in people with diabetes.

Diabetic nerve damage (neuropathy) and microvascular dysfunction (microangiopathy) are severe and prevalent complications to diabetes. Millions of people worldwide suffer from the diabetic neuropathy with substantial individual and socioeconomic burdens. It is estimated that 10-15% of all persons with diabetes have peripheral neuropathy in their feet at the time of diabetes diagnosis and up to 50% of people with diabetes have the complication after 10 years of disease. Approximately 8-20% of people with peripheral neuropathy suffer from painful neuropathy. The complications are often diagnosed in late stages where damages are irreversible due to a lack of easy-to-use and objective methods of accessing early nerve and microvascular damages.

Presently, neuropathy is assessed by subjective and crude measuring modalities, which do not allow for assessment of early detrimental changes in the nerves. Such changes are often seen in small nerves fibres in the skin, only accessible for investigation by skin punch biopsies.

The optical skin biopsy study is a multi-disciplinary collaborative project bringing basic and clinical researchers together to develop new optical methods of neuropathy assessment. The method developed will be a combination of existing modalities and will be tested in healthy controls and in people with diabetes with varying degrees of neuropathy.

The project will deliver results on optical methods for combined assessment of diabetic neuropathy and angiopathy. The project will present a working combination of existing devices which in the future could be used for easy screening of diabetic neuropathy in out-patient diabetes clinics.

Read more here: (ORBIT)

Lay description
Optical imaging is indispensable in advancing neurological disease diagnostics as it can obtain insights of fast neurological processes in a large network of living brains with cellular resolution. The limited penetration depth of optical imaging in brain tissue can be surpassed using nonlinear imaging techniques. Nevertheless, current state-of-the-art nonlinear imaging techniques fall short in temporally resolving highly dynamic neuronal signalling owing to the lack of imaging speed. We propose a novel ultrafast endomicroscopy technique that would be a game changer for neuroscience: integrated optical phased array-based multi-photon lightsheet fluorescence microscopy. When fully developed, it will improve the imaging speed of living brains by more than two to three orders of magnitude. It has the promising potential to revolutionize current neurological studies and diagnostic methodology.

Project description
Neuroscience has been revolutionized by optical imaging in living tissue, which enables detection of neuronal morphology and activity in subcellular resolution in real-time with minimal invasion. However, the challenges reside on a substantial compromise of imaging in high speed, large scale, and high resolution. This lays a fundamental obstacle for neuroscientists to obtain mechanistic insights of fast neurological processes in a large network.

To overcome the challenges, we combine expertise in electronics, photonics, and neuroscience in a interdisciplinary manner, and we propose a novel microscopy technique: Integrated optical phased array-based multi-photon lightsheet fluorescence microscopy (OPA-MP-LSFM). Our new approach is innovative because:

(1) Multiphoton lightsheet excitation of brain tissue through multimode fiber and compressive sensing detection can be 100-1000 times faster than conventional multiphoton point scanning microscope (MPM);

(2) Replacing current wavefront shaping techniques with a novel integrated silicon-nitride optical phased array (OPA) has the potential to improve the imaging speed of lightsheet microscopy by more than two orders of magnitude.

In combination with compressive sensing-based wavefront monitoring, all speed bottlenecks for multiphoton lightsheet lensless microscopy will be removed. We will verify and validate the application of OPA-MP-LSFM in neuroscience through three imaging steps: immunostained and cleared whole brain samples, in vitro living brain slices, in vivo living mouse brains.

When fully implemented, the technology will lead to the next-generation ultrafast volumetric lensless nonlinear microscopy of living specimens with subcellular resolution. It has the promising potential to revolutionize current biological studies and diagnostic methodology.

Read more here (ORBIT)