Consortium

Politecnico di Milano is an excellent scientific-technological university for architecture, design and engineering. It is one of the most prestigious universities in the world, ranked 17th for Engineering, 9th for Architecture and 5th for Design on a global scale, and 1st in Italy in all the three aforementioned disciplines, according to the QS World University ranking. It has always focused on the quality and innovation of teaching and research, developing a fruitful relationship with the economic and productive reality through experimental research and technology transfer.

Politecnico di Milano is the first Italian university for projects funded by the European Commission under the 7th Framework Program for research and innovation with 281 projects and under Horizon2020. It boasts 272 Horizon 2020 projects (for over 118 MLN € of funding), and numerous other European, national, and regional projects. It has also delivered excellent performances related to technology transfer with 52 active spin-offs and 1.610 patents.

The Physics Department comprises 50 faculty members, 15 technical and administrative staff people, 80 PhD students and a number of PostDocs. The research activities of the Department are mainly experimental and focused on the two broad areas of Photonics and Nanotechnologies. The Physics Department has a long history and tradition in laser science and hosts more than 10 independent optics/photonics laboratories, mainly dedicated to ultrafast, nonlinear and biomedical optics. The nonlinear optics and spectroscopy group focuses on: (i) developing state-of-the-art femtosecond laser sources with pulse duration approaching the single optical cycle and broad spectral tunability; (ii) applying such pulses to time-resolved spectroscopy and microscopy with extreme time resolution.

In the implementation of the CRIMSON, POLIMI will be supported in management, administrative, and dissemination and exploitation tasks by its university foundation, Fondazione Politecnico di Milano (FPM). FPM was founded in 2003 through a joint effort between POLIMI, major municipality and regional institutions, and important corporations, to support the university’s research projects and contribute to innovating and developing the economic, productive and administrative environment. FPM gained an extensive experience in participation to research projects also with deep involvement of industry.

Role in the project

POLIMI will have a central role in the CRIMSON project. It will be not only the general coordinator (leader of WP6 focused on project management), but also the main responsible for several core activities. In particular, POLIMI will guide the development of one of the three main approaches in broadband CRS microscopy, namely SRS based on a multi-channel lock-in amplifier system, enabling high-speed detection of the vibrational spectrum in parallel over many Raman bands in the fingerprint region, up to 128 (WP1, Task 1.2). Furthermore, in WP4 POLIMI will lead Task T4.1, dealing with the initial clinical specifications required to design the prototypes of WP1, and Task 4.2, focused on the determination of the optimal working conditions to avoid cell and tissue photodamage due to laser irradiation.

POLIMI will also be a partner in most of the other Tasks. In particular, POLIMI will be in close contact with INT for the study of senescence in thyroid cancer in WP4 for the validation of the technique.

The Leibniz Institute of Photonic Technology (IPHT) is an interdisciplinary research facility based in Jena, Germany, researching the scientific basics of photonic processes and systems of the highest sensitivity, efficiency, and resolution. In accordance with its mission “Photonics for Life”, IPHT develops customized solutions to issues in the life and environmental sciences and medicine.

Following IPHT’s guiding principle “From ideas to instruments” research results are implemented in processes, instrumental designs, and occasionally even into laboratory prototypes to sustainably contribute to the needs of patients and consumers. The impact of the aging society and the defence of pandemics are the focus of the Leibniz research network “Medical Engineering: Diagnosis, Monitoring and Therapy.” This network was initiated by IPHT together with sixteen institutes of the Leibniz Association. Since 2014, IPHT holds the presidency within this network. Innovative and gentle methods shall help to detect diseases early, to examine the effect of therapies narrowly and match them better to the individual patient. IPHT will mainly contribute to the research and development of point-of-care rapid tests (POC) and medical imaging.

IPHT coordinates the new Leibniz Research Centre of Photonics in Infection Research (LPI) in Jena, which will be funded by the Federal Government. Technology developers, physicians and medical technology manufacturers bring light-based technologies for better diagnostics and therapy of infections from the idea to the application in the clinic. The Ministry certifies by the National Roadmap process that the research infrastructure LPI, which is unique in Europe, contributes to solving socially relevant issues. 150 million Euros were applied for the foundation of the LPI. The LPI bundles the expertise available in Jena in the fields of optics and photonics as well as infection research. This approach is unique and excellently suited for the early diagnosis of infectious diseases and the timely identification of suitable therapeutic responses – especially for multi-resistant pathogens.
The new research centre will be open to top national and international researchers and industrial users. This will lead to new diagnostic approaches and targeted therapeutic methods that will be transferred directly into application and industrial production. By focusing on questions of clinical validation and certification from the outset, the LPI can close the gaps in the implementation of research results that still exist in Germany and drastically shorten the time to market.
As coordinator of the recently expired COST Action BM1401 Raman4clinics – Raman based applications for clinical diagnostics, IPHT has pooled European expertise to step forward in the field of novel, label-free and rapid technologies based on a wide variety of Raman spectroscopies for the clinical diagnostics of body fluids, bacteria, cells and tissues. All participating research group were united in pursuing the goal of giving a major impetus in this vibrant field of research by aligning it to clinical requirements and application aspects (the unmet medical need) by means of COST as the best mechanism to progress the state of- the-art.

Role in the project

Development of a hyperspectral broadband CARS approach
Comparison of broadband CARS and SRS techniques in terms of performance (sensitivity, robustness, speed)
Development of artificial intelligence aided datapipelines (e.g. phase retrieval approaches, machine and deep learning) for hyperspectral CRI data modelling in the fingerprint region
Cell and tissue imaging with spontaneous Raman and hyperspectral broadband CARS in the fingerprint to unravel molecular details concerning cellular interaction in terms of understanding diseases or disease treatment (e.g. immune oncology)

IF-CNRS is a joint research unit (UMR7249) between CNRS, Aix-Marseille University and Ecole Centrale Marseille. IF currently hosts more than 150 researchers organised in 11 research groups equipped with state-of-the-art research infrastructure for nanofabrication, biology, imaging and engineering. The Institute is active member of the Institut Carnot network committed to develop industrial applications of research results. Institut Fresnel is also part of competitiveness cluster OPTITEC. With a community of about 200 members, including 125 companies, the OPTITEC Competitiveness Cluster federates the stakeholders in the photonics sector in the southeast of France. Bringing together highly innovative SMEs, major photonics-integrating industrial groups and leading academic partners, the Cluster has generated a strong dynamic of joint R&D projects and the development of new services and innovative products.

IF-Institut Fresnel is also a core laboratory of the large scale national imaging facilities France Bio Imaging and France Life imaging and have access to a broad variety of optical and electron imaging modalities across France through these networks.

Role in the project

IF-CNRS will be involved in the CRIMSON project as a key technology developer. Two novel technologies will be developed, the first one will be fast hyperspectral stimulated Raman scattering that enables to collect rapidly a molecular vibrational spectrum by means of a fast acousto-optics delay line (WP1 T1.3). The other key technology developed by IF CNRS will be the coherent Raman endoscope developed in WP2, T2.3, in close collaboration with the LIGHTCORE that will bring the innovations to the market. This unique flexible imaging probe will allow coherent Raman imaging in living tissues and will be a core technology for WP3 (AI-based modelling of biomedical CRS and Raman data) and WP4 (biomedical applications).

THE NATIONAL TUMOR INSTITUTE OF MILAN (Istituto Nazionale dei Tumori, INT), Foundation and government-designated centre for treatment and research (IRCCS), is a leading cancer center in Italy pursuing mainly clinical and translational research, exploring and developing the fields of biomedicine and public health, in order to deliver high-quality healthcare services. INT has recently been designated a “Comprehensive Cancer Centre” by the Organization of European Cancer Institute (OECI), in recognition of its excellence both in patient care and the development of new treatments. Starting from relevant clinical questions, translational research leads the laboratory results to the patient’s needs and, in the opposite direction, reports the interventions results to the preclinical research. This line focuses on the interactions between tumor, host (microenvironment) and environment, on the application of technological innovation (clinical trial) and not (diagnostics, imaging, innovative intervention).

Since 1997, INT has collaborated with the Open University (Milton Keynes, UK) to offer a PhD Program for young graduates in scientific disciplines. INT is a formal partner of the Università Statale degli Studi di Milano and hosts several university chairs. Since 2011, INT has been part of 14 EU-funded projects.

Role in the project

The team will focus its efforts especially in the context of WP4, where INT will be responsible for applying CRS microscopy and endoscopy to the case study related to senescence in thyroid cancer. In particular, INT will perform the following activities:
Presentation of the functional alterations in therapy-induced senescent cells resulting from abnormalities in morphology, mass, and the functions of their organelles, such as mitochondria, lysosomes, endoplasmic reticulum (ER), nucleus, etc.
Identification of CRS-spectral features corresponding to senescence-associated metabolic changes.
Support in the CRS-based classification of senescence cells (WP3).
Supporting means to identify senescence-associated metabolic changes by CRS imaging in screening of senescent phenotypes in clinically relevant contexts.

The “Institut National de la Santé Et de la Recherche Médicale” (INSERM) is the French National Institute of Health and Medical Research. INSERM is the only public research organization in France entirely dedicated to human health. Its objective is to promote the health of all by advancing knowledge about life and disease, treatment innovation, and public health research. It brings together 15,000 researchers, engineers, technicians, and administrative staff.
In particular, the “Centre de Recherche des Cordeliers” (CRC) is a research center of excellence located in the center of Paris and administrated by INSERM. CRC develops fundamental, translational and clinical research in the field of biology and health. CRC’s research projects are multidisciplinary, mainly in the fields of oncology, immunology, the study of metabolism and the major physiological functions of the body.

Within CRC, the Kroemer lab studies the molecular details of cellular stress pathways, both inside them (via apoptosis, autophagy, senescence, necroptosis etc.) and outside them (via the release of metabolites and macromolecules, the activation of inflammatory/immune or neuroendocrine pathways etc.). The goal is to understand the pathophysiology of aging and aging-related morbidities, placing special emphasis on cancer and its treatment with chemotherapy or immunotherapy. The lab attempts to achieve these goals by using metabolomics and cell biological high-throughput technology within a continuum between fundamental, pharmacological translational and clinical research.

Role in the project

The Kroemer lab will provide a disease-relevant model as a challenge to CRS microscopy.
The key interest of the Kroemer laboratory is the role of metabolism in inflammation and disease. We recently identified a pharmacological target (ACBP/DBI) whose antibody-mediated neutralization or inducible knockout has pro-autophagic, anorexigenic (appetite-inhibitory) and anti-obesity effects, reducing high-fat diet-induced hepatosteatosis.
Non-alcoholic stepatohepatitis (NASH) is a frequent condition that often advances towards liver cirrhosis and hepatocarcinogenesis, calling for the development of novel therapeutic strategies. We will study several models of NASH to define the effects of ACBP/DBI neutralization with respect to autophagy induction, lipophagy, microsteatosis and macrosteatosis, using an orthogonal approach that involves cultured hepatocytes (HepG2) and multiple in vivo mouse models of NASH (high-fat/high-fructose diet, methionine-choline deficiency, genetically NASH-prone Ob/Ob and Foz/Foz mice).
We will employ a series of complementary technologies beyond CRS microscopy, for which the challenge will be to (co)localize lipid droplets, mitochondria, autophagosomes and lysosomes in living cells, in vitro (in cultured hepatocytes and organoids), ex vivo (from freshly explanted mouse livers) and on archival tissue (from necropsies).

These technologies involve genetically modified cell lines or mice expressing a fluorescent biosensor (in which autophagosomes recruit the transgenic biosensor GFP-LC3). We will use conventional and confocal fluorescence microscopy of labelled cells to visualize lipid droplets and different organelles, subcellular fractionation techniques to accurately localize lipids and other metabolites in different compartments, as well as mass spectrometric metabolomics/lipidomics to investigate the impact of ACBP/DBI on NASH.
This orthogonal approach (i.e. the comparison of the results obtained by CRS microscopy with those obtained by established biochemical and microscopic techniques) will validate the CRS technology in a real-world setting, while yielding precious information on the pathogenesis of NASH and its pharmacological resolution.

The Department of Otorhinolaryngology, Head and Neck Surgery, of the Jena University Hospital (JUH) provides state of the art patient care and research in the field of otorhinolaryngology. Clinically, the faculty of the department enjoys a national and international reputation for providing highest quality and the state of the art patient care in all areas of otorhinolaryngology. The department is also recognized for its cutting edge clinical and basic science research in head and neck cancer. The Jena University Hospital is the only University Hospital in the federal state of Thuringia. Therefore, Department of Otorhinolaryngology, Head and Neck Surgery, is also the only academic Department of Otorhinolaryngology in the federal state.

The Department of Otorhinolaryngology is a certified head and neck cancer centre. The department maintains its own registered biobank with more than 1500 biopsies of head and neck cancer patients. The Department is involved in many important studies in the entire range of the head and neck medicine. The Department has advanced experience with in-vivo-applications of confocal minimal endoscopy, near-infrared-endoscopy and ex vivo at tissue sections with nonlinear spectroscopic procedures (SHG, TPEF, CARS) and Raman spectroscopy in combination with histopathological expertise.

Role in the project

Together with RDEFT, JUH is a clinical partner in the projects for all questions and experiments related to head and neck cancer, head and neck cancer models, immune system reaction and immunotherapy. The clinical partner is needed to guarantee the orientation to clinical needs and clinical applicability. JUH will take over tasks related to specification and validation of the developed settings applied to specimens of head and neck cancer and will apply the tools in the clinical setting. JUH will provide the access to patients, specimens and provides details histological data for all specimens. JUH is integrated in WP4 (clinical applications). In WP4 JUH takes part in T 4.1 (clinical specifications), i.e. to define the clinical needs and to guarantee the clinical fitting. JUH is involved in T 4.2 (Ethics) to define the ethical issues from the clinical point of view and to write the ethics committee proposals for T 4.5 (Head Neck Oncology).

JUH is a key partner in T 4.5 for the delivery of tissue and clinical data of patients with head and neck cancer as well as to apply the developed technology.

The Active Fiber Systems GmbH (AFS) is a spin-off company founded in 2009 from both the Fraunhofer IOF Jena and the Institute of Applied Physics at the University of Jena. With these roots in cutting-edge laser physics and state-of-the-art engineering, AFS represents the expertise of innovative solid-state-laser development.
The mission of AFS is to transfer outstanding experimental results from Jena’s laboratories to reliable laser systems suitable for scientific and industrial applications. Worth to be mentioned that customized laser solutions with most demanding parameters are key expertise of AFS. AFS’s product portfolio can be separated into three markets: powerful femtosecond scientific laser systems (up to 12mJ pulse energy, >1.2kW average power), robust 100W- class femtosecond lasers for materials processing applications and compact all-fiber turnkey ultrafast lasers for life science.

AFS has a strong focus on research and development, always aiming to push state-of-the-art laser systems towards and beyond their physical limitations. This results in a variety of outstanding laser parameters only available from AFS.

Role in the project

The focus of AFS lies on the first essential component in the planned project: the driving laser source. Depending on the particular requirements of the project partners, AFS will develop turnkey all-fiber ultrafast laser systems with the goal of both offering challenging laser parameters (high power, tunability, etc.) and being compact, robust and reliable, since the ultimate project goal is to develop a solution ready for clinical use. Starting from the existing light sources in the AFS product portfolio, different paths and technologies will be developed in order to address the different application approaches of the partners. In particular, it is planned to investigate new bandwidth and pulse-duration regimes, the accessibility of higher power values, a reduced noise behaviour and an improved tunability. All these parameters will evolve during the project by steady feedback between all partners aiming for a light source with optimum parameters for the desired application.

Lightcore Technologies SAS, French Reg. No. 852495548 (RCS Marseille) is a deep-tech startup engaged in research, development, manufacturing, and sales of optical and biomedical equipment. As a spin-off from Institut Fresnel, XLIM Research Institute and PhLAM (Laboratory of Physics of Lasers, Atoms and Molecules), the company unites the expertise in both research and engineering to develop cutting-edge nonlinear optical imaging tools and technologies for biomedical and scientific applications. The product portfolio of Lightcore Technologies covers multiphoton imaging endoscopic probes and microscopes, including custom-developed solutions.

Role in the project

LIGHTCORE’s role in the CRIMSON project will be the development and manufacturing of a portable scanning coherent Raman scattering (CRS) endoscopic imaging probe. Embedding the developed driving laser source from AFS or interfacing the source from the CSR microscope delivered by CRIL, the company will elaborate a standalone or add-on solution to perform endoscopic CRS imaging. Starting from the existing multiphoton endoscope design, the system configuration will be adapted to provide a compact and robust solution suitable for research and clinical use. A modular approach will be investigated to better suit different application plans of the project partners, evolving during the project timeline with their feedback. The ultimate LIGHTCORE target is to provide a flexible imaging probe enabling coherent Raman imaging in living tissues to be used as a core technology for WP3 (AI-based modelling of biomedical CRS and Raman data) and WP4 (biomedical applications).

Cambridge Raman Imaging Ltd. Registered in England and Wales. Company number: 11256678 Cambridge Raman Imaging (CRIL) is a spinout from the University of Cambridge supported by the Politecnico di Milano. The company was formed to commercialise new technology in the use of ultrafast lasers for Coherent Raman Scattering (CRS) microscopy. The immediate target is for healthcare, but other applications will also be developed.

Role in the project

The company CRIL Ltd. will focus on developing a scanning CRS microscope for manufacture/sale for medical and pharmaceutical applications and also for licence to other manufacturers. The company is aware of the considerable hurdles to adoption of new medical technology and will be working with regulatory agencies from the outset to ensure that relevant standards are met.

3RDPLACE is an Italian SME founded in 2010 and focusing on data governance, data modeling and data monetization. Its mission is to turn data gathered from different sources into valuable and actionable insights.
Our main expertise is in the field of machine learning, computer vision, data mining, data visualisation, cloud computing, advanced Big-Data architectures, real-time data processing and alternative data collection & analysis.

3RDPLACE operates in both domestic and international markets, serving more than 50 organizations of any size and belonging to different sectors including transportation, healthcare, retail, finance, consumer product goods, and luxury.

Role in the project

3RDPLACE will lead WP3 where an AI-based modelling for biomedical Raman images will be developed; in addition, as part of WP2, a graphical user interface (GUI) for the CRS microscope will be developed.

In WP3, 3RDPLACE will lead the research for development of an innovative solution for tissue classification based on image processing and machine learning. In particular, our contribution will start with performing an initial pre-processing step on the broadband coherent Raman raw data. Subsequently, our commitment will aim to develop a machine learning approach to overcome the limitations of current techniques in retrieving the phase signal from CARS spectra, particularly pertaining to nonlinear effects introduced by noise that is not modelled in state-of-the-art methods such as KK and MEM. The phase reconstruction and regularization task will be tackled using generative approaches, already used in the applied deep learning literature for image restoration, supersampling and style transfer. The training of the model will be carried out using manually labelled samples (gold standard techniques) and the observed performances compared with spontaneous Raman, whose diagnostic power has already been demonstrated.
Regarding the GUI, 3RDPLACE will liaise with CRIL to design an intuitive interface to handle all interactions with the novel broadband coherent Raman microscope developed in WP2. This GUI will allow to easily calibrate and fine-tune microscope’s parameters; furthermore, it will provide a rich set of dashboards for data exploration and results visualisation.
The work will be organised following an agile methodology with regular releases in order to meet deadlines and share all development phases with the consortium.