Small but mighty! This applies to the new optoacoustic sensors that we are developing in the RSENSE project. By using modern laser diodes, we are making our technology smaller and also much cheaper. On the one hand, the sensors are intended to enable the early diagnosis of cardio-metabolic diseases such as diabetes. On the other hand, the sensors can identify pollutants such as black carbon in exhaust gases and are intended to be used in the automotive sector.

Medical sensors:

Disease detection today occurs at a late stage, after the manifestation of clinical symptoms, although early disease detection is the best possible first step for efficient intervention and therapy of many diseases. Modern healthcare needs direct frequent monitoring of critical information for leading to early detection or home-based monitoring of cardiovascular and metabolic diseases. Most medical measurements for this kind of information either are invasive (blood-samples) or require specialized instrumentation only available in hospitals and clinics, such as MRIs. Today, portable optical sensors, such as FitBit or Apple, measure simple information that is not appropriate for complex diagnostics. Desired critical information remains elusive with such optical sensors. This is because optical sensors cannot accurately disentangle depth, absorption and scattering contributions, neither in frequency nor in time-domain modes, due to the diffuse nature of the light measured. RSENSE overcomes these issues mainly by using optoacoustics sensors (OA) with unique features. We aim to advance data analytics that can integrate also other information with the unique biological, metabolic and environmental parameters measured, not available to any other non-invasive sensor today, and the potential to offer quantitative assessment of disease using a simple single-point, non-invasive 1 second measurement.

Environmental sensor:

Clean air is pivotal for public health as poor air quality is associated with a series of diseases, especially of the respiratory system, including asthma or lung cancer. The spectrum of air pollutants is broad and includes greenhouse gases and other particles. Transport sector, energy production, and industry use engines that are one of the main sources of gaseous and particulate emissions that deteriorate the air quality. Current devices that can measure different air pollutants are available, e.g. Portable Emission Measuring Systems (PEMS) or aetholometers. These devices come with major drawbacks: they are bulky, expensive, cannot measure multiple gases and particulates simultaneously, do not offer a broad characterization profile of emissions and environmental pollutants, or require correction algorithms for different aerosols. Especially, portable detection of emissions is similarly problematic or even not possible. RSENSE aims at opening up a new era in on-board diagnostics by allowing frequent measurements of emissions for on-board use in various areas, e.g. automobiles, ships, and industries. Our sensor can revolutionize environmental sensing by using a dense urban network of inexpensive sensors providing real-time information and diagnostics on environmental or vehicle conditions. This information is crucial to inform about environmental conditions and enforce guidelines protecting public health. Additionally, the measurements help to understand environmental and climate effects of specific particles.

The skin is not only our largest organ, but also the scene of numerous diseases. Using Raster-Scan Optoacoustic Mesoscopy (RSOM) that we have developed, we can look inside and under the skin to better understand and combat diseases such as skin cancer or psoriasis. Throughout the history of medicine, physicians have relied on surface features of the skin to gain insights into various diseases. Alterations in skin color or appearance often signify underlying conditions, whether localized to the skin or indicative of systemic issues. However, the human eye's capabilities are limited to superficial observation, lacking the ability to penetrate beneath the skin's surface and accurately assess what lies beneath. Similarly, conventional optical tools such as cameras and microscopes are confined to shallow depths of penetration. RSOM, however, revolutionizes this paradigm by facilitating highly detailed visualization deep within the layers of the skin. This innovative technology provides accurate depictions of various pathophysiological parameters, including intricate details of microvascular structure and function, as well as measurements of oxygenation and lipid content. These insights, obtained through RSOM, surpass the limitations of visual skin inspection, offering a more precise understanding of disease development and progression. In the WINTHER project (https://winther.munichimaging.eu/), we also use the skin as a window into diseases such as diabetes. We applied RSOM integrated with artificial intelligence (AI) to investigate diabetes-related skin changes. We captured high-resolution images of skin microstructures in both diabetic and non-diabetic individuals. AI algorithms were then employed to analyze these images, detecting subtle alterations indicative of diabetes, such as changes in blood vessel density and skin thickness. In this way, the stage and progression of diabetes can be monitored from taking quick, non-invasive images of the skin. In the OPTOMICS project (https://optomics.munichimaging.eu/), three worlds of science come together to revolutionize our understanding of diabetes: we combine optoacoustic imaging with the help of RSOM of diabetes patients with their multi-omics data (genome, proteome) and artificial intelligence. In this way, we create a digital twin model for type 2 diabetes.

In fluorescence molecular endoscopy (FME), patients are administered fluorescent dyes (fluorophores) that specifically bind to diseased tissue and are activated by excitation light. This causes the diseased tissue to glow on the monitor in the treatment room. This enables surgeons to remove even the smallest lesions, i.e. tumor tissue in the early stages, because it stands out clearly from healthy tissue. We innovate FME technologies to revolutionize the early detection, diagnosis and treatment of diseases. In the ESCEND project (https://www.escend.eu/), patients were administered a fluorescent dye that specifically binds to cancerous tissue by spraying it into the esophagus. This enabled doctors to discover lesions that were not visible with conventional inspection using white light endoscopy. Within ESCEND we advanced the evidence on minimally invasive FME, which is on the verge of clinical translation and with immense clinical impact and commercialization potential. We showed that FME can detect disease earlier, with higher specificity and sensitivity, and stratify disease in terms of cancer progression over the current state of the art. With a sensitivity and positive predictive value of 98.6% and 88.8%, respectively, ESCEND further highlighted that the “red flag” operation of FME can lead to reduced biopsies during surveillance, compared to the standard Seattle protocol. Moreover, ESCEND showed that FME can identify 115% more lesions compared to the general endoscopist, and 26% more lesions compared to a Barrett expert. These astonishing results define the socioeconomic impact of ESCEND, which can be translated to ~21,000 lives saved and >€2.9 Billion saved for new cases of esophageal cancer diagnosed every year by switching from treating metastasized disease (€150,000 average cost) to curative endoscopic mucosal resection (EMR) (<€10,000) in Europe alone. Importantly, ESCEND and its results fully comply with the frameworks identified within the Europe’s Beating Cancer Plan and the US Healthy People 2030 initiatives, even though our project precedes the publication of those two initiatives in 2021 and 2020 correspondingly. Currently we are planning the Phase III clinical trial to statistically confirm the findings of ESCEND on a much larger population of patients and, thus, achieve the ambition that a hybrid white-light and fluorescence endoscope will become the new BE diagnostic standard in the near future. In another application we further advance the FME technology and apply it to inflammatory bowel disease. Millions of people suffer from inflammatory bowel disease that makes their lives difficult. To this day, it is not known whether the expensive drugs reach the inflammation and whether the dose is sufficient for the patient. In the msGUIDE project (https://msguide.munichimaging.eu/), we are developing a novel endoscope and drugs with fluorescent dyes that will enable us to quantify drug distribution and concentration in the intestine and identify individual drug target cells.

Frequent blood glucose monitoring is vital for effective diabetes management, given the global diabetic population surpassing half a billion (according to WHO). The traditional method of using finger pricks, involving painful blood drop extraction, raises infection risks and discourages regular monitoring, impacting overall care. Though implantable patch microneedles offer a promising alternative, they do not eliminate infection risks. Additionally, they measure glucose in interstitial fluid, not directly in the blood, which is the clinically relevant measure for effective diabetes management. Making life with diabetes easier is the goal of the GLUMON project. To detect glucose in the blood without blood extraction, we developed a novel biosensor called “Depth-gated mid-IR Optoacoustic Sensor” (DIROS). This biosensor uses a combination of mid-infrared light and optoacoustic technology to measure glucose levels in small blood vessels under the skin. By enabling measurements beyond 100 µm, DIROS can access the human microvasculature layers in the skin at the junction between the epidermis and dermis, typically located at depths of 20 to 80 µm. DIROS utilizes a smart algorithm to concentrate on specific tissue areas, disregarding signals from the outer skin layers. In mouse experiments, DIROS demonstrated heightened sensitivity in detecting glucose in blood-rich areas compared to the fluid around cells. During a glucose tolerance test, DIROS more accurately reflected changes in glucose levels than traditional methods. Notably, DIROS enhanced accuracy by mitigating the influence of factors such as humidity and lipids, common challenges for other glucose sensors. DIROS could transform how we measure glucose, offering accurate and sensitive detection directly in the blood, which is more precise than methods focusing on less specific fluids like interstitial fluid. This breakthrough holds transformative potential for the future of diabetes care, offering a more comfortable and convenient alternative to traditional methods. Transitioning from successful laboratory testing, the next crucial phase involves conducting clinical studies to validate its efficacy.

In the SWOPT project we are developing an optoacoustic system that can display individual, living cells and their function deep in the tissue. We achieve this by using markers that bind to cells that we want to see or are produced by them and whose signal we can switch on and off in the image using a light pulse. This allows us to hide the disturbing background as desired. SWOPT is a novel imaging technology that will break through the penetration limits of optical microscopy to visualize individual cells and their function in vivo through several millimeters to centimeters of depth. SWOPT will exploit (1) optoacoustic imaging, a modality which combines signal generation similar to optical imaging with the whole animal imaging capability of ultrasound readout, and uniquely augment it with (2) photoswitching to resolve signals from single labeled cells from deep within live tissue. This will achieve volume sampling abilities surpassing any optical microscopy by at least three orders of magnitude (> 5 x 5 x 5 mm imaging volume). SWOPT will develop the necessary breakthrough instrumentation and concepts: unique multiplexed diode illumination, novel ultra-wideband transducer technology, dedicated inversion algorithms that incorporate photoswitching in the three-dimensional reconstructions, and uniquely tailored classes of photo-switching transgene and synthetic molecular tools. The exceptional capabilities of SWOPT will be demonstrated by proof-of-concept work resolving cellular dynamics and functions in a whole tumor in a model of renal cancer in vivo.