Diagnostics and Sensing: minature sensors and cameras are helping revolutionize patient treatment

"We are currently working on monitoring the development of Alzheimer. In the advanced stages of the disease, a change occurs in the relation of concentration between two proteins – Amyloid beta and Tau – secreted to the spinal fluid. The most common test today is complex, invasive and requires hospitalization. A lumbar puncture (spinal tap) procedure takes place in order to assess the Alzheimer's progress, in which the proteins are extracted from the spinal cord with a needle and examined in a lab to assess their concentration. This allows doctors to see whether a new experimental drug improves the patient's condition and if a change in lifestyle delays or expedites the disease. Lumbar puncture is an expensive, lengthy, and unpleasant procedure that is performed at a medical center. As a result, it is generally performed only once every six months at most. This low frequency does not always help in locating the reason for the deterioration in the Alzheimer patient's condition," Zalevsky explains.

Prof. Zeev Zalevsky. Photo: Amit Shaal

Zalevsky has developed two different technologies in the lab, combining them both to help solve the problem. One of the technologies enables optical sampling behind a scattering medium (behind the tissue during lumbar puncture) while the second technology allows the identification and measurement of chemicals and other substances inside the area under examination. "The concept we developed combines both technologies," he explains. "The non-invasive treatment takes place in the clinic and without extracting spinal fluid. The patient sits on a chair and the light from the device behind him scans the relevant area inside the spinal fluid behind the tissue. The information received from the light's distribution is analyzed with a Raman spectroscope – a sensitive device with enhanced resolution that is capable of checking for the existence of the relevant proteins. This technology is in its initial phases of commercial development and we are presently in the final stages prior to finalizing an investment in the incentive Incubator. We have been fortunate to receive support from the Israel Innovation Authority on this project."

Prof. Zalevsky is already responsible for dozens of innovative ideas and revolutionary studies leading to unique technological developments which have been commercialized into useful products in the fields of electro-optics and bio-medical applications. Today, he is focusing on research in the fields of bio-medical sensing, super-resolution, and nano-photonics. "My goal is not just to conduct research but also to bring to fruition technologies that will benefit the end user and I am happy to collaborate with the Innovation Authority to achieve this goal. The Authority offers special programs for initiatives in their early phases, exactly at the complex stage at which they need to recruit investors in order to evolve into a startup with a mature product. In certain cases, some of the mature technologies I took part in developing have already progressed to the Authority's advanced programs such as the startup incubators and commercialization," he elaborates.

The Innovation Authority supported another of Zalevsky's unique initiatives – an addition to the CT system that can supply a CT image with enhanced resolution and less radiation. This technology was commercialized to a startup company called LensFree. The main beneficiaries are the doctors who are exposed to radiation throughout the day, despite the protective lead vests they wear. As he explains "Behind this CT system is a special hardware that, combined together with a smart algorithm, enhance the resolution of the picture and allows to take a picture with less radiation. The system is also being currently checked by doctors who perform mammography."

A Thin Endoscope with Unique Algorithmics

Another project combining algorithmics and hardware in bio-medical applications is a development connected to the field of micro-endoscopy. Sometimes, a need arises for internal medical treatment that necessitates a close-up look at the area to be treated. The two most common endoscopic technologies are 'chip-on-the-tip' – a camera that enters the body, sees an image and transmits it via electric cables; and fiber endoscope – an optic fiber inserted into the body with a sensor (or camera) that remains outside the patient's body.

These technologies have several significant drawbacks. First, the need for sterilization after each treatment; second, the small diameter of the optic fiber or camera that prevents a higher-resolution picture; third, the amount of blood in the body that may distort the transmitted picture. "The endoscope that we developed addresses these problems. It is very thin with a small diameter but its algorithmics enable a resolution-enhanced image despite the blood. The part of the endoscope entering the patient's body is disposable so there is no problem of sterilization. This technology was commercialized seven years ago from my lab and the startup company Zsquare is currently in advanced stages. The product is subject to medical regulation procedures and I hope that it will be released soon," Zalevsky says.

Laser Light and Vibrations for Remote Diagnosis

Five years ago, one of the oldest projects occupying Zalevsky's time over the last 15 years became a startup company by the name of ContinUse Biometrics. The technology, developed in the laboratory at Bar Ilan in collaboration with a colleague from Valencia in Spain, is capable of remote medical diagnosis by means of laser light and a camera with special optics. "The patient positions himself in front of the sensor and is illuminated by a laser light. The light diffusing from the tissue is absorbed by the special-optics camera and processed algorithmically. The algorithm analyzes the changes in the time and space of the vibrations in the tissue and diagnoses the patient's condition according to the pattern of the light diffusion. The sensor is extremely sensitive and can absorb the tempo and nature of the vibrations with nanometric precision. The vibrations characterize the human body because we are made of vibrating molecules, blood flow, and vibrations connected to basic vitality parameters such as breathing and heartbeats," Zalevsky explains.

ContinUse Biometrics' camera. PHoto: Tal Azoulay

This technology may also prove useful with Corona. It can be used for sensing the onset of pneumonia, respiratory problems, rhonchus, rapid pulse, high blood pressure, rising temperature, oxygen saturation in the blood etc., all from another location and without proximity to the sensor or the presence of a physician. Such a device can be placed at the entrance to a shopping mall for example, to check if shoppers are developing similar symptoms.

As part of the research, Zalevsky also attempted to read thoughts. "When we use our brain, blood flows to a specific area according to the type of action we initiate. Blood flow is related to nano-vibrations which we can detect from a distance and is the base of the technology we developed. Science needs a multi-disciplinary approach to ensure sufficient depth and applications that will benefit mankind," he summarizes. "There is such a large scope of knowledge and abundance of diverse fields of expertise that it's impossible to specialize in everything, and the correct way to advance a scientific development with high scientific and practical impact is to combine forces and knowledge from different fields."

Reducing the Use of Antibiotics

A recent revolutionary scientific development is a 15-minute blood test that can translate and decode the complex signals of our immune system to identify what is causing an infection. The test, developed by MeMed, addresses a prevalent and major clinical dilemma with far-reaching consequences – is the infection bacterial and therefore in need of antibiotic treatment or viral? Because the clinical symptoms of viral and bacterial infections are very similar, the patient is frequently prescribed antibiotics even when they are unnecessary.

The impact of such a test is dramatic not merely because the patient receives the appropriate treatment, but also because it prevents unnecessary prescription of antibiotics, helping to reduce the creation of bacteria that are resistant to antibiotics. "Bacteria that are resistant to antibiotics is one of the major health challenges of the 21st century," says Dr. Eran Eden, the company's CEO and founding partner. "MeMed's existing solution overcomes the limitations of the diagnostics available today which either supply an answer only after a few days, require access to the pathogen, cannot identify new species, or cannot distinguish between colonizers and the disease-causing agent."

MeMed CEO Eran Eden. Photo: Amit Shaal

A major milestone was recently achieved when the company received regulatory clearance to market the second generation rapid-result test in Europe and Israel. According to Eden "The innovation of the MeMed test is that it is not based on sampling the cause of the infection but rather, decodes the individual's immune response to the disease-causing agent. We have developed a small device to measure the levels of three proteins in the blood and algorithmically combine the measurements to differentiate whether the infection is bacterial or viral."

Technology that Combines Different Disciplines

MeMed was founded about a decade ago by Dr. Eran Eden (CEO) and Dr. Kfir Oved (CTO). "We are backed by several of the leading venture capital funds in the US and Asia and have also established a subsidiary company in the US," Eden says. "The company has raised approximately 100 million dollars so far and received grants of 35 million dollars from the American Department of Defense and from the EU. The company is capable of manufacturing medical devices according to the highest standards. Our product has the potential to impact the lives of so many people around the world."

"The process of developing an advanced technology is a lengthy one, especially when it integrates several different disciplines. MeMed's diagnostic system encompasses in-depth know-how and expertise across four different dimensions: clinical medicine; molecular immunology; artificial intelligence; and machine engineering. The Innovation Authority is promoting this Bio-convergence approach, as it leads to significant breakthroughs. The synthesis of different disciplines, which is not at all trivial, poses an imposing hurdle at the beginning of the process but later constitutes a huge advantage."

Thanks to grants from the European Union and the American Department of Defense, MeMed did not require direct financing from the Innovation Authority however the ISERD (the Israel-Europe Research & Innovation Directorate), operating at the Israel Innovation Authority, has contributed to MeMed's success in various areas. According to Eden, "We are extremely grateful to ISERD for their assistance during the initial stages and their continued support. We are presently in contact with the Authority to advance future Bio-convergence projects."

Over 90% Successful Identification

As Eden explains, the development process was highly complex. "It took four years of gathering, measuring, and analyzing clinical samples to discover the basis of the test. During our research we scanned the protein space of the human body and checked how it responds to different viruses and bacteria. One challenge, for example, was for the test to be applicable to people of all ages. In the end, we identified 3 proteins that we named after ice-cream flavors: toffee, cherry, and pecan."

"After the discovery study of more than 1000 patients, we conducted a validation study of 777 children together with one of Europe's leading pediatricians", Eden explains. "The results reproduced sensitive and specific detection (>90%) with very low probability of missing bacterial infections. We have continued performing additional large-scale studies thanks to financing that we received from the EU with the goal of creating a tremendous mass of clinical data to support the quality and reliability of the test."

The first generation of the test provided an answer after 2 hours. However, we realized that a quicker answer of only minutes was needed to increase the test's usefulness. "My partner Kfir had a revolutionary idea – to miniaturize a large machine that is capable of measuring the three proteins accurately and rapidly," says Eden. "As a result, we embarked on a lengthy engineering process that was accelerated by an award from the American Department of Defense, won with the help of Dr. Tanya Gottlieb who oversaw the liaison with them.

"The resultant platform that we developed is capable of measuring multiple proteins simultaneously. In the future, it can be applied not only in our test that differentiates between bacterial and viral infection but also in any test involving proteins," he concludes.

Dr. Itai Kela, Scientific Director of the Bio-Convergence Program:

"The coronavirus crisis has accentuated the challenges we are encountering in the field of medicine and the growing significant need for new innovative solutions. One of the fundamental problems with the Corona virus is the lack of efficient and rapid diagnostic tools. It presently takes 3 days to receive test results and about 5 days until people are notified that they were exposed to Covid-19 patients. This is too long and prevents the efficient severance of the chain of infection. We would be in a much better situation if results could be received in 15 minutes. Bio-convergence is the means that will enable the development of innovative diagnostics which facilitate better and faster identification."

The article was written in collaboration with the Israel Innovation Authority, responsible for the country’s innovation policy. Its role is to nurture and develop Israeli innovation resources, while creating and strengthening the infrastructure and framework needed to support the entire knowledge industry.