Feed the brain: translating the needs of preterm newborns in order to nourish them properly

Davide Contini: I am Associate Professor of Engineering Physics at Politecnico di Milano. Our research focuses on the study of the interaction of light with highly disordered media, such as biological tissues. We approach the problem from every point of view: from basic physics, that is, the description of how light propagates inside these models of materials, which also include, for example, fog, which, like biological tissue, is a highly scattering medium and follows certain physical laws, through to practical applications. I began working on these topics in 2004, during my degree thesis, so it has now been more than twenty years.

From an engineering point of view, we develop instruments that make it possible to investigate biological tissue and extract information directly linked to its physiology. In particular, we focus on two aspects: how the tissue is oxygenated, meaning how much oxygen it receives, and how the tissue is perfused, meaning how much blood passes through it. We could in fact have perfectly oxygenated blood that, however, does not reach all areas because of poor perfusion, generating a lack of oxygen where it is needed.

These two aspects can be studied in an entirely non-invasive way, without causing harm or requiring samples to be taken. This enables continuous monitoring, 24 hours a day, which is particularly valuable for a fragile population such as preterm newborns. For these little ones, who in extreme cases can weigh less than one kilogram, even the repeated withdrawal of a few millilitres of blood for traditional analyses can be a problem.

Caterina Amendola: I am a researcher in Professor Contini's research group. I graduated from Politecnico in 2018 in Engineering Physics and then continued with a PhD. Although my degree thesis dealt with other topics, such as X-ray phase-contrast imaging of biological tissues using synchrotron light, I have always been interested in the medical field of application.

I had already worked with preterm newborns together with Davide at Clinica Mangiagalli; then we also worked on applications concerning the brain, such as functional mapping, and on muscle, both in athletes and in older people, to assess oxygenation and muscle metabolism. Since I began, my work has ranged from the development of instrumentation to data analysis models for obtaining highly accurate results, through to clinical and laboratory applications.

CA: Explained simply, the goal of the project is to find a way to personalise the care of the preterm newborn as much as possible, so that they receive the support and nourishment they need, at the most appropriate moment, so that they can grow in the best possible way.

As a research group, led by Professor Alessandro Torricelli, we began working on preterm infants more than twelve years ago. We were coordinators of the European BabyLux project, within which we had already developed instruments capable of carrying out measurements directly in the neonatal intensive care unit. Since then, collaboration with the Policlinico di Milano and Clinica Mangiagalli has been active, and it continues today through a Joint Lab between Politecnico and the Policlinico.

Having gained this experience, our colleagues in Padua, coordinated by Prof. Sabrina Brigadoi, who proposed this research, contacted us to oversee the instrumentation development part. The European consortium is composed of 11 partners and covers all aspects of the problem, from neonatology to technology.

Frontier research of this kind, especially in the medical field, must necessarily be multidisciplinary: it is no longer conceivable for it to be conducted only by physicians or only by engineers; forces must be combined. While abroad the coexistence of mathematicians, physicists, engineers and physicians within neuroscience departments is the norm, in Italy it is a more complex process. As Politecnico, we have moved in this direction precisely by creating Joint Labs, where researchers share the same physical spaces, fostering the continuous exchange of information and knowledge.

DC: We are specifically developing the instrument that performs measurements of cerebral oxygenation and perfusion in the newborn. The preterm newborn is in an environment that they were not expected to encounter so early, and consequently their development is not complete. There is an immediate lung problem because the lungs are not yet ready to breathe air, and this can be reflected at cerebral level with oxygen and perfusion deficiencies. Over the last ten years, in industrialised countries, the survival rate of preterm babies has increased dramatically thanks to the excellent work of physicians and the effectiveness of new protocols.

DC: The real problem now is ensuring that the consequences these children may have in adulthood are minimised. So it is not only necessary to guarantee their survival, but also to guarantee that there is no brain damage. Modern research is focusing on this.

In Padua they have prepared a very ambitious study programme: it is an EIC Pathfinder project (a funding programme for high-risk, high-potential research) that aims to modify the feeding protocol for these newborns. Because it is necessary not only to ensure that oxygen reaches the brain, but also to ensure that all nutrients arrive when they are needed and in the quantities required. Current feeding protocols are very standardised and are based, for example, on the child's weight, without active real-time monitoring that signals whether something is changing at cerebral level (for example because of blood glucose variations).

DC: A standard protocol can work perfectly for one newborn but not be optimal for another. We are trying to broaden its scope to prevent the neurological problems that may arise during the care pathway.

The idea of the project is to introduce active and continuous control: cerebral monitoring of oxygenation and perfusion is combined with constant monitoring of blood glucose and other metabolites, managed through minimally invasive instrumentation developed by another partner, and the data flow into a Digital Twin, an actual digital twin of the newborn. This system simulates the conditions of the specific newborn and predicts their nutritional needs in advance. In this way, feedback is given to the physician who, before a crisis occurs, can intervene by providing and modulating the child's feeding.

At present, there are no instruments as complete as the one proposed in this project. By using these non-invasive techniques and non-bulky machines that can remain beside the cot without moving the child, physicians will have the tools to identify any adverse event in a timely manner.

CA: We use near-infrared light, in a spectral window between 650 and 850 nanometres. The instrument uses two main techniques: one to monitor blood oxygenation and one for perfusion, meaning blood flow. The combination of these data allows us to assess oxidative metabolism, that is, the speed at which oxygen is extracted from the blood in the brain.

For oxygenation, we use pulsed lasers with pulses of around 100-150 picoseconds. The light spreads through the tissue and reaches the brain. The two main phenomena that occur through the interaction of light, in this spectral range, with biological tissues are absorption and scattering. Absorption is linked to the type of constituents, called chromophores, found inside the tissue, while scattering modifies the path that light follows inside the tissue and allows it to exit the tissue, enabling us to detect the light that has reached the cerebral cortex. By studying the shape of the pulse re-emitted by the tissue, we can estimate the absorption and diffusion parameters. In this specific spectral range, the two main chromophores that absorb photons are oxygenated haemoglobin and deoxygenated haemoglobin. Since they have different absorption spectra, the use of different wavelengths allows us to measure their concentration and calculate saturation, meaning the percentage of oxygenated haemoglobin present in the tissue. To do this, the instrument uses two pulsed lasers, single-photon detectors and electronic boards to reconstruct the shape of the pulse. The entire light path takes place through optical fibres, both from the laser to the probe and from the probe to the detectors.

To assess perfusion, on the other hand, we use a technique called DCS (Diffuse Correlation Spectroscopy). In this case we use continuous-wave, high-coherence lasers and exploit the coherence of laser light.

DC: Yes, we are responsible for the working group that develops the instrument. Within this group, several organisations collaborate, both academic and corporate. Pionirs srl, a spin-off of Politecnico, ICFO (Institute of Photonic Sciences in Barcelona) and University College London have produced the different modules. Politecnico handled the coordination of these activities and the final integration. Dave srl, a company specialising in medical systems, is also participating in this project. It handled the software interface between the instrument and the medical staff, making it extremely intuitive.

When designing for clinical practice, the engineering aspect of the interface is fundamental. Although the instrument is currently being validated and is not yet used for diagnoses, it will operate in an extremely high-pressure environment such as intensive care. We cannot expect a physician or a nurse to have to manage fifty different software windows as we do in the laboratory. The instrument must operate almost automatically and must not hinder the clinical routine; otherwise it would be unusable in practice, despite the quality of the technology.

CA: The project started in 2023, and it is a great achievement to have managed to align so many different areas of expertise (engineering, physics, medicine, psychology and nursing) from the earliest discussion phases, even defining together the smallest practical details. The instrument has been completed and now we have to start the clinical protocols, which will take place in two facilities: the Azienda Ospedaliera di Padova and the University College Cork hospital in Ireland.

We are currently awaiting regulatory authorisations. If the process proceeds regularly, we expect to bring the instrument into the clinic and acquire the first data by the end of the summer. This phase of the project does not yet involve a full clinical trial, but rather the collection of preliminary data useful for obtaining future funding for the actual clinical trials.

DC: Having developed the instrument according to good technical practice standards, we know its performance under controlled laboratory conditions. However, field application is different. Thanks to past experience (Caterina herself has spent many nights in neonatal intensive care in Milan), we have tried to foresee and resolve the known critical issues in advance.

What we are curious to see is whether other problems will arise and, above all, how effective the solutions we have implemented will have been. Since this is an observational study, the idea is to monitor newborns over entire days and then retrospectively correlate the data we obtain with the data collected in clinical practice, to verify whether there are characteristics in our traces that may in some way be useful for preventing certain types of critical issues.

There will then be a very long phase of data analysis carried out on a small population, but the idea is to collect a great deal of data on these few children and then verify and improve the models that simulate the child's physiology in order to predict the evolution of physiological parameters.

At the end of this very interesting account, the impression is that the horizon outlined by this research redefines the very concept of technological care, showing how frontier physics can adapt to the needs of life at its most vulnerable moment. While awaiting the data that will come from the wards in Padua and Cork at the end of the summer, the path toward personalised medicine, capable of protecting the future and neurological development of the most fragile children, now appears decidedly closer.