The LUMEN project, led by Dr. Emanuele Riva from the Department of Mechanical Engineering, delves into the forefront of neurostimulation technology through the development of advanced acoustic metamaterials. Its core focus lies in optimizing transcranial focused ultrasound (tFUS), a non-invasive modality increasingly harnessed to treat movement disorders like Parkinson’s disease and essential tremor. One of the paramount challenges in current tFUS applications is the unintended dispersion of “leaky-Lamb waves,” acoustic waves scattered irregularly by the complex barrier of the human skull. These waves diminish the precision and efficacy of ultrasound brain stimulation, limiting clinical outcomes.

To confront this obstacle, LUMEN proposes a pioneering approach that engineers acoustic metasurfaces capable of controlling the emission direction of these leaky-Lamb waves at their source. Acoustic metasurfaces, a class of precisely arranged nanostructures, manipulate the propagation of sound waves through subwavelength scale modifications. By integrating biocompatible implants fashioned with these metasurfaces, the project aims to significantly refine the focal targeting of ultrasound energy. The anticipated effect is twofold: enhanced accessibility of the technology, and a remarkable increase in the precision of stimulation, especially in previously hard-to-reach peripheral brain regions. This advancement may revolutionize treatment protocols for millions suffering from debilitating tremors and neuropathic pain, extending therapeutic benefits to diverse patient profiles.

Dr. Riva’s background in structural dynamics and elastic wave mechanics underpins this ambitious enterprise. Having earned his PhD with honors from Politecnico di Milano, his research portfolio is distinguished by expertise in metamaterials and wave propagation, encompassing vibration control and energy harvesting technologies. His engagement with academic publications and patents, along with co-founding a specialized company in vibrational acoustics, demonstrates a rare blend of fundamental research and entrepreneurial innovation essential for bridging theoretical concepts with clinical applications.

Parallel to LUMEN’s endeavor, the ALFRED project, spearheaded by Dr. Claudio Conci from the Department of Chemistry, Materials, and Chemical Engineering “Giulio Natta,” embarks on a radically novel diagnostic frontier. ALFRED stands for Positron Annihilation Lifetime Spectroscopy for Revealing and Quantifying Inflammation and Endothelial Diseases. It exploits the particle physics technique of Positron Annihilation Spectroscopy (PAS) to detect early-stage inflammatory signatures with unparalleled resolution and non-invasiveness. Inflammation’s stealthy onset often eludes conventional diagnostic tools until manifest symptoms appear, delaying timely intervention in conditions ranging from cancer to neurodegenerative and cardiovascular diseases.

PAS uniquely harnesses the behavior of positrons—antiparticles of electrons—that, upon interacting with electrons in biological tissue, annihilate and emit gamma rays. The timing and spatial characteristics of this emission can reveal microscopic changes in tissues at the molecular and cellular levels. By adapting this technique to medical imaging, ALFRED seeks to quantify localized inflammation with sensitivity far exceeding existing modalities. This fusion of bioengineering, nuclear medicine, and particle physics could reshape preventive healthcare by intercepting disease processes before irreversible damage ensues.

Dr. Conci, whose academic genesis blends biomedical and bioengineering disciplines, has honed his expertise through multidisciplinary collaborations with Italy’s leading research institutes. His career focus on ethical imaging solutions and miniaturized medical diagnostic devices lays the foundation for ALFRED’s integrative methodology. The project exemplifies the translation of fundamental physics into tangible, life-saving medical technologies.

Politecnico di Milano’s distinction as Italy’s prime locus for Horizon Europe funding underscores its strategic role in fostering scientific excellence. Housing 362 projects amounting to over 175 million euros and securing 39 ERC projects worth over 41 million euros, the institution exemplifies leadership in advancing frontier research. The selection of LUMEN and ALFRED among 478 ERC-funded projects in 2025 highlights their exceptional potential to redefine medical engineering paradigms.

ERC Starting Grants fuel early-career researchers who have recently obtained their doctorates but stand at a critical juncture to embark on independent scientific trajectories. The grants encourage audacious, foundational research peering beyond existing knowledge frontiers. Both projects resonate with this mandate, as they challenge established constraints within their respective domains and engage interdisciplinary synergies.

The potential impact of LUMEN extends beyond treating motor symptoms; by enhancing the precision of ultrasound wave focusing via metamaterial engineering, it opens avenues for neuromodulation therapies targeting a broad spectrum of neurological disorders. Its emphasis on affordability and accessibility further ensures that such advanced treatments may reach underserved populations worldwide, addressing health equity issues intrinsic to medical innovation.

Conversely, ALFRED’s promise lies in revolutionizing diagnostics by unveiling invisible biological processes that underpin inflammation—a precursor to numerous chronic and acute conditions. With the capacity to detect molecular perturbations non-invasively and at an early stage, this technology could enable clinicians to devise personalized treatments, optimize therapeutic windows, and ultimately improve prognoses.

Taken together, these initiatives exemplify how convergence science—melding material science, applied physics, bioengineering, and clinical medicine—can surmount longstanding limitations in healthcare. Their anticipated breakthroughs signify a future where non-invasive, precise, and rapid interventions become standard components of disease management, elevating patient care to unprecedented levels.

As the LUMEN and ALFRED projects forge ahead under the Politecnico di Milano umbrella, their trajectories illuminate the vital landscape where technological innovation intersects with urgent societal health needs. Supported by the visionary backing of the European Research Council, these projects embody the transformative potential of early-stage scientific ambition nurtured within world-class research environments.

The collaborative fabric woven through both projects, spanning multiple disciplines and institutions, reflects the modern ethos of scientific inquiry. It is this intersectional approach that fuels novel methodologies—from manipulating acoustic metamaterials at the microscale to applying positron physics in biological systems—ushering in a new era of medical diagnostics and therapeutics backed by precise, physics-based technologies.

In an era increasingly defined by personalized medicine and minimally invasive interventions, the LUMEN and ALFRED projects position themselves front and center as beacon initiatives. They are poised not only to deepen understanding of complex physiological phenomena but also to translate this knowledge swiftly and safely into patient-centered solutions. The coming years will be pivotal in witnessing how these ERC-funded endeavors reshape the sonic and imaging landscapes underpinning essential neurological and inflammatory disease care.

Subject of Research: Acoustic Metamaterials for Focused Ultrasound Neuromodulation; Positron Annihilation Spectroscopy for Inflammation Detection

Article Title: Pioneering Neuromodulation and Inflammation Diagnostics: Politecnico di Milano’s ERC-Funded Breakthroughs in Medical Engineering

News Publication Date: 2025

Web References:
https://mediasvc.eurekalert.org/Api/v1/Multimedia/69a8ade3-3d36-4432-9738-a036ceaebfb6/Rendition/low-res/Content/Public

Image Credits: Claudio Conci

Keywords: Acoustic Metamaterials, Focused Ultrasound, Neuromodulation, Positron Annihilation Spectroscopy, Inflammation Detection, Biomedical Engineering, Structural Dynamics, Particle Physics, Neurodegenerative Diseases, Medical Imaging, Non-invasive Diagnostics, European Research Council

The study centers on two specific superficial cervical lymphatic vessels, scLV-1 and scLV-2, selected due to their proximity to the skin’s surface and their unique innervation patterns. Unlike the deeper dorsal cervical lymphatics (dcLVs), these vessels present an accessible target for non-invasive manipulation. Notably, these lymphatics feature smooth muscle cells encased by adrenergic sympathetic nerves, identified via tyrosine hydroxylase staining, distinct from cholinergic parasympathetic innervation. This sympathetic regulation likely plays a crucial role in modulating lymphatic function in the head and neck regions.

To investigate whether CSF drainage could be augmented through intact skin, the researchers crafted a mechanical device capable of applying precisely controlled downward strokes at varying force magnitudes. Low-magnitude forces ranged from 0.01 to 0.02 kilogram-force (kgf), while high-magnitude forces reached 0.04 to 0.08 kgf. These stimuli were administered in carefully delineated regions: from the periorbital area to the mandible, from the nasal sidewall to the mandible, and along the trajectory of scLV-1 and scLV-2 towards the submandibular lymph node. Each session involved cyclic application of strokes directed at these regions, interspersed with rest periods.

The efficacy of this approach was validated using TMR–dextran, a fluorescent tracer infused intracisternally to track CSF movement. Following 5 minutes of low-magnitude mechanical stimulation, tracer accumulation in scLV-1 and scLV-2 more than doubled, exhibiting a 2.29-fold average increase in fluorescence intensity relative to controls. Conversely, high-magnitude stimulation produced vessel constriction and dramatically diminished tracer uptake by 89%, underscoring the critical importance of force modulation in optimizing lymphatic function.

Expanding upon these findings, the researchers extended mechanical stimulation to a longer duration—20 one-minute sessions—and assessed tracer transit from the subarachnoid space (SAS) to the submandibular lymph node. The result was a striking tripling (3.01-fold increase) of tracer fluorescence in the ipsilateral lymph node following low-force stimulation, with no comparable changes observed contralaterally. High-force stimulation again suppressed tracer accumulation, highlighting a biphasic response dependent on mechanical load.

Importantly, to distinguish whether observed effects reflected enhanced CSF clearance or merely mechanical displacement of lymph within the vessels, the team injected TMR–dextran directly into a lateral ventricle, combining this with low-magnitude stimulation. Subsequent measures of CSF removal at the cisterna magna revealed a significant 23% decrease in tracer concentration associated with stimulation, providing compelling evidence of true augmented CSF clearance from the SAS rather than passive lymphatic flushing.

Real-time intravital imaging further elucidated the temporal dynamics of lymphatic tracer uptake post-stimulation. Fluorescence intensity in the superficial cervical lymphatics more than doubled within one minute of a single low-magnitude stimulation session and remained elevated over a five-minute observation window. Notably, mechanical forces elicited modest dilation of the lymphatic vessels and a transient surge in spontaneous contraction amplitude. However, basal contraction frequency, ejection fraction, and overall fractional pump flow remained unchanged, suggesting stimulation primarily enhances vessel capacity without disrupting intrinsic contractile rhythms.

Addressing potential concerns regarding desensitization, repeated daily low-magnitude mechanical stimulation over four days neither altered contraction parameters nor diminished stimulation efficacy. This indicates a sustainable therapeutic window in which mechanical modulation can reliably amplify CSF drainage without adverse effects on lymphatic physiology, supporting the feasibility of translational application.

Mechanistic insights were gleaned through pharmacological inhibition of nitric oxide (NO) synthesis using N(ω)-nitro-L-arginine methyl ester (L-NAME). Administration of L-NAME decreased vessel diameter, contraction amplitude, ejection fraction, and fractional pump flow in scLV-1, affirming NO’s pivotal role in lymphatic spontaneous contractility. Moreover, NO blockade attenuated the augmentation of CSF drainage following mechanical stimulation by approximately 31%, underscoring NO signaling as a key modulator of lymphatic responsiveness.

The translational potential of the approach was bolstered by application in aged mice exhibiting baseline CSF drainage deficits (approximately 30% lower than young adults). Mechanical stimulation induced substantial increases in tracer accumulation: a 2.81-fold rise at the submandibular lymph node after 20 minutes of low-magnitude stimulation and a 4.7-fold elevation within scLV-1 and scLV-2 after 5 minutes. These magnitudes closely paralleled those observed in younger animals, effectively counteracting age-related drainage impairments.

Collectively, these results confirm that precisely calibrated, non-invasive mechanical stimulation of superficial cervical lymphatics can substantially enhance CSF outflow and lymphatic clearance, even in aged organisms. The specificity of low-magnitude forces and the involvement of adrenergic innervation and nitric oxide signaling provide mechanistic depth, while sustainability and efficacy in aging highlight clinical promise.

This innovative strategy invites exciting prospects for ameliorating neurological conditions linked to compromised CSF clearance, such as neurodegenerative diseases, hydrocephalus, or traumatic brain injury. By leveraging accessible superficial lymphatic pathways through gentle, controlled skin manipulation, new therapeutic modalities could emerge that circumvent invasive interventions and tap into the body’s intrinsic drainage systems.

Future studies may delve deeper into optimized stimulation parameters, long-term effects, and the interplay between lymphatic contractility and neural regulation. The clear demonstration of functional lymphatic modulation bridges mechanobiology and clinical neuroscience, positioning this work at the vanguard of neurovascular and lymphatic research.

As we stand at the threshold of harnessing the skin’s superficial lymphatics to mediate brain fluid homeostasis, this landmark study reframes our understanding of lymphatic network accessibility and control. It offers not only a novel scientific framework but also a hopeful path toward non-pharmacological strategies to mitigate age-related and pathological declines in CSF clearance.

Subject of Research: Non-invasive mechanical stimulation of superficial cervical lymphatics to enhance cerebrospinal fluid drainage.

Article Title: Increased CSF drainage by non-invasive manipulation of cervical lymphatics.

Article References:
Jin, H., Yoon, JH., Hong, S.P. et al. Increased CSF drainage by non-invasive manipulation of cervical lymphatics. Nature (2025). https://doi.org/10.1038/s41586-025-09052-5

Image Credits: AI Generated