The review, authored by Erika P. Plata-Menchaca of the Universitat Autònoma de Barcelona and Hamad Medical Corporation in Doha, and Enrique Hernández-Jiménez of Loop Diagnostics and the University of Barcelona, takes an unusual angle. Instead of ranking biomarkers by diagnostic accuracy or area under the receiver operating characteristic curve, the authors organize candidate technologies by their regulatory status, intended clinical use, sample type, turnaround time and workflow compatibility. The framing follows the 2026 Surviving Sepsis Campaign guidelines, which emphasize early clinical recognition with validated scores, sensible diagnostic strategies and responsible antimicrobial use and de-escalation. A biomarker, they argue, should be judged by whether it can support a concrete decision, whether to admit, escalate, start or stop antibiotics, or monitor more intensively, within the sepsis pathway.

The starting point is the familiar panel of conventional soluble markers. Procalcitonin, C-reactive protein, interleukin-6 and lactate are widely available, analytically standardized and compatible with routine laboratory workflows, and procalcitonin in particular has accumulated regulatory credentials, with multiple CE-marked assays in Europe and several FDA-cleared platforms in the United States supporting antibiotic initiation or discontinuation claims in specific populations. Lactate, although not specific to sepsis, remains central to severity assessment and shock recognition. The weakness of this entire class is biological non-specificity: CRP and interleukin-6 reflect inflammation in general, and procalcitonin concentrations are confounded by surgery, trauma, renal dysfunction, sampling time and non-infectious inflammation. These markers are useful components of assessment, the authors conclude, but they cannot capture the host-response complexity embedded in the Sepsis-3 definition of the syndrome.

A second generation of soluble and hematological markers aims to sharpen that picture. Presepsin, a soluble fragment of the innate immune receptor CD14, and mid-regional proadrenomedullin, a marker of endothelial dysfunction and vascular stress, both performed well in a meta-analysis of adult sepsis diagnostics, with proadrenomedullin slightly ahead. In practice, presepsin is framed as an infection and sepsis support marker available for near-patient testing in Europe on a dedicated chemiluminescent platform, while proadrenomedullin is more compelling for severity, deterioration risk and level-of-care decisions. Pancreatic stone protein has gone further down the regulatory road: the FDA cleared the IVD CAPSULE PSP assay on the abioSCOPE nanofluidic system in 2024 as an aid in early detection of sepsis in high-risk adult ICU patients, and it is also certified under the EU In Vitro Diagnostic Regulation. Monocyte distribution width, a measure of monocyte shape variability generated automatically by Beckman Coulter hematology analyzers, illustrates yet another implementation model, embedding a sepsis screening signal directly into the routine complete blood count for adult emergency department patients.

The most conceptually significant shift, however, is toward molecular and cellular host-response diagnostics that classify the patient’s biological state rather than detecting a pathogen or a single inflammatory protein. SeptiCyte RAPID, an FDA-cleared RT-qPCR assay running on the Biocartis Idylla cartridge platform, measures a two-gene expression signature involving PLAC8 and PLA2G7 to help distinguish infection-positive sepsis from infection-negative systemic inflammation in ICU patients on their first day of admission. TriVerity, from Inflammatix, extends the logic with a 29-transcript host-response signature read by automated RT-LAMP on PAXgene whole blood, designed to differentiate bacterial from viral from non-infectious illness and to estimate the likelihood of mechanical ventilation, vasopressors or renal replacement therapy within seven days in adult emergency patients. IntelliSep, from Cytovale, takes a biophysical route, using deformability cytometry to measure the mechanical properties of activated leukocytes and stratify emergency department patients by risk of sepsis with organ dysfunction within three days.

A further layer comes from functional immune assays, which measure what immune cells can actually do after stimulation rather than merely how much of a protein they are producing at baseline. Endotoxin tolerance, the blunting of leukocyte responsiveness to a lipopolysaccharide challenge after prior inflammatory stress, is a well-established model of immune reprogramming in sepsis, and studies of monocyte HLA-DR expression and ex vivo tumor necrosis factor-alpha responses support its clinical relevance. In a 2024 study, patients with positive blood cultures produced significantly less TNF-alpha after LPS stimulation than culture-negative patients, linking bacteremia-associated sepsis to functional innate immune suppression. That biology now underpins SeptiLoop, a CE-marked Class C near-patient test under the EU IVDR in which heparinized whole blood is stimulated with LPS and TNF-alpha is detected by lateral flow, identifying patients at risk of induced immunosuppression during suspected bacterial bloodstream infection. The review notes transparently that one of its co-authors is the founder of the company developing this test, and that it was assessed under the same descriptive criteria as every competing technology.

Artificial intelligence adds a complementary strategy: rather than relying on any single analyte, machine-learning models integrate many weakly informative signals, from vital signs and demographics to routine laboratory values and sepsis biomarkers, into risk scores. The regulated exemplar is the Sepsis ImmunoScore, an FDA-authorized software-as-a-medical-device that combines up to 22 electronic health record inputs, including procalcitonin, CRP and lactate, to assess the presence of or progression to sepsis within 24 hours in adults being evaluated for suspected sepsis. The authors caution, however, that AI is not a substitute for validated biological measurement. Its value depends on representative training data, transportability between institutions, calibration, handling of missing data, explainability, avoidance of alert fatigue, and, crucially, prospective evidence that model-guided actions improve outcomes. The most plausible future, they suggest, pairs regulated biomarkers supplying reproducible biological signals with AI integrating them into clinical context.

Underlying the entire review is a persistent translational gap. A molecule can be biologically plausible and statistically associated with sepsis yet still lack a regulated product, a defined intended-use population, validated decision thresholds, workflow compatibility, or any evidence that acting on the result improves outcomes. The regulatory landscape is also tightening and fragmenting. The EU IVDR has raised the evidentiary and quality bar for in vitro diagnostics, particularly higher-risk and near-patient assays, and the first four modules of the EUDAMED database became mandatory on 28 May 2026, increasing transparency across Europe. Regulatory status, the authors stress, must always be reported by jurisdiction and intended use: CE-IVD certification, FDA 510(k) clearance and other national approvals do not imply identical claims, populations or workflows, and the same biological signal may serve very different decisions, from early recognition and prognosis to antimicrobial de-escalation and immune phenotyping.

The authors are candid about their own limitations. The review involved no formal risk-of-bias assessment, evidence grading or quantitative meta-analysis, and comparisons across technologies are complicated by heterogeneous populations, sepsis definitions, reference standards and endpoints. Regulatory status is jurisdiction- and product-specific and changes over time, and many emerging diagnostics and AI tools still lack prospective studies demonstrating an impact on patient outcomes. Even so, the direction of travel is clear. Sepsis diagnostics are moving beyond isolated inflammatory analytes toward integrated, multi-layered host-response testing, combining soluble severity markers, hematology-derived parameters, transcriptomic classifiers, leukocyte biophysical assays and functional immune measurements. The decisive question for each new test is no longer whether its target is associated with sepsis, but whether a certified product, deployed where clinicians actually work, reduces diagnostic uncertainty at the moments when that uncertainty determines treatment, resource use and survival.

Subject of Research: Translation of sepsis biomarkers from discovery into regulated in vitro diagnostic tests

Article Title: From sepsis biomarker discovery to regulated in vitro diagnostics: evidence, certification status and implementation gaps

Article References: Plata-Menchaca, E. P., & Hernández-Jiménez, E. (2026). From sepsis biomarker discovery to regulated in vitro diagnostics: evidence, certification status and implementation gaps. Frontiers in Medical Technology, 8, Article 1916860. https://doi.org/10.3389/fmedt.2026.1916860

Image Credits: AI Generated

DOI: 10.3389/fmedt.2026.1916860

Keywords: sepsis, biomarkers, in vitro diagnostics, procalcitonin, host response, FDA clearance, EU IVDR, transcriptomics, immune monitoring, artificial intelligence, antimicrobial stewardship, point-of-care testing

The origins of device regulation in Europe are unusual, and arguably the root of many current problems. In the United States, legislation controlling pharmaceutical safety followed deaths from sulfanilamide syrup in 1937, and the first European Economic Community directive on medicines was a direct response to the thalidomide disaster of 1957 to 1962. American device legislation likewise grew out of a 1970 expert report chaired by Theodore Cooper, which attacked an unquestioning acceptance of safety claims unsupported by scientific fact. Europe’s device rules, by contrast, were not precipitated by any scandal and were not designed after objective analysis. They emerged from requests to the European Commission by manufacturers’ trade associations, and when the first Medical Device Directive was drafted in the late 1980s, policymakers applied the so-called New Approach adopted by the Council of Ministers in 1985, a framework intended to harmonise standards for industrial products across the common market, not to safeguard patients.

Under that New Approach, the evaluation of evidence demonstrating that a device conformed with requirements was outsourced to independent, private inspection companies known as notified bodies. Those organisations remain central to the system today: manufacturers must submit technical documentation, quality management systems and clinical evaluation reports to a notified body for all medium-risk Class II and high-risk Class III devices, and for nearly all in vitro diagnostics, before receiving the certificates of conformity required for CE-marking and market access. With hindsight, the authors argue, applying an industrial harmonisation model to high-risk medical devices was a poor decision. Notified bodies effectively act as quasi-regulators, deciding whether devices are approved, yet as private companies operating in a competitive marketplace they are not bound by European requirements for public access to documents. Their dual role also limits the advice they can give to the very companies whose products they assess, because of inherent conflicts of interest, and oversight by national authorities has often been inadequate.

The original directive’s rules were deliberately written in rather abstract terms, leaving manufacturers to decide for themselves what clinical studies were needed. Concerns accumulated over decades: standards varied between notified bodies, some devices reached patients with insufficient evidence, and serious complications and deaths were reported from high-risk implantables approved on claims of equivalence to existing devices without any new clinical investigation. A public consultation launched by the Commission in 2008 eventually produced the Medical Device Regulation, which came into force in 2021, alongside the In Vitro Diagnostic Medical Devices Regulation. The MDR aimed to raise standards of evidence for high-risk devices, but its central requirement remained vague, asking only for clinical data providing sufficient clinical evidence. Common specifications, which would have set mandatory scientific standards for particular device types, were never realised, apparently due to limited regulatory capacity. Instead, guidance documents issued by the Medical Device Coordination Group are voluntary, interpretation varies between member states, and the type of clinical evidence required for new high-risk devices, whether observational or experimental, is still not defined.

The MDR also created unintended consequences for patients. Massive recertification requirements and unpredictable, protracted conformity assessments drove up costs, and manufacturers withdrew some essential products from the market, including well-established technologies and devices designed for children. A perception spread that Europe had become hostile to device innovation, and the Austrian National Public Health Institute is now monitoring device availability on behalf of the Commission. The scheduled five-year review of the legislation was brought forward after intense lobbying from industry and other stakeholders, culminating in the December 2025 draft regulation. At a High-Level Conference on Medical Devices: Innovation and Patient Safety held in Brussels in March 2026, European Commissioner for Health Olivér Várhelyi declared that a major overhaul was absolutely necessary, but insisted it must come without compromising on patient safety. How to reconcile those goals is the central question of the reform.

One project has supplied much of the evidence base for answering it. CORE–MD, Coordinating Research and Evidence for Medical Devices, was funded by the EU Horizon Europe programme from 2021 to 2024 and led by the European Society of Cardiology together with the European Federation of National Associations of Orthopaedics and Traumatology, with support from the Biomedical Alliance in Europe. Every stakeholder group, including national regulatory agencies and notified bodies, contributed to an extensive review of the system. The consortium confirmed deficiencies in the evidence available for high-risk devices, a dearth of randomised trials and a high risk of bias in many published studies. It proposed a progressive framework matching observational studies and controlled trials to each stage of a device’s life-cycle, and separately described alternative methodologies under the banner of large simple trials, including registry trials and pragmatic studies, which could make rigorous randomised evidence feasible at realistic cost.

The contrast with medicines regulation is instructive. The US Food and Drug Administration and the European Medicines Agency both implement scientific approaches to support regulatory decision-making, whereas for devices the EU has emphasised interpretation of legal rules applied by a patchwork of independent organisations. The authors argue that reform should set explicit standards for demonstrating clinical efficacy where needed for high-risk therapeutic implants, while retaining simpler safety and performance requirements for low-risk devices. Clinical evidence should represent women as well as men, and safe, effective technologies should be equitably accessible to all patients, including children and those with rare conditions. The in vitro diagnostics regulation needs its own tailored policies rather than a copy of the device framework: the authors call for relaxed restrictions on sharing laboratory-developed tests between health institutions, and for the abolition of IVDR Article 5.5 d, which forbids use of an in-house test if an equivalent CE-marked product exists, a rule they say stifles diagnostic innovation in favour of market monopolies.

The European Medicines Agency is set to play a much larger role. The MDR already established Expert Panels of independent clinicians and scientists who provide non-binding opinions on notified bodies’ clinical evaluations of selected high-risk devices. The Screening Panel has judged that roughly ten per cent of high-risk submissions require a full scientific opinion; sixteen have been published, most identifying deficiencies in clinical evidence, yet every reviewed device was still granted market access, prompting calls for transparency about how notified bodies act on expert recommendations. A recent analysis of thirty-four opinions found that nearly half of expert comments concerned the sufficiency of clinical evidence supporting benefit–risk determinations. Under the draft regulation, the panels’ remit will expand to advising the Commission, member states, notified bodies and manufacturers, contributing to guidance and common specifications, and designating breakthrough and orphan status for promising devices. The authors welcome this but warn that delivery is impossible without major investment: the Commission unit coordinating the regulations has only one medically qualified officer, while notified bodies employed 4,099 full-time staff in conformity assessment in 2025.

The deeper prescription is cultural as much as legislative. The authors endorse a definition of regulatory science as the use of scientific approaches to determine which policies and standards best assure safety and efficacy, so that approved technologies improve individual outcomes and public health without disproportionate over-regulation. They want regulatory science to become a recognised subspecialty for clinicians, laboratory scientists, epidemiologists, statisticians and engineers, supporting the EMA and notified bodies alike, with medical associations supplying high-quality evidence from comprehensive device registries. CORE–MD insights already shaped consensus recommendations submitted to the Commission by the Biomedical Alliance on behalf of thirty-five professional associations. Among their warnings: easing conditions for establishing equivalence would repeat a mistake that caused major problems under the old directive, and deleting the standard of sufficient clinical evidence risks more subjectivity rather than consistency. A new high-risk implantable, they argue, should not enter an existing class without a randomised trial against an active comparator or evidence from objective performance criteria. With equivalent standards promoted globally through the International Medical Device Regulators Forum, Europe has a chance to break free from recurrent legislative revisions, if it commits to funding regulatory science as a public good.

Subject of Research: Reform of the European Union regulatory framework for medical devices and in vitro diagnostics

Article Title: Empowering regulatory science for medical devices in Europe

Article References: Fraser, A. G., Byrne, R. A., Dequeker, E. M. C., Kjærsgaard-Andersen, P., Kolaček, S., Melvin, T., Nelissen, R. G. H. H., Szymański, P., & Macintyre, E. (2026). Empowering regulatory science for medical devices in Europe. The Lancet Regional Health – Europe, 71, Article 101876. https://doi.org/10.1016/j.lanepe.2026.101876

Image Credits: AI Generated

DOI: 10.1016/j.lanepe.2026.101876

Keywords: medical devices, EU regulation, MDR, IVDR, notified bodies, European Medicines Agency, regulatory science, CORE-MD, clinical evidence, in vitro diagnostics, CE-marking, patient safety

The heart of the technology is deceptively small: spherical nanoparticles roughly 30 nanometers across, each built around a core of iron oxide wrapped in a protective silica shell. This architecture gives the particles two crucial properties at once. The iron oxide core makes them strongly magnetic, allowing them to be maneuvered and concentrated within a sample without the lengthy centrifugation steps that conventional immunoassays demand, while the silica shell provides a chemically stable surface onto which the researchers attach thousands of molecular structures that mimic the antigenic determinants of beta-lactam antibiotics. Ezequiel Pérez-Inestrosa, Professor of Organic Chemistry at the University of Malaga and one of the study’s authors, describes each particle as acting ‘like a tiny magnet covered with thousands of molecular hooks.’ If a patient’s blood contains IgE antibodies responsible for the allergy, those antibodies are captured far more readily than with existing methods.

The significance of that capture efficiency becomes clear when the immunology of drug allergy is considered. IgE antibodies are extraordinarily scarce in the bloodstream, and the allergic response to penicillins is directed against haptens, small chemical fragments that only become immunologically visible when they are covalently bound to carrier proteins in the body. Recreating these hapten-carrier complexes faithfully on a solid support is a formidable synthetic chemistry challenge, and it is precisely where the Malaga team’s organic chemistry expertise proves decisive. By presenting a dense, well-defined array of antibiotic-derived structures on the nanoparticle surface, the platform maximizes the probability that even low-abundance, clinically relevant IgE molecules will bind, and the magnetic separation then allows those bound antibodies to be isolated and measured cleanly against a low background of noise.

Performance in the laboratory translated directly into diagnostic accuracy. In the study, the researchers analyzed blood samples from nearly one hundred people: 50 patients with confirmed amoxicillin allergy and 44 individuals who tolerated these antibiotics without incident. The system detected virtually all true cases of allergy while substantially reducing both false negatives and false positives, according to María José Torres, Professor of Medicine and one of the study’s lead researchers. The platform was benchmarked against two established techniques, ImmunoCAP, the most widely used commercial test, and the conventional radioallergosorbent test known as RAST. The gap in sensitivity, particularly for amoxicillin, was stark. Where the nanoparticle platform flagged 98 percent of confirmed allergic patients, ImmunoCAP managed only around 17 percent, a shortfall that means the majority of genuinely allergic individuals have historically received negative results that offer false reassurance.

The stakes of getting these diagnoses right are far higher than they might first appear. Penicillin allergy is dramatically overdiagnosed. Although between 8 and 25 percent of the population report being allergic to these antibiotics, only between 1 and 10 percent actually are. That gap between perception and reality leaves millions of people carrying an incorrect label in their medical records, and the consequences cascade through their subsequent care. Patients mislabeled as penicillin-allergic are treated with alternative drugs that are generally less effective and more toxic, and the substitution contributes to the emergence of bacterial resistance, one of the most pressing threats in modern medicine. ‘This incorrect label leads to the use of alternative drugs that are generally less effective, more toxic and contribute to the emergence of bacterial resistance,’ Pérez-Inestrosa explains. He stresses that identifying these cases safely would make it possible to remove thousands of incorrect diagnoses that currently shape and constrain patients’ treatment.

Beyond accuracy, the new platform promises to make the diagnostic journey itself safer and simpler. The definitive test for drug allergy has long been the drug provocation test, in which the patient is deliberately given the suspected medication under close medical supervision. It is informative, but it carries genuine risks, including the possibility of triggering a severe systemic reaction, and it requires specialist settings and considerable time. The nanoparticle-based assay, by contrast, can be performed rapidly in the laboratory on a simple blood sample, without exposing the patient to the drug at all and without the lengthy centrifugation procedures that slow down conventional workflows. A reliable in vitro alternative of this kind could allow clinicians to triage patients efficiently, reserving provocation testing only for cases where it is truly necessary.

The study is also a showcase for collaborative, translational science. Alongside the University of Malaga’s Department of Organic Chemistry, where Yolanda Vida and María I. Montañez serve as the study’s lead authors, the work drew on the IBIMA BIONAD Platform, the Inflammatory Diseases Network (REI) and the Regional University Hospital of Malaga, combining synthetic chemistry, materials science, immunology and clinical allergy expertise in a single program. That breadth matters, because a diagnostic technology that lives or dies on the precision of surface chemistry must ultimately prove itself against the messy, variable reality of patient sera, and few single laboratories possess the full range of skills needed to close that loop.

The implications, if the technology survives the scrutiny that now follows, extend beyond the penicillins. Beta-lactams are the world’s most prescribed class of antibiotics, and reliable, rapid allergy diagnosis would unlock first-line therapy for the vast majority of people currently denied it. There are also immediate operational benefits: shorter laboratory turnaround, reduced reliance on radioisotope-based legacy assays such as RAST, and the potential for standardization across centers because the magnetic separation is straightforward to automate. The authors themselves, however, are careful about the pace of translation. In light of their findings, they emphasize the need for further, larger multicentre studies and formal clinical validation before the platform can be introduced into hospitals and used routinely, a prudent stance given that diagnostic tests must perform consistently across diverse populations and instrumentation.

Still, the trajectory of this work is a reminder of how materials science quietly reshapes clinical medicine. Thirty-nanometer spheres of iron oxide and silica, decorated with molecular hooks synthesized by organic chemists, have turned a notoriously unreliable diagnostic corner into something that approaches certainty. For the millions of patients whose misplaced allergy label steers them toward inferior antibiotics, and for the clinicians trying to reconcile a 98 percent sensitivity figure with the 17 percent of the status quo, that tiny magnetic scaffold may prove to be one of the most consequential pieces of chemistry in the allergy clinic in years. The University of Malaga team’s findings, published in Materials Today Bio, mark the point at which magnetic nanoparticles moved from the bench toward a clinically relevant role in the diagnosis of beta-lactam allergy.

Subject of Research: Magnetic nanoparticle-based in vitro diagnosis of allergy to beta-lactam antibiotics such as amoxicillin and other penicillins

Article Title: Uma scientists develop a new technology that improves the diagnosis of allergy to antibiotics such as amoxicillin and other penicillins

Article References: Uma scientists develop a new technology that improves the diagnosis of allergy to antibiotics such as amoxicillin and other penicillins. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: magnetic nanoparticles, penicillin allergy, amoxicillin, beta-lactam antibiotics, IgE antibodies, in vitro diagnostics, ImmunoCAP, drug provocation test, antibiotic resistance, University of Malaga, Materials Today Bio, allergy diagnosis