After hip fracture, older adults experience burdensome treatments and high mortality; they may therefore benefit from palliative care (PC). Best practices for PC integration during inpatient hip fracture care remain understudied. To determine frequency of inpatient PC process documentation for seriously ill older adults with hip fracture and explore clinicians' perspectives on observed documentation patterns. We used an explanatory sequential mixed-methods design. In a cohort of seriously ill adults ≥66 years old admitted for hip fracture from 2016-2019 at an academic health system, natural language processing was used to measure documentation of inpatient PC processes: healthcare proxy designations, code status limitations, goals of care conversations (GOCC), hospice discussions, and specialty PC. We then conducted semi-structured interviews (n=10) with clinicians, exploring perspectives on documentation rates. Transcripts were coded thematically using a mixed deductive-inductive approach. Among 1,433 hip fracture admissions, GOCC, hospice discussions, and specialty PC were documented in <25% each. Clinicians viewed these rates as reflective of under-documentation and under-delivery. Workflow barriers included lack of standardized processes and diffusion of responsibility across interdisciplinary teams. Emphasis on efficient perioperative optimization and minimizing prolonged hospitalizations competed with perceived time for delivery of GOCC and specialty PC. Clinicians described a rescue-oriented surgical culture in which the palliative value of surgical repair for hip fracture paradoxically limited surgeons' view on their role in GOCC. PC process documentation during hip fracture admissions was low. Limited standardization, role uncertainty, and cultural factors limited PC documentation and delivery, highlighting opportunities to strengthen PC integration in surgical care.
Measurement errors may be constant, change in predictable, systematic ways, or vary randomly and unpredictably. When discussing measurement errors, the distinction between systematic and random errors is often poorly characterized. Both systematic and random errors can occur at any stage of the testing process. Errors that occur during the measurement phase can be formally evaluated and quantified, for example, using CLSI evaluation protocol guidelines. Here, we assert that the assignment of measurement error labels, random and systematic, depends on the perspective of the observer and the availability of information. Random errors are usually quantified as imprecision or measurement uncertainty (MU), whereas systematic errors that remain approximately constant over time are quantified as biases. As more information becomes available, errors that were previously perceived as random may become predictable and thus considered systematic. Manufacturers/developers, users, and regulators of measurement procedures (MP) can have very different perspectives, including different levels of available knowledge, and these differences can affect perceptions of which errors are predictable. Therefore, whenever a bias is reported or discussed, its scope must be clearly stated. Similarly, whenever an imprecision or an uncertainty is stated, the sources of variation included in the estimate must also be detailed. Determining whether a source of error is systematic or random in each scenario ensures it can be meaningfully quantified and expressed.
Environmental exposures are increasingly associated with kidney and cardiometabolic disease in children. This review summarizes current understanding of the potentially hazardous effects of air pollution, chemical toxicants, and heavy metal contamination on pediatric kidney health and cardiometabolic risk factors for chronic kidney disease (CKD), as well as the potentially protective effect of green space. We highlight the critical windows of childhood development, during which the kidneys may have varying susceptibility to environmental exposures. We also discuss challenges and possible solutions to adequately powered studies at the intersection of environmental health and pediatric kidney disease. Environmental exposures are both ubiquitous and modifiable. Therefore, elucidating the contribution of environmental exposures to the increasing global burden of CKD will be crucial to informing strategies for kidney disease prevention, starting in childhood. IMPACT: We summarize current evidence on the associations between environmental exposures-including air pollution, chemical toxicants, and heavy metal contamination-and pediatric kidney disease and related cardiometabolic risk factors, as well as the potentially protective effect of green space. We highlight how the impact of environmental exposures on the kidneys may vary during different critical windows of childhood development. Lastly, we discuss methodological challenges and potential solutions, such as using novel technologies and approaches to adequately power studies toward the goal of environmental intervention for chronic kidney disease (CKD) prevention.
Allogeneic transplantation is a cornerstone treatment for hematologic malignancies and organ failure, yet its success is limited by graft-versus-host disease (GvHD) and allograft rejection. Conventional broad-spectrum immunosuppression compromises protective graft-versus-leukemia (GvL) effects and anti-infectious immunity, creating an urgent need for precision tolerance strategies. CD4+Foxp3+ regulatory T cell (Treg)-directed strategies offer a promising solution but expanding stable, functional Tregs ex vivo and in vivo remains challenging. Given the pivotal role of the Tumor Necrosis Factor Receptor Superfamily (TNFRSF) in Treg biology, this review aims to critically examine how its members control Treg function and how these pathways can be leveraged for Treg‑based therapies. We systematically analyze key TNFRSF members - TNFR2, OX40, CD40, Fas, CD27, 4-1BB, GITR, and DR3 - detailing their dichotomous roles in Treg function and translational potential. We highlight how agonism of TNFR2 or DR3 offers selective Treg expansion while preserving GvL activity, and how CD27 and 4-1BB serve as valuable markers for isolating highly suppressive Treg subsets. We further discuss translational challenges, including the paradoxical effects of OX40 and GITR, which can either enhance or impair Treg function depending on the inflammatory milieu, and the vulnerability of Tregs to Fas-mediated apoptosis during ex vivo expansion. We also discuss CD40-CD40L blockade as a complementary strategy to empower endogenous Tregs. By synthesizing current knowledge, this review provides a rational roadmap for using selective agonism, blockade, or phenotypic selection to bolster Treg‑based therapies for GvHD, offering practical information for both laboratory and clinical efforts to optimize Treg manufacturing and achieve durable tolerance.
High biocompatibility and three-dimensional printability of gels make them highly promising for the food industries. Appropriateness of gels for the food industry depends heavily on their mechanical characteristics and molecular dynamics. For identifying dynamic molecular information at the atomic level, molecular docking (MD) and molecular dynamics simulation (MDS) are thought to be viable methods. They can be used as a tool in creating food gels because they may investigate chemical bonding, particular binding sites, changes in spatial structure, and binding energy between molecules, as well as assess the ideal conformation. MD techniques can reveal the biopolymer interactions. Promising methods include data-driven protein engineering, which designs proteins using computer techniques. The history and evolution of MD techniques are discussed in this article, with a focus on their uses in the food-based gel field. Lastly, research avenues for enhancing the quality attributes of food-based gels via MD and MDS are discussed.
Multi-infarct dementia (MID) is a major subtype of vascular cognitive impairment, second only to Alzheimer's disease as a leading cause of dementia worldwide. Unlike neurodegenerative dementias, MID results from recurrent vascular insults, producing stepwise cognitive decline. Animal models have become indispensable for understanding MID mechanisms and testing therapies, yet no single model fully captures human disease complexity. This review synthesizes current knowledge of embolic, chronic cerebral hypoperfusion, hypertensive, and large animal models of MID. We compare methodological strategies, neuropathological features (including white matter injury, neuroinflammation, and blood-brain barrier disruption), and behavioral outcomes. Key limitations include poor replication of infarct heterogeneity, absence of comorbidities, and translational failures. Emerging directions such as multi-hit paradigms and mixed dementia models are discussed. We conclude that integrative, multifactorial models are essential for improving translational relevance and developing effective therapies.
Accumulating evidence indicates that diabetes is associated with increased risk of several cancers. The strongest evidence has been reported for cancers of the breast, colorectum, endometrium, liver, pancreas, and gallbladder. However, distinguishing causal relationships from associations driven by shared risk factors such as obesity, aging, and lifestyle behaviors remains challenging. Several biological mechanisms have been proposed to explain these associations. Key pathways include the effects of insulin resistance and compensatory hyperinsulinemia on mitogenic signaling pathways, including PI3K/AKT/mTOR and MAPK, as well as the influence of adiposity, chronic inflammation, and altered metabolic substrates on tumor initiation and progression. Hyperglycemia may also contribute by promoting tumor metabolism and cellular proliferation, although its independent contribution remains debated. These mechanisms likely interact to create a protumorigenic metabolic environment in individuals with diabetes. Obesity, which frequently co-occurs with diabetes, further amplifies these risks through altered adipokine secretion and increased estrogen production, highlighting the interrelated contributions of metabolic and hormonal factors. The relationship between diabetes and cancer has important clinical implications. Diabetes has been associated with worse cancer prognosis and higher cancer-related mortality, highlighting the importance of integrated management strategies. The impact of antihyperglycemic therapy on cancer risk and progression has been extensively studied, and ongoing research continues to evaluate potential protective or tumor-modifying effects. In this article, we summarize the epidemiologic and pathophysiologic evidence describing the relationship between diabetes and cancer and discuss strategies for risk mitigation, screening, and management.
Nanozymes represent a transformative convergence of chemistry, nanotechnology, and biomedicine, giving rise to a new generation of enzyme-mimicking nanomaterials. Unlike natural enzymes that function optimally within narrow physiological ranges, nanozymes exhibit exceptional structural adaptability, tunable catalytic activity, and superior stability, making them highly promising for translational biomedical and oncological applications. This review focuses on the chemistry-guided design principles that govern nanozyme performance, emphasizing how composition, size, morphology, crystal facets, defect engineering, and surface functionalization collectively influence catalytic behavior. The discussion covers a wide range of enzyme-like activities, such as peroxidase, oxidase, catalase, and superoxide dismutase mimetics, multi-enzyme and cascade catalytic mechanisms and the underlying chemistry of these activities. Furthermore, this review explores the broad biomedical landscape of nanozymes, spanning biosensing, diagnostics, tumor microenvironment (TME) modulation, reactive oxygen species (ROS)-mediated cancer therapy, antibacterial and antioxidant interventions, imaging, theranostics, and tissue engineering. Special emphasis is placed on the emerging role of nanozymes in cancer diagnosis, targeted therapy, cancer nanotheranostics, and precision oncology. Despite remarkable progress, challenges persist regarding toxicity, substrate specificity, in vivo stability, and large-scale reproducibility. Advances in rational chemical design, computational modeling, green synthesis, and integration with smart nanomedicine approaches are expected to address these limitations. In essence, this review underscores that chemistry not only drives the creation of nanozymes but also directs their evolution into next-generation oncological and biomedical platforms, enabling precise, multifunctional, and patient-tailored therapeutic strategies for translational cancer medicine.
Rarity provides a challenging case for contemporary priority setting. On the one hand, many philosophers and economists argue that rarity has no inherent moral value, and thus that rare diseases merit no special treatment in priority setting decisions simply because they are rare. On the other hand, existing priority-setting practices demonstrate a higher willingness to pay for rare disease treatments. We argue that special priority for rare diseases might be justified on egalitarian grounds. Specifically, we develop and defend what we call the "bad numbers luck" argument for prioritizing rare diseases. This is a variant of the luck egalitarian idea of bad price luck. We conclude by discussing how higher willingness to pay, adjusted priority-setting processes, and a broader societal focus on rare diseases could address such injustices. Recognising bad numbers luck clarifies the relationship between fairness and efficiency in health care priority setting.
The mechanical responses and properties of breast epithelial cells are known to change during malignant transformation and progression due to the dynamics of their actin cytoskeleton network organization and the resulting viscoelastic deformability. Studying the viscoelastic creep behavior of breast cells may reveal new avenues for developing novel cancer diagnostic and therapeutic biomarkers and improving fundamental biophysical understanding of the disease. Here we present an approach that uses functional principal component analysis (fPCA) to distinguish between the viscoelastic responses of malignant and non-malignant live breast cells that are subjected to shear flow in microfluidic channels under in-situ observation with optical, fluorescence, and confocal microscopy. The fPCA method extracts critical features of cell viscoelasticity from the in-situ measured creep responses of non-tumorigenic breast cells (MCF-10A), less metastatic triple-negative breast cancer (TNBC) cells (MDA-MB-468), and highly metastatic breast cancer cells (MDA-MB-231). The results demonstrate distinguishable clustering patterns for the three types of cells in the first principal component (PC) and the second PC space. The first PC, indicative of the overall level of creep compliance, accounts for more than 98% of the total variance in the observed creep responses. The scores of the cells examined on the first PC axis increase with increasing cancer malignancy. They also correlate highly with the average moduli and viscosities extracted from viscoelastic models (-83% correlation with moduli and -85% correlation with viscosities). This suggests a direct link between the malignancy of cancer and the overall creep compliance level that is governed by cell viscoelastic properties. The implications of the results are discussed for the detection of non-tumorigenic and tumorigenic breast cells at different stages of cancer progression.
To describe the structure and benefits of an Academic Pharmacy elective designed on the pillars of academia: Teaching, Scholarship, and Service. The Academic Pharmacy elective was developed as an introduction to the career of pharmacy faculty framed in the academic pillars of teaching, scholarship, and service. The three-credit elective was divided into two hours of weekly class meetings and one credit hour consisting of 30 h of in-person practical teaching in the first-year skills laboratory course as a near peer teachers (NPT). The elective met weekly for an in-person two hour lecture over 15 weeks. The course employed a threshold-based honors, pass, and fail grading system that emphasized participation and major projects, including development of a scholarship project plan and completion of an educational design activity. The pillar of service was addressed through course classroom discussions. Since 2018, 54 third-year students have completed the elective, with approximately six to seven each year (range of four to twelve students per year). Students enrolled in the elective have collectively taught 1620 h over the past eight years. The scholarship projects have led to 32 poster presentations and 8 manuscripts with the third-year students and course coordinators. Course coordinators utilized the pillars of academia to design the Academic Elective. Faculty and the institution have recognized the impact on teaching and scholarship through quantity of teaching hours and number of scholarly outputs, respectively. However, the impact of the scholarship aim for the course has not been well captured and may require additional structured methods to assess student contributions and participation in this pillar. This manuscript describes how this elective was designed, so that faculty from other institutions may consider if they want to implement a similar structured elective.
Mammalian models are widely employed in the research of human diseases. Behavioral tests in animals is a critical evaluative approach in scientific research, offering insights into complex disease pathophysiology and facilitating the assessment of novel therapeutic interventions. Currently, behavioral testing paradigms are extensively applied in mammalian research, particularly in rodent models. Compared to rodents, the brains of large mammals exhibit closer anatomical and biochemical homology to the human brain, thereby endowing them with significant value in neuroscience. Numerous neurological disorders have been successfully used large mammals as models, with the widespread application of behavioral testing methods for these species. This review summarizes established behavioral testing methodologies developed for both small and large mammalian species, and discusses their applications, efficacy, and limitations.
Maple syrup urine disease (MSUD) is an autosomal recessive inborn error of metabolism caused by a deficiency of branched-chain ketoacid dehydrogenase, the enzyme involved in the second step of branched-chain amino acid catabolism. Of the three branched-chain amino acids (leucine, valine, and isoleucine), accumulation of leucine is the predominant factor causing acute metabolic decompensation in patients with MSUD. In February 2025, eight expert physicians met to discuss the management of acute metabolic decompensation and propose recommendations after literature review (four guidelines and 20 other articles of interest). A practical clinical algorithm was established. Newborn screening was acknowledged to be a successful method of diagnosing MSUD at birth, facilitating early intervention to prospectively manage MSUD and reduce the frequency and severity of acute metabolic decompensation, although it was noted that infants with severe MSUD often present with acute metabolic decompensation before being diagnosed. The experts also identified several barriers to and gaps in the management of acute metabolic decompensation, and MSUD more generally, proposing potential actions to improve clinical outcomes. Acute metabolic decompensation requires prompt, effective treatment by a multidisciplinary team to ensure that circulating plasma leucine levels are rapidly reduced without causing complications (particularly cerebral edema). Where available, intravenous branched chain amino acid-free solutions (e.g., Maapliv, now approved in Europe) may represent an important treatment option. Adequate resources (treatments, laboratory services, dialysis units) are essential for effective management of acute metabolic decompensation. Liver transplantation is an accepted viable option for the long-term prevention of acute metabolic decompensation in eligible patients. Research is ongoing into new treatment options for MSUD, such as gene therapy. Optimal management of acute metabolic decompensation in patients with MSUD requires prompt, effective treatment to reduce leucine levels without causing complications. A ready-to-use branched chain amino acid-free intravenous solution has been recently approved in Europe and research into new treatment options is ongoing.
Microplastics (MPs) have emerged as pervasive contaminants in aquatic environments and are increasingly recognized as a critical stressor in constructed wetlands (CWs). To systematically evaluate the behavior and fate of MPs, this review followed PRISMA guidelines, retrieving and screening over 405 peer-reviewed publications from 2019 to 2025 across Web of Science, Scopus, and Google Scholar. Using a rigorous inclusion criterion based on data quality and experimental relevance, 131 key studies were selected for in-depth synthesis and comparative analysis. Beyond serving as effective physical barriers that consistently achieve removal efficiencies exceeding 90%, CWs function as dynamic biogeochemical reactors where MPs undergo extensive aging, transformation, and biofilm colonization, thereby triggering complex long-term ecological risks. The roles of plants, substrates, microorganisms, and animals in MPs retention and transformation are critically evaluated, together with the influence of MPs properties (polymer type, size, and morphology) and wetland configurations on removal efficiency. Furthermore, the ecological responses of CWs under MPs exposure are comprehensively discussed. MPs exposure was found to significantly alter microbial community diversity, potentially inhibiting nitrogen removal and promoting greenhouse gas (CH4 and N2O) emissions. Particular attention is given to the aging behavior of MPs, additive release, pollutant adsorption, and their coupled ecological risks. Current challenges, such as the lack of standardized extraction methods and insufficient understanding of MPs-induced clogging, are identified. Finally, future research directions are proposed to enhance MPs management in CWs, aiming to balance pollutant removal performance, ecological safety, and long-term sustainability of wetland systems.
Periprosthetic joint infections (PJIs) are one of the most dreaded complications of arthroplasty. Although relatively rare with an incidence of 1-2%, the absolute burden of PJIs is growing over time as the volume of performed arthroplasties increases. PJIs are associated with significant morbidity, mortality, and healthcare costs. Treatment is challenging and may require multiple revision surgeries, reimplantation, and/or amputation. The main issue is the delayed detection of PJIs, which permits progression of the infection into robust biofilms resistant to conventional antimicrobials. Early-detection strategies should focus on identifying infection during the pre-biofilm, planktonic phase, when it remains responsive to medical therapy. Implantable smart sensors are an innovative way to obtain local, real-time monitoring of the implant microenvironment to achieve this objective. In this translational review, an overview of PJIs and biofilm formation will first be provided. The current diagnostic approach to PJIs will then be reviewed along with its limitations to highlight opportunities for innovation. Fundamentals of smart sensor technology and examples of devices designed to detect markers of early infection will then be discussed. Research on smart sensors for the post-operative monitoring of orthopedic implants is in its infancy and has yet to be widely adopted into clinical practice. Strengths, limitations, and clinical significance of smart sensors in development will be discussed to inform recommendations on future directions. STATEMENT OF SIGNIFICANCE: Periprosthetic joint infection (PJI) is one of the most serious complications after hip and knee replacement surgery, yet current diagnostic tests often fail to detect infection early, when treatment is most effective. This review is the first to comprehensively evaluate the potential of implantable "smart sensors" that can monitor the joint environment in real time to detect early signs of infection. By comparing different sensor designs and highlighting both opportunities and limitations, our work bridges orthopaedic surgery, materials science, and bioengineering. These insights are significant for guiding future biomaterial-based diagnostics, with the long-term goal of improving outcomes for the rapidly growing population of patients undergoing joint replacement worldwide.
Anaphylaxis during pregnancy is a rare but potentially life-threatening condition for both mother and fetus, requiring rapid recognition and immediate treatment. Although the fundamental mechanisms of anaphylaxis in pregnancy are similar to those in nonpregnant women, physiological adaptations of pregnancy, peripartum exposures, and fetal considerations substantially complicate diagnosis, management, and prevention, contributing to variability in care and avoidable adverse outcomes. In this multidisciplinary review, experts in allergy-immunology, obstetrics, anesthesiology, and epidemiology synthesize current evidence on the epidemiology, triggers, pathophysiology, diagnostic challenges, management, outcomes, and prevention of anaphylaxis throughout pregnancy, labor, and delivery. We highlight how gestational cardiovascular and respiratory changes may obscure classic diagnostic features, emphasize the safety and critical importance of prompt intramuscular epinephrine use as first-line therapy, and review maternal and fetal outcomes associated with timely versus delayed intervention. Strategies for risk stratification, allergology workup, prevention of recurrence, and implementation of coordinated care pathways are discussed. This review underscores the need for increased awareness, structured interdisciplinary collaboration, and integration of prevention-focused strategies across obstetric and allergy care. By providing a practical, evidence-based framework, it aims to support health professionals in optimizing diagnosis, management, and maternal-fetal safety when anaphylaxis occurs during pregnancy.
Determining trace heavy metals (Cd, Pb, Hg, As) in food remains challenging due to complex matrix interferences from proteins, lipids, and coexisting ions. Metal-organic frameworks (MOFs) and covalent organic frameworks (COFs) are promising sensing platforms owing to their high surface area and task-specific functionalization. Crucially, MOF-COF hybrids engineered via precise interfacial design exhibit enhanced conductivity, stability, and anti-interference capabilities, significantly improving robustness in food matrices. This review summarizes recent progress in utilizing functional MOFs, COFs, and their hybrids for food safety monitoring. It emphasizes synergistic structural design, sensing mechanisms, and matrix-resistant signal transduction. Furthermore, we discuss representative applications and portable point-of-care testing (POCT) devices. Finally, the review outlines current limitations and future directions to guide the practical deployment of robust MOF/COF sensors for accurate heavy metal detection in real food samples.
Mitochondria are central hubs of cellular metabolism and signalling, and their dysfunction underlies a broad spectrum of human diseases, including rare mitochondrial disorders as well as common neurodegenerative and metabolic conditions. Mitochondrial diseases are genetically heterogeneous disorders caused by mutations in nuclear or mitochondrial DNA that impair oxidative phosphorylation (OXPHOS), resulting in reduced ATP production and cellular energy failure. Despite a shared bioenergetic defect, these diseases display marked clinical variability, and the mechanisms underlying this heterogeneity remain poorly understood. At present, no curative therapies are available, although several metabolic and experimental approaches have shown promise in preclinical models. Mitochondrial dysfunction is commonly associated with altered redox homeostasis and increased production of reactive oxygen species (ROS), which can damage mitochondrial components, including mitochondrial DNA, and further impair respiratory chain function. At the same time, ROS also act as context-dependent signalling molecules, with effects that vary according to concentration, localization, and cell type complicating their interpretation in disease mechanisms and therapy development. In this review, we summarize current concepts in mitochondrial disease pathophysiology focusing on unresolved questions that limit mechanistic understanding and clinical translation. We critically evaluate the role of ROS in disease progression and signalling, discuss how the alternative oxidase (AOX) has emerged as a valuable experimental tool to dissect ROS-related mechanisms and reveal unexpected aspects of mitochondrial dysfunction and disease variability.
Malnutrition is common in adult patients with cancer and is associated with increased complications, treatment toxicity, and mortality. Accurate estimation of energy requirements is essential to individualize nutrition care; however, resting energy expenditure (REE) in oncology is highly variable due to tumor characteristics, disease stage, inflammation, and treatment effects. Predictive equations and weight-based estimates may fail to capture these metabolic differences, potentially leading to inappropriate nutritional prescriptions. This case-based tutorial aims to illustrate the clinical interpretation and application of indirect calorimetry (IC) in adult oncology patients. Nine adult oncology patients were selected to represent a range of common and complex metabolic scenarios encountered in practice. Cases were obtained from ambulatory and inpatient settings across multiple tumor types and treatment stages. Clinical context, nutritional history, anthropometric measures, body composition and handgrip strength, Global Leadership Initiative on Malnutrition (GLIM) classification, and IC measurements are presented. Case discussions interpret measured REE, estimated total energy expenditure (TEE) accounting for physical activity level, and energy balance relative to intake. Measured REE showed heterogeneity across clinical scenarios, including both hypermetabolic and hypometabolic states. In several cases, IC-derived energy requirements differed markedly from the guideline weight-based recommendation in oncology. Some factors associated with variability included inflammation, liver metastases, sarcopenia, and surgery. These clinical scenarios illustrate the marked variability in REE in oncology patients and demonstrate how IC can provide more accurate energy assessments than weight-based recommendations. This case-based tutorial highlights the role of IC in guiding individualized nutritional assessment and supporting precise energy prescription in oncology.
While the liver has astonishing regenerative capabilities, its potential wanes in pathological conditions such as fibrosis, cirrhosis and carcinoma, posing significant global health challenges. The regenerative process is critically dependent on the regulated cellular signals, extracellular matrix (ECM), and its mechanical dynamics. Accordingly, hydrogel-based tissue engineering strategies replicate the liver ECM microenvironmental architecture, including bioactivity, biocompatibility, porosity, and stiffness. Studies have demonstrated that hydrogels, whether derived from natural polymers, synthetic materials, or decellularised liver tissue, can be fine-tuned in their properties. However, many fail to recapitulate the dynamic mechanical, immunological, and vascular cues required for regeneration. Studies have reported that the ECM-derived hydrogel helps preserve the phenotype (KRT, AAT, HNF4α) and functions (CYP activity, albumin & urea production) of hepatocytes. Therefore, dECM-based hydrogels are particularly important for cellular transplantation and the delivery of bioactive agents for liver regeneration. However, deviations from the normal stiffness range of 4-6 kPa may trigger pathological responses, such as hepatic stellate cell (HSC) differentiation into myofibroblasts, leading to liver fibrosis. Ineffective decellularisation can cause scaffold rejection during transplantation. Additionally, because vascularisation is critical given the liver's rich blood supply, endothelial cells tend to spread randomly within hydrogel scaffolds. The random spreading of endothelial cells can lead to the deformation of lobular zonation, which profoundly impacts hepatocyte functions and has been documented to affect conditions like hepatocellular carcinoma and alcoholic/non-alcoholic fatty liver disease (AFLD/NAFLD). In discussing hydrogel-based strategies, the article highlights the importance of addressing immunogenic concerns and matrix remodelling during decellularisation. It also argues that current studies lack integration of vascular-based zonation, which is fundamental to accurately mimicking the liver's native structural and functional architecture. This approach will facilitate the development of relevant patient-specific models.