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    David Alexander Christian Messerer, Paul Müller, Lisa Wohlgemuth, Frederik Münnich, Laura Stukan, Adam Omar Khalaf Mohamed, Jürgen Benjamin Hagemann, Alexander Sebastian Koller, Darko Jovanovski, Simon Lauer, Rebecca Traut, Leonard Schöbel, Bertram Dietrich Thomaß, Finn Münnich, Eberhard Barth, Manfred Weiss, Andreas Liebold, Bettina Jungwirth, Markus Huber-Lang

    Corrected Proof
    (2026) DOI: 10.1016/j.mmr.2026.100010
    Abstract：Background:Early recognition of sepsis remains difficult in clinical practice because conventional humoral biomarkers such as C-reactive protein, procalcitonin, and interleukin-6 (IL-6) exhibit unfavorable, slow-release kinetics and rise hours after the onset of infection. Flow cytometry enables upstream, cell-based immunomonitoring, but its clinical use is restricted by poor standardization of fluorescence measurements. In this study, the neutrophil cellular response capacity (CRC) was developed and evaluated as a standardized approach for rapid assessment of systemic inflammation in bacteremia and sepsis.Methods:The CRC is based on a flow cytometry-based framework that defines a stable maximal stimulation reference point for neutrophil granulocytes. The CRC was evaluated in a human ex vivo whole blood bacteremia model with graded exposure to Escherichia coli and compared with humoral inflammatory markers. Next, the CRC was assessed in a prospective intensive care unit sepsis cohort. Moreover, preliminary validation was performed in an independent sepsis cohort and in patients undergoing cardiac surgery.Results:In the bacteremia model, the CRC of neutrophil markers CD10, CD11b, and CD66b increased in a dose-dependent manner with increasing bacterial burden and detected inflammation at lower pathogen burdens than IL-6 and other humoral mediators, with a superior area under the receiver operating characteristic curve. In clinical sepsis, the CRC discriminated patients from age- and sex-matched healthy volunteers, with the CRC of CD11b showing the highest diagnostic performance. CRC values increased over time in patients with sepsis, consistent with immunological recovery. The maximal stimulation reference point for CD11b remained stable across inflammatory states, cohorts, and instruments. In addition, the CRC more precisely captured the onset and resolution of surgery-induced inflammation than conventional biomarkers.Conclusions:The CRC provides a rapid, standardized, and robust cell-based immunomonitoring tool that outperforms traditional humoral markers in experimental bacteremia and reliably identifies sepsis in clinical cohorts, strongly supporting its use as a novel biomarker for earlier, more precise sepsis diagnosis and monitoring.  
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  • REVIEW

    Cheng-Kun Cao, Xin-Yi Xu, Fei Liang, Min Yao, Yuan-Yuan Chen, Xiao-Kun Li, Zhi-Jian Su

    Corrected Proof
    (2026) DOI: 10.1016/j.mmr.2026.100009
    Abstract：Nanobodies (Nbs), the antigen-binding single-domain fragments derived from camelid heavy-chain antibodies (Abs), have rapidly become a focus of biomedical research due to their compact size, high stability, strong antigen affinity, and ease of molecular engineering. This review systematically outlines their structural and functional features, current strategies for acquisition, screening, optimization, and large-scale production, and comprehensively discusses their wide-ranging applications in therapeutics, diagnostics, and basic research. Specifically, Nbs have shown outstanding efficacy in tumor, toxin, infectious, and cardiovascular disease treatments, while serving as versatile tools for molecular imaging, biosensing, protein purification, structural analysis, and intracellular regulation. The challenges of immunogenicity, off-target effects, and industrial-scale manufacturing are also critically examined. Furthermore, the integration of artificial intelligence in structure prediction, de novo design, and immunogenicity assessment has opened powerful new avenues for rational Nb engineering. Combined with emerging technologies such as gene therapy, nanomaterial delivery, and multispecific architectures, these advances promise to accelerate clinical translation. Overall, Nb technology is poised to become a cornerstone of next-generation precision medicine and biotechnology, offering innovative solutions for disease diagnosis, targeted therapy, and molecular discovery.  
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  • RESEARCH

    Minjin Jeong, Lucas G. Vattino, Maja Djurisic, Kevin P. Rose, Hiroshi Hyakusoku, Svetolik Spasic, Xiao-Jie Ma, Hiroaki Mohri, Ronna Hertzano, Anne E. Takesian, Konstantina M. Stankovic

    Corrected Proof
    (2026) DOI: 10.1016/j.mmr.2026.100008
    Abstract：Background:Spiral ganglion neurons (SGNs) relay auditory sensory information from the cochlea to the brain. Their loss results in permanent hearing impairment in humans due to their limited regenerative capacity. Progress in hearing restoration has been constrained by the inaccessibility of human inner ear tissue and challenges in generating functionally mature human SGN-like neurons from stem cells in vitro.Methods:To generate human SGN-like neurons from human induced pluripotent stem cells (hiPSCs), we recapitulated key signaling pathways involved in human inner ear development. On day (D) 11 of differentiation, nerve growth factor receptor-positive cells (precursors of pre-placodal ectoderm and neural crest) were isolated using magnetic sorting. From D18 to D25, cultures were treated with sonic hedgehogs to induce otic neural progenitors. Neuronal maturation was subsequently promoted by a cocktail of brain-derived neurotrophic factor, neurotrophin-3, and insulin-like growth factor-1, which supports SGN development. Cellular identity and functionality were assessed using single-cell RNA sequencing, immunocytochemistry, whole-cell patch-clamp electrophysiology, co-culture assays, and calcium ion (Ca2+) imaging.Results:hiPSC-derived SGN-like neurons exhibited morphological, molecular, electrophysiological, and functional characteristics of SGNs in vivo. Neurons acquired bipolar morphology and were wrapped by glial cells. Transcriptomic analysis revealed that SGN-like neurons were distinct from other neuronal lineages and showed similarity to type I and type Ⅱ SGNs based on expression of synaptic and intrinsic excitability-related genes. Electrophysiological recordings revealed progressive hyperpolarization of resting membrane potential and emergence of overshooting action potentials, consistent with neuronal maturation. In co-culture systems, human SGN-like neurons formed functional synaptic connections with mouse cochlear hair cells and cochlear nucleus neurons, evidenced by Ca2+ transients and induction of the immediate early gene c-Fos.Conclusions:This study reports a robust and reproducible protocol for generating human SGN-like neurons from hiPSCs, providing a versatile platform for studying human auditory development, disease modeling, drug screening, and cell-based therapies for hearing restoration.  
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  • REVIEW

    Wei Long Ng, Paulo Bartolo

    Corrected Proof
    (2026) DOI: 10.1016/j.mmr.2026.100006
    Abstract：Three-dimensional (3D) bioprinting integrates engineering, materials science, and biology to fabricate living tissues with precise spatial control. By enabling the layer-by-layer deposition of cells and biomaterials, it overcomes many limitations of traditional scaffold-based tissue engineering and offers new opportunities for regenerative and personalized medicine. This review presents a comprehensive overview of recent advances in 3D bioprinting. It introduces a systematic, ASTM-aligned classification of key bioprinting modalities, extrusion, jetting, and vat photopolymerization, along with their respective material and biological design requirements. It also summarizes recent progress in bio-ink development and crosslinking strategies that improve print fidelity and functional tissue maturation. In addition, the review highlights applications in both systemic disease modelling and treatment (such as cardiovascular, endocrine/metabolic, and neurodegenerative disorders) and localized tissue repair (including skin, musculoskeletal, cartilage, and bone), emphasizing their relevance to civilian healthcare and military medicine. By combining technological innovation, biological insights, and regulatory considerations, this review outlines how advances in multi-modal bioprinting and intelligent process control can accelerate the translation of laboratory research into clinically viable, patient-specific therapies, driving the next generation of regenerative medicine.  
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  • REVIEW

    Noor Obaidi, Olivia Agee, Irene Yau, Robert Moritz, Kristo Nuutila

    Corrected Proof
    (2026) DOI: 10.1016/j.mmr.2026.100007
    Abstract：From cold-weather training to deployments in high altitude and arctic conditions, frostbite injury and its sequelae remain a serious concern in military operations. Frostbite harms tissue in two distinct ways. The first involves ice crystal formation within tissue, resulting in mechanical damage and ischemia. The second occurs secondary to the inflammatory and prothrombotic state caused by reperfusion from rewarming frozen tissue. Frostbite injuries can be classified in a number of ways, but no perfect system exists. Initial work-up and diagnosis are primarily clinical. However, in equipped treatment facilities, advanced imaging modalities such as technetium-99m (99mTc) bone scintigraphy, magnetic resonance angiography, single-photon emission computed tomography/computed tomography (SPECT/CT), and more can play a role in diagnosis and treatment. In resource-constrained environments, such as the deployed setting, management should involve an algorithmic approach. After concurrent hypothermia and/or trauma have been evaluated for and treated, active rewarming should take place so long as there is no risk of refreezing. During re-warming, surgical consultation and evacuation considerations should be considered. Once evacuated to a definitive treatment facility, thrombolytic as well as other therapies may be indicated. Unless there is evidence of severe damage or infection, surgical management is typically delayed until injury margins are fully demarcated. Longer-term prognosis is dependent on severity, with deeper injuries often resulting in longer hospital stays, more amputations, and chronic disability. Looking forward, future frostbite research should aim to bridge field and hospital care with the goal of minimizing tissue loss and accelerating functional recovery.  
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  • RESEARCH

    Qing-Qing Wu, Yang Xiao, Ying-Ying Hu, Xiang-Yu Yang, Xin-Yi Yan, Ke-Qiong Deng, Zhi-Li Jin, Wei Zhang, Jian-Lei Cao, Li-Hua Ni, Yong-Zhen Fan, Zhi-Bing Lu, Xiao-Rong Hu

    Corrected Proof
    (2026) DOI: 10.1016/j.mmr.2026.100004
    Abstract：Background:Mitochondrial quality control is essential for limiting myocardial injury induced by ischemia/reperfusion(I/R), a major contributor to adverse outcomes after reperfusion therapy. This study aimed to determine whether the deubiquitinase ubiquitin-specific protease 18 (USP18) regulates mitophagy during cardiac I/R injury and thereby represents a potential therapeutic target to attenuate myocardial I/R injury.Methods:Cardiac-specific USP18 knockout mice were subjected to cardiac I/R injury. To elucidate the role of USP18 in mitophagy regulation and cardiac I/R injury, we performed RNA sequencing, proteomic mass spectrometry, transmission electron microscopy, and mitophagy assays. In parallel, adeno-associated virus serotype 9 (AAV9)-mediated overexpression of USP18, knockdown of Parkin and phosphatase and tensin homolog-long (PTEN-L), and administration of an anti-PTEN-L neutralizing antibody were used to elucidate the underlying mechanisms. Additionally, serum samples from patients with ST-segment elevation myocardial infarction (STEMI) were collected to assess clinical relevance.Results:USP18 expression was upregulated in mouse hearts following I/R injury and in ischemic human heart tissue. Cardiac-specific USP18 deficiency mitigated I/R-induced acute myocardial injury, mitochondrial dysfunction, and adverse cardiac remodeling, whereas USP18 overexpression exacerbated these pathological changes. Mechanistically, USP18 interacted with PTEN-L, which in turn bound to and inhibited the phosphorylation and translocation of Parkin to mitochondria, thereby suppressing mitophagy. Parkin knockdown abolished the cardioprotective effects conferred by USP18 deficiency, whereas PTEN-L knockdown reversed the detrimental effect of USP18 overexpression. Moreover, PTEN-L also exerted pathogenic effects via a paracrine mechanism, as neutralizing PTEN-L with an antibody attenuated cardiac I/R injury. Serum PTEN-L levels were elevated in STEMI patients, particularly postintervention.Conclusions:USP18 impairs mitophagy and exacerbates cardiac I/R injury through a PTEN-L-Parkin axis, involving both intracellular and paracrine mechanisms. Targeting the USP18-PTEN-L pathway may represent a novel therapeutic strategy to alleviate myocardial I/R injury.  
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