Abstract
Polytrauma with predominant musculoskeletal (MSK) injury, resulting from blast, blunt, and crush mechanisms, remains a leading and complex challenge in both military and civilian medicine. These injuries not only disrupt tissues structurally but also trigger systemic cascades involving immune imbalance, endothelial dysfunction, mitochondrial stress, and premature cellular senescence. Such pathological processes contribute to both immediate clinical instability and long-term complications such as fibrosis, aberrant bone formation, neuroinflammation, and chronic disability. Conventional injury assessments, which rely heavily on anatomical scoring and nonspecific blood markers, fail to capture the dynamic molecular landscape underlying these conditions. To address this critical gap, we performed a comprehensive scoping review integrating evidence from basic science, translational studies, and clinical research published between January 2000 to June 2025, with particular emphasis on recent advances. The review highlights the discovery and validation of emerging blood-based and molecular biomarkers, including fatty acid-binding protein 3, syndecan-1, galectin-3, and trauma-associated microRNAs, as well as innovative diagnostic paradigms such as wearable biosensors, minimally invasive liquid biopsy platforms, and artificial intelligence (AI)-driven analytics. Unlike prior reviews, our analysis uniquely integrates findings across both military and civilian trauma contexts, providing actionable frameworks for clinical application. Building on these insights, we outline a practical roadmap: 1) deploy integrated multi-marker panels for early risk stratification, 2) expand inclusive trauma biobanking to capture diverse injury phenotypes, and 3) use adaptive, data-driven tools for real-time triage and personalized intervention. This approach links acute systemic responses to downstream recovery and rehabilitation, offering actionable guidance for both military and civilian trauma systems.
Keywords: Musculoskeletal (MSK) injury, Polytrauma, Biomarkers, Endothelial dysfunction, Biosensors, Artificial intelligence (AI)
1. Background
Polytrauma resulting from blast, blunt, and crush mechanisms, frequently involving severe musculoskeletal (MSK) injury, represents a defining challenge of modern warfare and an enduring global health burden across civilian populations [1], [2], [3], [4], [5], [6]. On the battlefield, high-energy injuries from blasts, gunfire, vehicular rollovers, and other combat exposures dominate the trauma spectrum [7], with U.S. Joint Trauma analyses demonstrating a predominance of extremity injuries in modern combat, frequently manifesting as open fractures, vascular disruption, polycompartmental muscle injury, and traumatic amputation [8]. Importantly, these patterns are not unique to military environments. Analyses from the World Health Organization, alongside reports from recent conflicts, including Ukraine and Gaza, demonstrate that urban combat, mass-casualty events, and constrained evacuation and surgical resources produce comparable high-acuity injury profiles in both combatants and civilians [9], [10], [11], [12]. These converging trends emphasize the urgent need for adaptable, scalable trauma systems capable of responding to increasingly complex injury patterns across both military and civilian settings, where delays in evacuation and constrained rehabilitation resources amplify both acute mortality and long-term disability [13].
The term polytrauma with significant MSK injury refers to mechanism-driven traumatic injury in which MSK damage is a dominant contributor to systemic pathology, rather than the primary causal insult. In civilian contexts, such polytrauma with significant MSK injury arises from road traffic accidents, industrial and agricultural hazards, falls, interpersonal violence, and increasingly, natural disasters [14]. Road traffic injuries alone account for more than 1.3 million deaths and up to 50 million nonfatal injuries annually, with over 90% of fatalities occurring in low- and middle-income countries (LMICs) [15]. Large-scale disasters, such as the 2015 Nepal earthquake [15] and the 2023 Türkiye-Syria earthquake [16], have demonstrated the catastrophic orthopedic and soft-tissue trauma caused by crush injuries, further emphasizing the need for scalable and context-specific interventions.
Despite differences in biomechanics, blast, blunt, and crush injuries converge on several common systemic pathways that extend beyond structural tissue disruption [17], [18]. Blast trauma generates high-pressure shockwaves and rapid acceleration-deceleration forces [19]; blunt trauma results from sudden compressive and shear loading [20]; crush trauma reflects prolonged compression with ischemia-reperfusion injury [21]. All three activate shared molecular cascades: damage-associated molecular patterns (DAMPs) such as high-mobility group box 1 (HMGB1) [22] and mitochondrial DNA (mtDNA) initiate Toll-like receptor (TLR) and NOD-like receptor (NLR) signaling [23], leading to immune dysregulation, endothelial dysfunction, mitochondrial stress, and premature cellular senescence. These systemic responses drive sepsis, multi-organ dysfunction, heterotopic ossification (HO), chronic inflammation, and impaired tissue repair [24], [25]. Importantly, most existing diagnostic and classification systems, such as the Injury Severity Score or Gustilo-Anderson classification [26], remain anatomically oriented and fail to capture this evolving biology, limiting their ability to reflect evolving systemic and molecular pathophysiology. This disconnection between structural scoring and systemic pathophysiology represents a central barrier to advancing precision trauma medicine. Although leading reviews have previously detailed the systemic consequences and immunopathology of trauma [27], [28], the current work uniquely integrates developments in multi-omics, molecular biomarkers, and digital diagnostics to propose a unified, evidence-driven framework for both military and civilian trauma care.
To address this gap, the present review integrates emerging evidence across three domains: 1) the shared and divergent molecular mechanisms of blast, blunt, and crush injuries; 2) the discovery and application of translational biomarkers for risk stratification and real-time monitoring; and 3) novel therapeutic frontiers spanning immunomodulators, endothelial stabilizers, regenerative interventions, and senotherapeutics. By bridging military and civilian perspectives, we outline a pathophysiology-informed framework for trauma management that links early molecular events to downstream systemic, functional, and psychosocial outcomes, thereby supporting scalable, lifespan-spanning solutions for global trauma systems.
2. Search strategy and review methodology
This review employed a structured narrative methodology with scoping elements to synthesize current evidence on the pathophysiological mechanisms, diagnostic innovations, and biomarker frontiers relevant to polytrauma with significant MSK injury across both military and civilian settings. While informed by principles of the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for scoping reviews (PRISMA-ScR), the framework was deliberately adapted to balance systematic rigor with flexibility, enabling integration of findings from preclinical mechanistic studies, translational research, and clinical investigations [29]. Elements of the PRISMA-ScR framework were adapted to ensure transparency and reproducibility, including definition of key concepts, inclusion/exclusion criteria, and thematic categorization of studies. However, full systematic database strings, deduplication counts, and quantitative synthesis were not performed, as the objective was conceptual integration rather than exhaustive enumeration. The goal was to generate a comprehensive, thematically structured synthesis that bridges molecular pathophysiology with emerging diagnostic and therapeutic applications, reflecting the evolving shift toward precision and systems-based trauma care.
A systematic literature search was conducted across 4 major databases: PubMed, Web of Science, Scopus, and Embase, covering publications from January 2000 to June 2025. A combination of controlled vocabulary such as medical subject headings (MeSH) terms and free-text keywords were used, encompassing “MSK injury, polytrauma, blast injury, blunt trauma, crush syndrome, inflammation, endothelial dysfunction, DAMPs, cellular senescence, biomarkers, cytokine storm, heterotopic ossification, military medicine, combat injury, civilian trauma, translational medicine, proteomics, metabolomics, lipidomics, transcriptomics, single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, extracellular vesicles (EVs), exosomes, circulating cell-free DNA (cfDNA), mitochondrial DNA (mtDNA), multi-omics integration, systems biology, network modeling, artificial intelligence (AI), machine learning (ML) and precision diagnostics”. To maximize inclusivity and capture global perspectives, no language restrictions were applied. Reference lists of relevant reviews and eligible studies were also hand-screened to ensure important contributions not identified in the initial search were included. Although full database strings, deduplication counts, and PRISMA flow metrics were not reported, search transparency and reproducibility were strengthened by documenting databases, time frames, and key search domains. In line with our emphasis on translational and systems-level insights, we also included seminal clinical studies that applied scRNA-seq and single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq) to circulating leukocytes in trauma patients, which defined early immune response trajectories and epigenetic reprogramming after polytrauma.
Eligibility criteria were designed to capture both breadth and depth. Studies were included if they reported original research, clinical trials, or comprehensive reviews addressing the pathophysiology, systemic immune or endothelial responses, or diagnostic innovations relevant to polytrauma with MSK injury, with specific attention to blast-, blunt-, or crush-related injuries. Preclinical and translational investigations on biomarker discovery, validation, or diagnostic technologies were prioritized. Exclusion criteria encompassed case reports, editorials, and opinion pieces lacking mechanistic or diagnostic evidence, as well as studies focused exclusively on polytrauma without major extremity injuries, such as isolated thoracic, abdominal, or neurotrauma.
Findings from eligible studies were narratively integrated across seven thematic domains: 1) epidemiology and comparative mechanisms of military versus civilian trauma; 2) systemic inflammatory and immune dysregulation; 3) endothelial dysfunction and microvascular collapse; 4) trauma-induced cellular senescence and fibrotic remodeling; 5) traditional vs. emerging biomarker strategies; 6) advances in diagnostic technologies, including multi-analyte, multi-omic, and real-time monitoring platforms; and 7) translational gaps and future priorities. These themes were selected because they represent recurring focal points across the literature and map directly onto both mechanistic pathways and clinical applications. Emphasis was placed on temporal dynamics, mechanistic insight, and clinical relevance, with results organized into conceptual frameworks and tabular summaries for clarity.
3. Pathophysiological and biomechanical mechanisms of polytrauma with MSK injury
3.1. Biomechanical triggers
Polytrauma with MSK injury arises when external mechanical forces disrupt tissue integrity and cellular homeostasis, the magnitude, direction, and duration of force shaping the severity and clinical manifestation of injury [30]. Although blast, blunt, and crush mechanisms differ in their physical origins and epidemiological contexts, they share downstream biological consequences that extend from localized tissue disruption to systemic inflammation and multi-organ dysfunction syndrome (MODS) [22], [23], [28]. Understanding their unique biomechanical triggers and convergent molecular pathways is critical for improving diagnosis, triage, and treatment in both military and civilian trauma care.
Blast trauma, the defining injury mechanism of modern warfare, is characterized by the rapid propagation of high-energy shock waves generated by explosive detonation [19], [31]. The sudden overpressure exerts disproportionate stress on air- and fluid-filled structures such as the lungs, gastrointestinal tract, and auditory system, producing severe barotrauma [32]. Skeletal muscle and vascular endothelium are vulnerable to shear-related microvascular injury, which can promote ischemia and contribute to compartment physiology [33], [34]. The complexity of blast trauma is amplified by its polymechanistic profile: secondary injuries from high-velocity fragments, tertiary injuries caused by bodily displacement and blunt impact, and quaternary effects involving burns, toxic inhalation, or radiation exposure [35], [36]. This layered injury pattern underscores the systemic complexity of blast trauma, where overlapping mechanisms act synergistically to amplify tissue damage and systemic sequelae.
Blunt trauma, more common in civilian settings, typically results from road traffic accidents, falls, or sports-related collisions [20], [37]. These injuries involve the transfer of kinetic energy over a broad surface without skin penetration, producing contusions, hematomas, and lacerations of soft tissues [38]. Acceleration-deceleration forces further contribute to shearing of neurovascular bundles, ligaments, and connective tissue, often resulting in long-bone fractures, joint dislocations, and intramuscular hematomas [39]. These injuries trigger localized ischemia, inflammatory infiltration, and progressive fibrotic remodeling, processes that compromise MSK integrity and prolong functional recovery [40].
Crush trauma, most often encountered during industrial accidents or natural disasters, is defined by sustained mechanical compression, frequently lasting more than 30 min [41]. Prolonged ischemia leads to muscle necrosis and rhabdomyolysis [42], often progressing to compartment syndrome [43]. In addition, sustained compression induces biomechanical and structural damage to peripheral nerves, resulting in long-term sensory and motor dysfunction [44]. The release of compression initiates ischemia-reperfusion injury, in which the sudden restoration of blood flow generates reactive oxygen species (ROS) that overwhelm endogenous antioxidant defenses [45]. Reperfusion disseminates intracellular contents, including potassium, myoglobin, and DAMPs, into the systemic circulation, precipitating electrolyte imbalances, arrhythmias, acute kidney injury (AKI), and the life-threatening syndrome of crush shock [17], [46].
Despite these distinct physical triggers, blast, blunt, and crush trauma converge on a set of shared downstream pathways: cellular necrosis, DAMP release, endothelial disruption, microvascular collapse, and amplification of sterile inflammation [22]. This convergence highlights a unifying biological framework in which diverse injury patterns trigger common systemic responses, driving complications such as sepsis, MODS, and impaired regeneration [47], [48]. Recognizing these intersecting pathways not only enhances triage and acute care but also provides predictive insight into long-term outcomes, offering a foundation for precision approaches to trauma management across both military and civilian populations. At the molecular level, all three injury modalities initiate sterile inflammatory cascades driven by DAMPs, including mtDNA, HMGB1, and heat-shock proteins, which propagate endothelial dysfunction and immune dysregulation across organ systems [22], [49], [50]. Blast injury uniquely couples these molecular signals with shear- and pressure-mediated endothelial rupture [18], whereas blunt trauma preferentially promotes inflammatory infiltration and fibrotic remodeling within MSK tissues [40]. Crush injury further amplifies systemic toxicity through ischemia-reperfusion-driven ROS generation and electrolyte release, contributing to AKI and cardiac instability [41], [46]. A comparative summary of these biomechanical triggers and downstream pathophysiological features is presented in Table 1 [18], [23], [28], [31], [33], [36], [37], [38], [39], [40], [41], [43], [44], [46], [51], highlighting their distinct mechanical origins and overlapping systemic biology. Although these shared downstream pathways explain much of the acute inflammatory and vascular pathology seen across trauma types, blast injury in particular imposes an additional layer of systemic disruption that extends beyond MSK structures. Blast-induced polytrauma with significant MSK injury manifests not only as complex fractures and extensive soft-tissue damage but also as profound neuroimmune and endocrine dysregulation that shapes the trajectory of tissue regeneration and long-term functional recovery. These chronic sequelae align with established frameworks describing blast-related neurotrauma as a driver of persistent disability, neuropsychiatric comorbidity, and systemic dysfunction, particularly in military populations [51]. Incorporating mechanisms such as neural inflammation [52], hypothalamic-pituitary-adrenal (HPA) axis perturbation [53], and injury-induced cellular senescence [54] into the pathophysiological framework provides a more integrated understanding of how blast exposure drives persistent, multisystem dysfunction, thereby reinforcing the need for precision trauma care.
Table 1.
Comparative pathophysiological features of blast, blunt, and crush injuries.
| Feature | Blast trauma | Blunt trauma | Crush trauma | Shared/Convergent pathways | References |
|---|---|---|---|---|---|
| Primary mechanical trigger | High-energy shock waves, rapid overpressure | Rapid deceleration, broad-surface impact | Sustained mechanical compression (>30 min) | All disrupt tissue integrity, trigger systemic stress responses | [18], [37], [46] |
| Tissue vulnerability | Air/fluid-filled organs (lung, gut, ear), muscle, and endothelium | Soft tissue, long bones, joints, and neurovascular bundles | Skeletal muscle, kidneys, and peripheral nerves | Microvascular rupture, ischemia, compartment syndrome | [33], [40], [44] |
| Unique sequelae | Poly-mechanistic (fragmentation, displacement, burns, inhalation injury) | Hematomas, ligament injury, joint dislocation | Rhabdomyolysis, crush shock, ischemia-reperfusion injury | Overlapping systemic inflammation, oxidative stress | [36], [39], [41] |
| Molecular triggers | Shear-induced DAMP release, endothelial rupture | Inflammatory infiltration, fibrotic remodeling | ROS burst, potassium/myoglobin release | mtDNA as unifying DAMP, extracellular HMGB1, heat-shock proteins | [23], [38], [43] |
| Systemic consequences | Barotrauma, vascular leak, multi-organ dysfunction | Hemorrhage, fibrosis, prolonged recovery | Electrolyte imbalance, arrhythmias, AKI | Sterile inflammation, immune dysregulation, and endothelial dysfunction | [18], [28], [40], [41] |
| Long-term outcomes | HO, PTSD, chronic disability | Joint degeneration, fibrosis, chronic pain | Chronic kidney disease, neuropathy, and muscle weakness | Fibrosis, senescence, impaired regeneration | [28], [31], [40], [41], [51] |
DAMPs. Damage-associated molecular patterns; HMGB1. High-mobility group box 1; ROS. Reactive oxygen species; mtDNA. Mitochondrial DNA; AKI. Acute kidney injury; HO. Heterotopic ossification; PTSD. Post-traumatic stress disorder
3.2. Molecular alarm
At the cellular level, polytrauma with MSK injury, whether from blunt force, blast exposure, or crush injury, disrupts tissue integrity and homeostasis, activating a conserved danger-sensing cascade often termed the molecular alarm [55]. This response begins when intracellular contents released from necrotic or stressed cells act as DAMPs [47]. Once in the extracellular space, DAMPs engage pattern recognition receptors (PRRs) on immune and stromal cells, initiating sterile inflammation that facilitates debris clearance, immune recruitment, and tissue repair [47], [55], [56]. While essential for survival, uncontrolled activation in severe or systemic trauma amplifies inflammation, destabilizes endothelial and metabolic networks, and accelerates progression toward MODS.
As shown in Fig. 1, mtDNA represents a unifying alarmin across blast, blunt, and crush trauma, underscoring its centrality in propagating sterile inflammation [23], [57]. However, mtDNA operates within a broader repertoire of DAMPs released following tissue disruption key mediators include HMGB1, which activates TLR2, TLR4, and the receptor for advanced glycation end products (RAGE) to sustain inflammatory signaling [50]; extracellular adenosine triphosphate (ATP), which reflects bacterial ancestry and potently stimulates innate immune activation; and neutrophil-derived S100A8/A9 (calprotectin), which amplifies TLR4-dependent pathways [58]. Additional alarmins, such as uric acid, heat shock proteins (HSPs), and fragmented extracellular matrix (ECM) components, reinforce these sterile inflammatory loops and highlight the redundancy built into trauma-induced signaling networks [59]. Experimental and clinical studies implicate mtDNA-driven PRR activation as a key amplifier of sterile inflammation after trauma, with associations to organ dysfunction [57].
Fig. 1.
Systems-level convergence of blast, blunt, and crush-induced polytrauma with musculoskeletal injury. This Venn diagram illustrates shared and distinct pathophysiological mechanisms across trauma modalities. Blast injuries are marked by shockwaves and barotrauma; blunt injuries by deceleration, soft-tissue and bone injury; and crush injuries by compression and rhabdomyolysis. Overlapping regions highlight common pathways such as compartment syndrome/ischemia-reperfusion (blast+crush), joint degeneration/hematomas (blunt+crush), and microvascular rupture/fibrosis (blast+blunt). At the center, mtDNA release as a DAMP, together with endothelial dysfunction and sterile inflammation, represents a unifying mechanism. mtDNA is positioned centrally because it integrates mechanical, metabolic, and inflammatory stress responses, acting as a pivotal driver of systemic injury propagation and chronic sequelae. mtDNA mitochondrial DNA, DAMP damage-associated molecular pattern.
Recognition of these trauma-associated DAMP signals occurs primarily through TLRs (particularly TLR2, TLR4, and TLR9), NLRs [particularly NOD-like receptor family pyrin domain-containing 3 (NLRP3)], and RAGE [60]. TLR engagement activates nuclear factor κ-B cells (NF-κB) and mitogen-activated protein kinase (MAPK) cascades via myeloid differentiation primary response protein 88 and TIR-domain-containing adapter-inducing interferon-β adaptors, driving cytokine and chemokine release [61]. In parallel, NLRP3 inflammasomes mediate caspase-1-dependent maturation of interleukin (IL)-1β and IL-18, while RAGE promotes chronic inflammatory and fibrotic remodeling [62], [63], [64]. These mechanisms generate a broad inflammatory network in which neutrophils, macrophages, dendritic cells, endothelial cells, and even parenchymal populations contribute to amplification. Moreover, blast-related polytrauma with significant MSK injury is compounded by neuroinflammatory cascades and accelerated cellular senescence within the nervous system [54], which exacerbates systemic immune dysregulation and impairs neuromuscular recovery. Upregulation of multiple TLRs [52], [65] and degeneration of neuronal cytoskeletal elements [66] identified in blast models highlight the shared molecular pathways linking central neural injury to peripheral MSK dysfunction. This interplay between neural and MSK damage highlights the multisystem complexity of blast polytrauma.
The downstream effects include robust cytokines, including IL-1β and IL-6 and tumor necrosis factor-α (TNF-α) secretion, chemokine-driven immune recruitment (C-X-C motif chemokine ligand 8, monocyte chemoattractant protein-1), and matrix metalloproteinase (MMP)-mediated tissue remodeling [67], [68]. Locally, these cascades clear necrotic debris and prime progenitor cells for regeneration [69]. However, systemic spillover, particularly in polytrauma, delayed evacuation, or resource-limited combat environments, transforms this protective program into pathology [30]. Dysregulated activation fuels systemic inflammatory response syndrome (SIRS), endothelial leakage, and progression to MODS, while overcompensatory suppression drives compensatory anti-inflammatory response syndrome (CARS), predisposing patients to sepsis [70], [71], [72].
The dual nature of the molecular alarm highlights both its evolutionary necessity and clinical risks [73]. For trauma care, particularly in austere or battlefield environments where systemic complications are often fatal, this pathway represents an attractive therapeutic frontier. Strategies under investigation include HMGB1 release inhibitors, PRR antagonists, inflammasome-targeted therapies, and selective cytokine blockade [74]. The therapeutic goal is not to extinguish this primordial defense but to recalibrate its amplitude and duration, preserving repair functions while preventing maladaptive systemic consequences. Such precision modulation may improve survival and recovery trajectories across both military and civilian trauma populations [75].
3.3. Systemic consequences
A systems biology perspective is increasingly essential for understanding polytrauma with MSK injury. Rather than viewing it solely as an anatomical disruption requiring surgical repair, it should be conceptualized as a multi-level cascade that begins with molecular danger signaling and can progress to systemic dysfunction. Early events such as the release of DAMPs, mitochondrial dysfunction, and endothelial barrier disruption initiate downstream immune dysregulation, neuroendocrine imbalance, and premature cellular senescence [23], [76]. Mapping these molecular signatures provides a foundation for rationally designed therapies that move beyond supportive care, enabling targeted immunomodulation, endothelial stabilization, senotherapeutics, and regenerative interventions. This framework emphasizes the need to link molecular pathways with clinical outcomes if trauma care is to evolve into a precision medicine discipline. In this context, severe polytrauma with extensive MSK injury exerts profound systemic consequences that extend well beyond the site of injury, disrupting immune, vascular, and metabolic homeostasis in ways that directly influence survival and recovery [77]. Rather than unfolding as isolated events, these responses represent dynamically interacting processes that form a pathophysiological trajectory from early hyperinflammation to long-term dysfunction [59], together shaping clinical outcomes in both military and civilian trauma care.
A central feature of this systemic response is immune dysregulation, which typically evolves along a biphasic but overlapping spectrum. The early phase is dominated by hyperinflammation, manifested clinically as SIRS [68]. Necrotic tissues release DAMPs that engage PRRs such as TLRs and NLRs, unleashing a systemic cytokine surge of TNF-α, IL-1β, IL-6, and interferon-γ (IFN-γ) [22]. This “cytokine storm” activates endothelium, promotes leukocyte adhesion, disrupts vascular barriers, and drives neutrophil recruitment, with the release of proteases, ROS, and neutrophil extracellular traps [78]. Clinically, these cascades present as fever, tachycardia, hypotension, hypermetabolism, and coagulopathy, and unchecked progression may culminate in MODS even in the absence of infection [71]. In parallel, the host mounts a CARS, intended to protect tissues but often overshooting into profound immunosuppression. This state is characterized by lymphocyte apoptosis, expansion of myeloid-derived suppressor cells (MDSCs), reduced monocyte expression of human leukocyte antigen-DR isotype (HLA-DR), and upregulation of immune checkpoint molecules such as programmed cell death protein 1 and cytotoxic T-lymphocyte-associated protein 4, accompanied by elevated IL-10 and transforming growth factor (TGF)-β [79], [80]. The consequence is a heightened susceptibility to secondary infections, delayed healing, and poor vaccine responses.
Recent cellular-resolution studies have further clarified these systemic immune alterations. Early scRNA-seq by Chen et al. [81], [82] applied high-dimensional scRNA-seq and scATAC-seq to circulating leukocytes from trauma patients, demonstrating distinct transcriptional and chromatin accessibility programs that stratified patients into immunologic endotypes and independently predicted outcome across heterogeneous critical illness etiologies. Building on these foundational observations, scRNA-seq by Maniar et al. [83] identified the expansion of systemic immunosuppressive myeloid cells and context-dependent macrophage phenotypes as key regulators of post-traumatic immune dysregulation, while complementary findings from Cheng et al. [84] demonstrated that early systemic immune biomarkers, including monocyte and lymphocyte subsets, predict bone regeneration outcomes after trauma. These insights highlight how cellular dysfunction interacts with molecular signaling networks to shape both immune resolution and tissue repair, complementing the molecular framework discussed above. Importantly, hyperinflammation and immunosuppression frequently coexist in a mixed antagonist response syndrome, producing unpredictable clinical trajectories. Increasingly, biomarker-guided strategies are being investigated to tailor immunotherapies, ranging from cytokine adsorption in hyperinflammation to checkpoint inhibition or immune cell transfer in states of immunosuppression [85].
In addition, trauma inflicts profound injury on the vascular endothelium, a phenomenon often described as “endothelial collapse” [86]. The endothelial glycocalyx, a protective gel-like layer regulating vascular permeability and cell-cell interactions, is rapidly degraded by heparanase and metalloproteinases following trauma, ischemia-reperfusion, and oxidative stress [87], [88]. Circulating fragments such as syndecan-1 and hyaluronic acid serve as biomarkers of this injury and correlate with poor outcomes [89], [90]. Loss of glycocalyx integrity exposes endothelial surfaces, destabilizes tight junction proteins such as claudin-5 and adherens junction proteins like vascular endothelial cadherin (VE-cadherin) and CD144, eventually leading to vascular leak, tissue edema, and hypoperfusion [88]. At the same time, upregulation of adhesion molecules fosters leukocyte plugging of the microvasculature, compounding tissue ischemia [86]. Endothelial barrier failure also drives trauma-induced coagulopathy (TIC), in which dysregulated hemostasis manifests as either fibrinolytic shutdown or hyperfibrinolysis, leading to a paradoxical coexistence of bleeding, thrombosis, and microvascular occlusion [91]. This complexity challenges conventional resuscitation strategies. Translationally, therapies that preserve endothelial function, including plasma-based resuscitation, albumin supplementation, and experimental glycocalyx stabilizers such as sulodexide and angiopoietin mimetics [92], represent promising strategies to mitigate early vascular failure in combat and civilian settings.
Trauma also disrupts systemic cellular and metabolic functions, particularly through mitochondrial injury, premature senescence, and neuroendocrine reprogramming. Sustained immune activation and endothelial injury create a hypoperfused, pro-oxidative microenvironment that impairs tissue regeneration. Persistent vascular leakage and loss of endothelial integrity limit oxygen and nutrient delivery to the injury site, while unresolved inflammation disrupts the balance between pro-repair macrophages and progenitor cell activation [93]. In addition, mitochondrial dysfunction restricts ATP availability and redox homeostasis, further constraining myogenic and osteogenic repair processes [94]. These intertwined disturbances explain why systemic inflammation and metabolic collapse translate into delayed functional recovery and poor structural outcomes after polytrauma [95].
Mitochondria, central to energy metabolism and redox balance, are impaired by ischemia-reperfusion and inflammatory cytokines, leading to oxidative phosphorylation failure, ATP depletion, ROS overproduction, and activation of permeability transition pores [96]. These changes drive apoptotic and necrotic cell death in skeletal muscle, liver, and immune cells, manifesting clinically as muscle weakness, acidosis, immune dysfunction, and delayed healing [97]. Concurrently, trauma accelerates stress-induced premature senescence in fibroblasts, endothelial cells, and progenitors, resulting in growth arrest mediated by p16INK4a/p21CIP1 pathways [98]. Senescent cells secrete a proinflammatory and proteolytic senescence-associated secretory phenotype (SASP) that disrupts regenerative niches and fosters chronic inflammation, fibrosis, and fracture non-union [99]. These dysfunctions are especially detrimental in aging or metabolically compromised patients [100].
At the neuroendocrine level, sustained activation of the HPA axis and sympathetic nervous system drives hypercortisolism, hyperglycemia, insulin resistance, and protein catabolism, while suppression of anabolic hormones such as insulin-like growth factor 1 (IGF-1), growth hormone, and testosterone impairs tissue repair [101]. Blast-induced polytrauma with significant MSK injuries frequently co-occurs with systemic neuroendocrine alterations that exacerbate catabolic metabolism and impair tissue repair. Experimental models demonstrate that repeated blast exposures dysregulate the HPA axis [53], altering cortisol secretion and affecting metabolic hormones such as adiponectin and leptin [102], which critically modulate muscle and systemic metabolic homeostasis. These endocrine perturbations represent a key mechanism by which blast associated polytrauma extends its impact beyond local MSK tissue damage to influence whole-body recovery trajectories, reinforcing the importance of considering systemic network dysfunction in trauma care. These changes converge into persistent inflammation, immunosuppression, and catabolism (PICS), a syndrome increasingly recognized as a major barrier to rehabilitation after severe injury [103]. Emerging therapies, including mitochondrial protectants such as mitochondria-targeted coenzyme Q10 analogue (MitoQ), elamipretide peptide (SS-31) [104], senolytics such as dasatinib and quercetin [105], and metabolic modulators such as β-blockers, insulin sensitizers, aim to interrupt these vicious cycles [106].
The systemic consequences of polytrauma with MSK injury are best understood as the product of tightly interconnected networks rather than isolated cascades. Immune dysregulation fuels endothelial collapse, endothelial injury amplifies immune activation through the release of additional DAMPs, and both processes converge on mitochondrial dysfunction, cellular senescence, and maladaptive neuroendocrine stress responses. This reciprocal interplay transforms trauma into a disease of systemic network dyscoupled four node cascade encompassing 1) immune activation via DAMP-, TLR-, and NLR-driven cytokine surges; 2) endothelial injury marked by glycocalyx shedding, increased permeability, and microvascular stasis; 3) mitochondrial dysfunction characterized by oxidative stress, impaired ATP generation, and metabolic collapse; and 4) premature cellular senescence with amplification of the SASP. Each node reinforces the others, cytokines accelerate glycocalyx degradation, vascular leak fosters tissue hypoxia and mitochondrial failure, mitochondrial DAMPs propagate innate immune activation, and SASP perpetuates chronic inflammation and fibrosis. This interlocked loop forms the mechanistic substrate linking acute instability to chronic sequelae.
4. Therapeutics
Therapeutic approaches for polytrauma with MSK injuries are rapidly evolving toward a precision, system-based paradigm that integrates immunomodulation, endothelial stabilization, regenerative medicine, metabolic support, and neuropsychiatric care. By targeting the interconnected biological and psychosocial pathways underlying trauma pathophysiology, these strategies aim to enhance survival, accelerate recovery, and reduce long-term disability in both military and civilian populations. Emerging interventions, including cytokine blockade, senolytics, mitochondrial rescue, and other targeted approaches, reflect a shift from generalized resuscitation toward mechanism-specific [107], precision-guided therapeutics that address not only acute injury responses but also the prevention of chronic complications and lifelong functional impairment (Table 2) [104], [108], [109], [110], [111], [112], [113], [114], [115], [116], [117], [118], [119], [120], [121], [122], [123], [124], [125], [126], [127], [128], [129], [130], [131], [132], [133], [134], [135], [136], [137], [138], [139], [140], [141], [142], [143], [144], [145], [146], [147], [148], [149], [150], [151], [152], [153], [154], [155], [156], [157], [158], [159], [160], [161], [162], [163], [164], [165], [166], [167], [168], [169], [170], [171], [172], [173]. While polytrauma with MSK injury is driven by a core four-node pathobiological cascade, therapeutic strategies exploit multiple interventional entry points within and between these nodes, including neuroendocrine and membrane-stabilizing interfaces that modulate system-level feedback rather than constituting independent pathological axes.
Table 2.
Emerging therapeutic targets and agents in polytrauma with MSK injury.
| Target | Agent | Mechanism of action | Translational development status | References |
|---|---|---|---|---|
| IL-1 pathway | Anakinra | Blocks IL-1 receptor, reduces SIRS and tissue damage | Clinical evidence in sepsis with MAS-like hyperinflammation; Trauma/MSK polytrauma evidence limited/indirect; Investigational/repurposing in trauma | [108], [109] |
| IL-6 pathway | Tocilizumab | Inhibits IL-6 receptor; Limits cytokine storm amplification |
Approved for RA, COVID-19; Trauma clinical trials ongoing | [110], [111], [112] |
| Extracorporeal immunomodulation | HA330 hemoperfusion | Resin-based extracorporeal adsorption of circulating cytokines reduces systemic inflammatory burden | Early clinical use in critical illness and sepsis; Limited trauma data |
[113], [114] |
| Alarmin pathways | Glycyrrhizin/anti-HMGB1 antibody | Inhibit HMGB1-TLR4/RAGE binding; suppress NF‑κB activation and downstream cytokine amplification | Preclinical trauma and hemorrhagic shock models; No clinical trials yet |
[115], [116], [117], [118], [119] |
| TLR4 signaling | TAK-242 (Resatorvid) | Inhibits downstream TLR4 signaling; Limits cytokine induction |
Preclinical and early clinical studies outside trauma; Trauma applications are investigational |
[120] |
| TLR4 signaling | Eritoran | Blocks TLR4-MD2 binding; Suppresses NF‑κB activation | Phase 3 severe sepsis trial (ACCESS) showed no reduction in 28‑day mortality; Trauma-specific efficacy not established | [121] |
| MDSC modulation | MDSC-enhancing therapies | Enhance immune regulation and reduce excessive inflammation; Preserve antimicrobial capacity | Preclinical trauma models | [122] |
| Alarmin S100A8/A9 | S100A8/A9-targeted nanoparticles | Nanoparticle-based sequestration or neutralization of S100A8/A9 reduces neutrophil recruitment, cytokine amplification, and microvascular injury | Preclinical trauma and systemic inflammation models | [123] |
| Endothelium/glycocalyx | Sulodexide | Stabilizes glycocalyx, enhances barrier integrity | Ongoing trials in endothelial dysfunction; Trauma applications under evaluation |
[124], [125] |
| Endothelium | FX06 | Improves vascular reactivity | Case series in COVID-19 ARDS; Phase II trials registered; Trauma-specific efficacy not established |
[126], [127], [128], [129], [130] |
| Endothelium | Atorvastatin | Reduces endothelial activation | Atorvastatin approved | [131], [132], [133] |
| Glycocalyx preservation | Doxycycline | Inhibits MMPs, reduces glycocalyx degradation, and endothelial barrier disruption | Preclinical trauma and acute lung injury models; Endothelial-protective effects under investigation | [134] |
| Glycocalyx mimetic | Dekaparin | Synthetic glycosaminoglycan mimetic that inhibits heparanase activity, preserves glycocalyx structure, and reduces endothelial permeability and TIC | Early translational development; Preclinical and pilot-model evidence |
[135] |
| Resuscitation | Fibrinogen-enriched plasma resuscitation | Restores fibrinogen deficits; Improves endothelial barrier stability and oncotic pressure; Enhances microvascular perfusion; Reduces TIC and vascular permeability |
Phase II trauma trials: improving coagulation and endothelial function | [136] |
| Plasma membrane | Poloxamer 188 (P188) | Amphiphilic triblock copolymer that selectively inserts into disrupted lipid bilayers, reseals damaged sarcolemmal regions, limits Ca²⁺ overload, and reduces secondary necrosis | Preclinical skeletal muscle, ischemia-reperfusion, and mechanical injury models; Early translational exploration | [137], [138], [139], [140], [141], [142], [143], [144] |
| Fibrosis pathway | Pirfenidone | Inhibits TGF-β signaling, fibroblast proliferation, and collagen synthesis | Approved for idiopathic pulmonary fibrosis | [145], [146] |
| Fibrosis pathway | Nintedanib | Inhibits PDGF, VEGF, and FGF receptor pathways; Prevents myofibroblast activation |
Approved for pulmonary fibrosis; Studied systemic fibrosis |
[147] |
| Senescent cells | Dasatinib plus quercetin | Induces apoptosis of senescent cells; Reduces SASP-driven inflammation |
Preclinical to phase II trials mainly in fibrosis/aging contexts | [148] |
| Senescent cells | Navitoclax (ABT-263) | BCL-2 family inhibitor (notably BCL-xL/BCL-2); Senolytic via apoptosis induction in senescent cells |
Preclinical senolytic evidence; Limited early-phase oncology trials; Translation constrained by thrombocytopenia |
[149], [150] |
| Senomorphic | Rapamycin | Inhibits mTOR signaling; Attenuates SASP production and modulates the senescent phenotype without inducing senescent cell death, thereby preserving regenerative capacity | Preclinical and early clinical studies in aging and fibrotic diseases; Trauma-specific data are lacking |
[151] |
| Regenerative | Mesenchymal stem cells (MSCs) | Provide paracrine, angiogenic, and immunomodulatory signals; Enhance myogenesis and osteogenesis; Reduce fibrosis and inflammation |
Robust preclinical evidence in volumetric muscle loss and fracture non-union models; Early-phase clinical studies reporting improved structural and functional outcomes |
[152], [153] |
| Biomaterials | ECM-derived scaffolds and silk-based biomaterials | Bioactive matrices that provide structural support, enhance angiogenesis, and deliver growth factors for tissue integration | Preclinical and early translational studies in MSK defect and repair models | [154] |
| Mitochondria | MitoQ | Mitochondria-targeted antioxidant; Prevents apoptosis |
Preclinical and early trauma models | [104] |
| Mitochondria | Elamipretide (SS-31) | Stabilizes cardiolipin; Preserves mitochondrial function |
Investigational, early clinical use | [155] |
| Oxidative stress/redox imbalance | N-acetylcysteine | Replenishes intracellular glutathione; Reduces ROS-mediated injury; Supports mitochondrial function and cellular viability |
Preclinical evidence in trauma/TBI-related models and critical care repurposing; Trauma-specific clinical evidence is limited | [156] |
| Metabolic | Metformin | AMPK activation, NF-κB suppression; Reduces hypercatabolism; Improves survival |
Retrospective ICU/ARF, sepsis, perioperative cohorts; Trauma-specific data limited | [157], [158], [159], [160], [161] |
| Metabolic | Propranolol (β-blockade) | Reduces catecholamine-driven catabolism; Preserves lean mass; Stabilizes metabolic state |
Trauma studies, pediatric and geriatric burn cohorts | [162] |
| Neuroinflammation | Minocycline | Reduces microglial activation; inhibits HMGB1 release; Stabilizes the BBB; Anti-apoptotic effects |
Repurposed from neurodegeneration; Trauma studies are emerging |
[163], [164], [165] |
| Neuroinflammation | Ibudilast | PDE inhibitor; suppresses glial cytokine production; Enhances neuroprotection |
Phase II in neuroinflammation and neuropathic pain | [166], [167], [168] |
| Psychiatric | SSRIs | Inhibit serotonin reuptake, enhance serotonergic neurotransmission, and reduce depressive and anxiety symptoms after trauma and PTSD | Established first-line pharmacotherapy for PTSD and depression; Not trauma-mechanism-specific |
[169], [170], [171] |
| Psychiatric | Adrenergic antagonists | Block central and peripheral adrenergic receptors, attenuating noradrenergic hyperarousal, autonomic overactivation, and trauma-related nightmares | Widely used in PTSD and trauma-related hyperarousal; Mixed evidence in trauma-prevention and chronic outcome modification | [170], [171] |
| Non-pharmacologic | Cognitive behavioral therapy and trauma-focused psychotherapies | Structured psychotherapies that restructure maladaptive cognitions, use graded exposure to extinguish fear circuits, and enhance coping and adherence | Guideline-recommended first-line treatment for PTSD and trauma-related disorders; Robust clinical trial evidence | [172] |
| Neuromodulation | Transcranial magnetic stimulation | Non-invasive neuromodulation of prefrontal and network-level activity modulates cortical excitability and connectivity to reduce depressive and PTSD symptoms | Approved for treatment-resistant depression; Emerging evidence and early clinical studies in PTSD and post-traumatic syndromes |
[173] |
IL. Interleukin; SIRS. Systemic inflammatory response syndrome; MAS. Macrophage activation syndrome; RA. Rheumatoid arthritis; SASP. Senescence-associated secretory phenotype; BCL-2. B-cell lymphoma 2; FX06. Fibrin-derived peptide 06; MitoQ. Mitochondria-targeted coenzyme Q10 analogue; SS-31. Elamipretide peptide; DAMPs. Damage-associated molecular patterns; TLR. Toll-like receptor; TLR4. Toll-like receptor 4; MD2. Myeloid differentiation factor 2; NF-κB. Nuclear factor κ-B cells; PDE. Phosphodiesterase; TGF-β. Transforming growth factor-β; PDGF. Platelet-derived growth factor; VEGF. Vascular endothelial growth factor; FGF. Fibroblast growth factor; MSK. Musculoskeletal; RAGE. Receptor for advanced glycation end products; MDSC. Myeloid-derived suppressor cell; ECM. Extracellular matrix; AMPK. AMP-activated protein kinase; HPA. Hypothalamic-pituitary-adrenal; BBB. Blood-brain barrier; mTOR. Mechanistic target of rapamycin; MMPs. Matrix metalloproteinases; TIC. Trauma-induced coagulopathy; Ca²⁺. Calcium ion; ICU. Intensive care unit; ARF. Acute respiratory failure; SSRI. Selective serotonin reuptake inhibitor; PTSD. Post-traumatic stress disorder; ARDS. Acute respiratory distress syndrome; ROS. Reactive oxygen species
4.1. Immunomodulation
Immunomodulatory therapies target the immune activation node, where dysregulated cytokine signaling drives systemic inflammation and immune paralysis [174]. Early cytokine-targeted therapies have received dominant attention, with agents such as Anakinra, an IL‑1 receptor antagonist, showing survival benefit in sepsis patients with hyperinflammatory, macrophage activation-like phenotypes, and its use in trauma-associated acute respiratory distress syndrome (ARDS) is currently extrapolated from these sepsis and critical illness data rather than supported by trauma-specific trials [108], [109]. Precision immunotherapy approaches have further supported phenotype-targeted use of IL‑1 blockade in macrophage activation-like syndrome to improve organ dysfunction in sepsis, highlighting the importance of biomarker-guided strategies despite the absence of trauma-specific trials [175].
IL-6 inhibition with tocilizumab remains less conclusive in trauma settings, with variable efficacy and safety concerns, although early-phase studies continue to refine its risk-benefit profile [110]. Beyond rheumatoid arthritis, IL‑6 receptor has shown benefit in severe COVID‑19-associated ARDS and systemic hyperinflammation, supporting its role in cytokine storm syndromes, while trauma applications remain investigational [111], [112]. Device-based immunomodulation approaches, particularly extracorporeal cytokine adsorption, have emerged as adjuncts for controlling hyperinflammation. HA330 hemoperfusion cartridges selectively remove circulating cytokines through resin-based adsorption and have demonstrated reductions in IL-6, TNF-α, and other inflammatory mediators in early trauma and critical care studies [114]. However, evidence to date is largely retrospective or small-scale and is derived primarily from sepsis/critical illness cohorts; robust trauma-specific survival or organ-protection data are still needed [113], [114].
Upstream targeting of alarmins, particularly HMGB1, represents an emerging immunomodulatory strategy. HMGB1-neutralizing antibodies and small-molecule inhibitors such as glycyrrhizin block HMGB1-TLR4/RAGE interactions, thereby reducing NF‑κB activation, cytokine amplification, and sterile inflammatory propagation. Glycyrrhizin has been shown to attenuate traumatic brain injury via HMGB1-RAGE inhibition in preclinical models [115], [116], [117], [118]. In addition, HMGB1 can signal via TLR5, contributing to neuroinflammation and pain hypersensitivity in vivo [119].
Downstream innate immune signaling has also been explored as a therapeutic target. TAK‑242 (Resatorvid) inhibits intracellular TLR4 signaling and is under early clinical evaluation outside trauma, including phase II trials in severe alcoholic hepatitis and acute-on-chronic liver failure [120]. Whereas Eritoran, a TLR4-MD2 antagonist, failed to reduce 28‑day all-cause mortality in the phase III ACCESS trial in severe sepsis and remains investigational without demonstrated trauma-specific efficacy [121].
More recently, next-generation cellular and nanoparticle-based interventions have emerged to refine immune recalibration. Modulation of MDSCs has demonstrated the capacity to dampen excessive inflammation while preserving antimicrobial function in experimental trauma models [122]. In addition, nanoparticle formulations targeting the alarmins S100A8/A9 have been engineered to sequester or neutralize these damage-associated proteins, thereby reducing neutrophil recruitment, cytokine amplification, and microvascular injury in preclinical models of systemic inflammation and trauma [123].
4.2. Endothelial protection
Endothelial-stabilizing therapies target the vascular injury node, aiming to preserve the glycocalyx, maintain microvascular integrity, and prevent TIC and organ failure [176]. Syndecan-1, a biomarker of glycocalyx degradation, shows a strong correlation with the severity of endothelial injury, increased vascular permeability, coagulopathy, MODS, and mortality in trauma and critical illness [124]. Among pharmacologic approaches, sulodexide has emerged as an endothelium-stabilizing agent. Supported by preclinical balloon-injury models and sepsis endothelial dysfunction studies, glycocalyx reconstruction and barrier integrity restoration [125]. Ongoing clinical trials focus on endothelial dysfunction, while trauma-specific applications remain under evaluation [124], [125]. Fibrin-derived peptide B β15-42 [fibrin-derived peptide 06 (FX06)] has been evaluated in early phase II trauma and critical illness studies, where it demonstrated potential to reduce vascular leakage and TIC [126], [127], [128], [129], [130]. Statins, particularly atorvastatin, provide pleiotropic endothelial and anti-inflammatory benefits, demonstrated in endothelial radioprotection and improved endothelium-dependent vasodilation outside trauma contexts [131], [132], [133]. Adjunctive strategies, targeting glycocalyx preservation, include doxycycline, an MMP inhibitor that reduces glycocalyx shedding and attenuates endothelial barrier disruption in preclinical trauma and acute lung injury models [134]. Moreover, synthetic glycosaminoglycan mimetics such as dekaparin replicate key structural domains of the endothelial glycocalyx to inhibit heparanase-mediated degradation, reduce vascular permeability, and attenuate TIC in early translational models [135]. At the resuscitation level, fibrinogen-enriched plasma resuscitation has gained attention as an endothelium-centered strategy. By restoring fibrinogen deficits, improving oncotic pressure, and stabilizing endothelial barrier function, this approach mitigates TIC and vascular permeability. Phase II trauma studies report improvements in coagulation parameters and endothelial integrity [136].
4.3. Restoration of plasma membrane integrity
Plasma membrane-repair strategies target the cellular barrier-integrity sub-node of the mitochondrial-endothelial injury axis, where mechanical disruption of the lipid bilayer initiates pathological calcium influx, bioenergetic collapse, and secondary necrotic cell death [137], [177]. Preservation and restoration of plasma membrane integrity are therefore critical prerequisites for effective recovery following blast and crush injuries, in which high-energy mechanical forces frequently overwhelm endogenous repair mechanisms [177]. Under physiological conditions, acute membrane disruptions are rapidly repaired through intrinsic mechanisms [178]. These include calcium-triggered annexin recruitment to the wound edge, where they promote membrane curvature, vesicle aggregation, and resealing [179]. Dysferlin plays an essential role in sarcolemmal repair by orchestrating vesicle fusion and patch formation at injury sites [180]. Stress-inducible chaperones such as HSP70 and HSP27 stabilize cytoskeletal-membrane interfaces and facilitate membrane resealing [181]. Preconditioning paradigms that upregulate these proteins can enhance intrinsic repair capacity and confer partial resistance to subsequent mechanical insults [182]. However, in the context of high-energy polytrauma, the magnitude and repetition of membrane disruption often overwhelm endogenous repair capacity. Sustained calcium influx, oxidative stress, and necrotic cell death result in amplifying both local and systemic inflammation [138], [183]. In this setting, exogenous membrane-stabilizing agents function as critical adjuncts to intrinsic repair mechanisms. Among these, amphiphilic triblock copolymers, particularly poloxamer 188 (P188), have emerged as leading membrane-sealants. P188 selectively inserts into disrupted lipid bilayers, stabilizes sarcolemmal defects, limits Ca²⁺ overload, and improves cell survival across multiple experimental injury models [139]. Foundational biophysical studies demonstrated polymer-mediated sealing of structurally damaged membranes [138], while early studies showed potent neuroprotection through amphiphilic triblock copolymers [140]. In skeletal muscle injury models, P188 reduced contraction-induced force decline in dystrophic mdx mice [141] and conferred marked protection in vivo [142]. Additional studies confirmed its ability to stabilize sarcolemmal integrity and limit calcium overload across ischemia-reperfusion and mechanical injury models [137], [143], and reperfusion injury [144].
4.4. Regenerative and anti-senescent therapies
Regenerative and anti-senescent therapies target the senescence-mitochondrial node, where early onset of cellular senescence and bioenergetic failure impair tissue repair and promote maladaptive fibrosis [184]. Rather than providing an exhaustive overview of regenerative modalities, this discussion emphasizes their relevance within the interconnected framework of immune dysregulation, endothelial dysfunction, and mitochondrial impairment. By restoring cellular energy homeostasis, modulating inflammation, and re-establishing vascular integrity, these approaches link early systemic disturbances to improved long-term regenerative outcomes, with measurable endpoints including enhanced tissue regeneration, reduced fibrosis, and improved functional recovery [185]. Among pharmacologic strategies, fibrosis-targeting small molecules such as pirfenidone and nintedanib, approved for pulmonary fibrotic diseases, are increasingly recognized as mechanistically relevant to trauma-induced tissue remodeling [145]. Pirfenidone reduces TGF-β-mediated fibroblast activation and collagen deposition [145], [146], whereas nintedanib inhibits platelet-derived growth factor, vascular endothelial growth factor, and fibroblast growth factor receptor signalling pathways, thereby limiting myofibroblast activation and fibrosis progression [147]. Beyond fibrosis control, senolytics aim to eliminate senescent cells that accumulate early after trauma and drive chronic inflammation through the SASP. Combinatorial dasatinib plus quercetin has demonstrated senolytic efficacy across aging and fibrotic disease models, reducing SASP-mediated inflammation and improving tissue function [148]. Navitoclax (ABT-263), a BCL-2 family inhibitor targeting BCL-xL and BCL-2, induces apoptosis in senescent cells and has shown senolytic activity in vascular, neurovascular, and cutaneous wound-healing models; however, translational application is constrained by dose-limiting thrombocytopenia observed in early-phase oncology studies [149], [150]. In contrast to senolytics, senomorphic agents modulate the senescent phenotype without inducing cell death. Rapamycin, through inhibition of mechanistic target of rapamycin signaling, suppresses SASP production and preserves regenerative capacity while limiting inflammatory amplification [151]. This approach may offer advantages in trauma settings where excessive clearance of senescent cells could impair early reparative processes. Although the majority of supporting evidence for these interventions originates from studies in aging and fibrotic disorders, their relevance to trauma is increasingly recognized. In the context of polytrauma, where early onset of cellular senescence contributes to sustained inflammation, impaired repair, and delayed recovery, regenerative and anti-senescent therapies remain hypothesis-generating translational prospects. Given the absence of trauma-specific clinical trials, focused preclinical and translational studies are required to define optimal timing, dosing, and safety profiles before clinical adoption [186].
4.5. Mesenchymal stem cells
MSC-based therapies provide paracrine, angiogenic, and immunomodulatory signals that enhance myogenesis and osteogenesis, reduce fibrosis, and restore tissue integrity after trauma. Robust preclinical evidence supports MSCs in volumetric muscle loss and fracture non-union models, with early-phase clinical studies reporting improvements in both structural repair and functional outcomes [152], [153]. Beyond cell-based therapies alone, biomaterial platforms play a critical role in optimizing MSC delivery and function. ECM-derived scaffolds and silk-based biomaterials serve as bioactive matrices that provide structural support while delivering growth factors and regenerative cues, thereby enhancing tissue integration and repair. In translational models, sequential delivery of TGF-β3 via silk fibroin/cartilage ECM scaffolds has been shown to promote chondrogenic differentiation of adipose-derived stem cells, underscoring the synergistic potential of combining MSCs with advanced biomaterial systems [154].
4.6. Metabolic stabilization
Metabolic stabilization therapies target the mitochondrial and neuroendocrine nodes, aiming to restore bioenergetic balance and counteract trauma-induced hypercatabolism [187]. Mitochondrial dysfunction is a central driver of post-traumatic organ failure, systemic inflammation, and delayed recovery, making metabolic resuscitation a critical component of precision trauma care [188]. Among mitochondria-targeted strategies, antioxidants such as MitoQ and SS-31 preserve oxidative phosphorylation and limit ATP depletion [189]. Evidence from Huntington’s disease models supports MitoQ’s ability to reduce mitochondrial toxicity and synaptic damage [104], while elamipretide stabilizes cardiolipin and improves mitochondrial function, as summarized in mechanistic reviews [155]. Beyond direct mitochondrial targeting, redox modulation represents an additional metabolic stabilization strategy. N-acetylcysteine replenishes intracellular glutathione stores and reduces oxidative stress, contributing to improved cellular viability and organ function in preclinical trauma and traumatic brain injury models [156]. Systemic metabolic regulation further involves modulation of endocrine and inflammatory signaling. Metformin, through AMP-activated protein kinase (AMPK) activation and NF-κB suppression, has demonstrated survival benefits in retrospective trauma cohorts and is under evaluation in prospective critical illness/intensive care unit (ICU) trials, including acute respiratory failure, sepsis, and perioperative populations. However, prospective trauma-specific clinical data remain limited [157], [158], [159], [160], [161]. Moreover, β-adrenergic blockade, most notably with propranolol, reduces catecholamine-driven hypermetabolism, preserving lean body mass and improving survival and metabolic balance, especially in pediatric and geriatric trauma and burn patients [162]. However, anabolic hormone replacement therapies have shown inconsistent benefits and safety concerns in clinical studies, limiting their routine application in trauma care [190].
4.7. Neuropsychiatric interventions
Neuropsychiatric interventions target the neuroendocrine-immune node, addressing HPA-axis dysregulation, neuroinflammation, and behavioral impairments that critically shape long-term trauma outcomes [191]. These interventions recognize that neuropsychiatric sequelae of trauma arise from tightly coupled biological and psychosocial processes rather than isolated central nervous system pathology. Among pharmacologic strategies, minocycline, a tetracycline derivative, has emerged as a leading neuroinflammation-modulating agent. Minocycline exerts neuroprotective effects through inhibition of microglial activation, suppression of HMGB1 signaling, stabilization of the blood-brain barrier, and anti-apoptotic mechanisms [163]. Preclinical and clinical studies support its capacity to reduce neuroinflammation and improve outcomes following central nervous system injury [164], [165]. Notably, in traumatic brain injury, minocycline reduced chronic microglial activation as demonstrated by positron emission tomography imaging, although concomitant increases in neurofilament light levels highlight nuanced and context-dependent efficacy [165]. Additional glial-modulating approaches include ibudilast, a phosphodiesterase inhibitor that suppresses glial cytokine production and enhances neuroprotection [166]. Preclinical studies and early-phase clinical trials in post-traumatic stress disorder and neuropathic pain support its potential role in mitigating trauma-associated neuroinflammation and central sensitization [166], [167], [168]. Symptom-targeted psychiatric pharmacotherapies remain integral to trauma care despite limited mechanistic precision. Selective serotonin reuptake inhibitors enhance serotonergic neurotransmission and are widely used to reduce depressive and anxiety symptoms following trauma and PTSD [169]. Adrenergic antagonists, by blunting noradrenergic hyperarousal and autonomic overactivation, are commonly employed to address trauma-related hyperarousal and sleep disturbances. However, both classes exhibit heterogeneous efficacy, and benzodiazepines are generally discouraged due to associations with adverse outcomes and dependence risk [170], [171]. Beyond pharmacologic therapies, non-pharmacological interventions play a central role in long-term neuropsychiatric recovery. Cognitive behavioral therapy and trauma-focused psychotherapies are guideline-recommended first-line treatments for PTSD and trauma-related disorders, demonstrating robust efficacy in reducing symptom burden and improving functional outcomes [172]. In addition, transcranial magnetic stimulation provides non-invasive neuromodulation of prefrontal and network-level activity and is approved for treatment-resistant depression, with emerging evidence supporting its utility in PTSD and post-traumatic neuropsychiatric syndromes [173]. Complementing these therapeutic strategies, emerging diagnostic and monitoring tools, including digital phenotyping, electroencephalogram analytics, and AI-assisted behavioral assessment, are under early translational development. These approaches aim to integrate biological and behavioral data to enable early detection, stratification, and personalized intervention, rather than serving as stand-alone therapies [192]. Early recognition and multidisciplinary integration of neuropsychiatric interventions are critical for optimizing neurobehavioral recovery and long-term quality of life, particularly in pediatric and high-risk trauma populations.
5. From traditional biomarkers to emerging molecular signatures
Traditional biomarkers such as creatine kinase (CK), lactate dehydrogenase (LDH), and myoglobin have long been utilized as frontline tools for evaluating polytrauma with MSK injury [193]. These markers primarily reflect myocyte injury and necrosis, offering early signals of muscle breakdown and associated risks such as rhabdomyolysis and AKI [194]. CK, particularly the muscle-specific CK-MM isoform, is the most widely used and commonly rises substantially following blunt or crush injuries [195]. LDH is sensitive to cellular damage but lacks muscle specificity due to its broad tissue distribution [196], whereas myoglobin rises rapidly but is transient because of its fast clearance [197]. Diagnostic performance remains modest: CK generally demonstrates AUC values of 0.70 – 0.75, and both LDH and myoglobin are influenced by injury or dysfunction in multiple organs [194]. Additional confounders, including liver injury, hemolysis, sepsis, metabolic disorders, strenuous physical activity, and impaired renal clearance, further reduce specificity and can obscure the true extent of muscle injury. As a result, although useful for detecting overt tissue necrosis, these traditional biomarkers provide only retrospective snapshots and cannot resolve the upstream immune, endothelial, and metabolic perturbations that drive systemic trauma biology.
Advancements in trauma diagnostics have accelerated the development of next-generation biomarkers that provide improved sensitivity and mechanistic resolution beyond conventional indicators of muscle necrosis. Among these, muscle-enriched circulating microRNAs (miRNAs) such as miR-206 and miR-486 correlate strongly with the extent of muscle injury and demonstrate diagnostic sensitivity and specificity exceeding 80% in early studies [198]. Complementing these injury-burden markers, miRNAs including miR-21 and miR-223 reflect inflammatory activation, fibrosis, and maladaptive tissue remodeling, linking molecular injury signatures to downstream repair failure [199]. EVs, including exosomes and microvesicles released by stressed or injured cells, further extend this diagnostic spectrum by transporting miRNAs, proteins, and lipids that report oxidative stress, mitochondrial dysfunction, and immune activation, while also actively modulating trauma-induced inflammation [200].
Among circulating protein biomarkers, fatty acid-binding protein 3, which is predominantly expressed in skeletal muscle [201], has demonstrated strong prognostic utility, with clinical data showing an AUC of 0.82 for predicting post-traumatic AKI, outperforming CK, and associations with trauma severity and complications such as compartment syndrome [202], [203]. Additional mechanistic biomarkers include galectin-3, which reflects persistent inflammation, fibrosis, and cellular senescence and has been linked to HO risk, although large-scale trauma-specific validation remains ongoing [204]. Beyond individual tissues, muscle-bone endocrine mediators, including myokines (irisin, myostatin, IL-6) and osteokines (osteocalcin, sclerostin, fibroblast growth factor-23), provide integrated readouts of metabolic crosstalk during regeneration and systemic stress [205]. Complementing these systemic markers, the collagen X degradation fragment has emerged as a real-time indicator of endochondral ossification and bone healing velocity, enabling dynamic monitoring of skeletal repair after trauma [206], [207].
Despite their promise, most of these biomarkers remain in early clinical development, with validation largely limited to single-center or pilot trauma cohorts using enzyme-linked immunosorbent assay or multiplex immunoassay platforms, underscoring the need for assay standardization, regulatory qualification, and multicenter validation prior to widespread clinical adoption [208].
Integrating biomarker discovery with therapeutic innovation forms a foundational paradigm for precision trauma medicine in polytrauma with MSK injury. Syndecan-1 elevation [89] may identify patients who would benefit from glycocalyx-protective agents such as sulodexide [127], [128] or FX06. Cytokine ratios, such as elevated IL-6 relative to IL-10, may guide the timing of IL-6 receptor blockade with tocilizumab [209]. Persistently high HMGB1 levels may inform the use of antagonists targeting DAMP- or TLR-driven inflammation [121]. Increased S100A8/A9 [210] may identify candidates for nanoparticle-based immunomodulation. Although these precision-guided approaches require validation through dedicated trauma trials, they exemplify how biomarker-informed stratification can shift trauma care from generalized resuscitation toward individualized, mechanism-targeted therapy.
Assessing the translational potential of biomarkers of polytrauma with MSK injury necessitates consideration of the distinctive conditions in military and civilian trauma care settings. Military trauma care is frequently delivered in austere environments characterized by delayed evacuation, constrained surgical capacity, and high injury complexity, conditions that favor biomarkers that are stable, rapidly quantifiable, and compatible with rugged point-of-care (POC) platforms [211], [212]. In these settings, biomarkers such as CK, myoglobin, fatty acid-binding protein 3 (FABP3), and select cytokines or DAMPs measurable through portable immunoassays are particularly valuable for early triage, evacuation prioritization, and prediction of complications including AKI and multi-organ dysfunction [89], [203], [213]
However, civilian trauma systems, which benefit from advanced imaging, comprehensive biobanking, and access to high-throughput laboratory infrastructure, are better positioned to deploy multiplex panels, circulating miRNA profiling, EV analysis, metabolic panels, and longitudinal biomarker surveillance. These capabilities allow deeper mechanistic stratification of inflammation, fibrosis, metabolic dysregulation, and impaired regeneration following MSK trauma [200], [204], [210]
The utility of biomarkers varies across clinical phases of trauma care, with acute, subacute, and chronic stages presenting distinct diagnostic priorities and operational constraints. In the acute phase, frontline military outposts depend heavily on rugged POC assays to enable rapid detection of hemorrhage, endotheliopathy, and muscle breakdown, whereas civilian trauma centers can deploy broader multiplex panels and advanced diagnostics within emergency department settings [214], [215]. During the subacute period, biomarker monitoring shifts toward prognostication of inflammatory burden, fibrosis, and optimal rehabilitation timing, occurring along evacuation chains in military contexts or within inpatient and rehabilitation services in civilian systems. Long-term care prioritizes surveillance of veterans and civilian patients at risk of disability, frailty, and chronic complications, with sustained monitoring of regenerative, anabolic, and neurotrophic mediators, most notably IGF-1, which plays a central role in MSK regeneration and repair [216], [217].
Clinical and translational studies have established phase-specific biomarker applications across military and civilian trauma environments, encompassing endothelial injury markers, immune mediators, metabolic regulators, and regenerative signals [203], [204], [210], [211]. Increasingly, these workflows are augmented by continuous wearable biosensors and AI-enabled analytics, enhancing predictive accuracy and individualized management across the trauma trajectory. These phase-dependent biomarker strategies and enabling technologies are summarized in Table 3 [203], [204], [210], [211], [213], [217], which outlines biomarker-guided approaches spanning acute, subacute, and chronic phases of trauma care.
Table 3.
Biomarker-guided phases of trauma management across military and civilian contexts.
| Phase | Military context | Civilian context | Key biomarkers/Technologies | Clinical utility | Evidence highlights | References |
|---|---|---|---|---|---|---|
| Acute (0 – 72 h) | Forward bases with limited labs, reliance on rugged POC devices | Advanced diagnostics in emergency departments | Syndecan-1, FABP, lactate, miRNAs, calprotectin (S100A8/A9), wearables | Rapid triage, early detection of hemorrhage/endotheliopathy, prediction of MODS | Syndecan-1 (AUC = 0.80), FABP3 | [203], [210], [211], [213] |
| Subacute (days-weeks) | Evacuation chain, transport prioritization | Inpatient and rehabilitation monitoring | Galectin-3, IL-6, HMGB1, mitochondrial DNA, EVs, metabolomics panels | Prognosis of inflammation, fibrosis, and optimized rehab timing | Galectin-3 correlated with HO risk | [204] |
| Chronic (weeks-years) | Long-term veteran follow-up | Disability care, aging-related management | IGF-1, BDNF, osteocalcin, CTX-II, DHEA-S, CRP, TNF-α | Tracking regeneration, systemic adaptation, and mental health | IGF-1 role in MSK repair | [217] |
POC. Point of care; FABP. Fatty acid-binding protein; FABP3. Heart-type fatty acid-binding protein 3; miRNAs. MicroRNAs; EVs. Extracellular vesicles; IL-6. Interleukin-6; HO. Heterotopic ossification; IGF-1. Insulin-like growth factor-1; BDNF. Brain-derived neurotrophic factor; CTX-II. C-terminal crosslinked telopeptide of type II collagen; DHEA-S. Dehydroepiandrosterone sulfate; CRP. C-reactive protein; TNF-α. Tumor necrosis factor-α; MODS. Multi-organ dysfunction syndrome; HMGB1. High-mobility group box 1; S100A8/A9. S100 calcium-binding proteins A8 and A9 calprotectin
6. Multi-analyte panels, real-time monitoring, and liquid biopsy approaches
The precision medicine era is redefining diagnostics for blast-, blunt-, and crush-related polytrauma with major MSK injury, shifting away from reliance on single biomarkers toward integrated, multidimensional platforms that capture the evolving biology of injury. This transition is particularly critical in complex polytrauma scenarios, such as battlefield blast exposures, urban crush injuries, and mass-casualty events, where heterogeneous damage patterns demand rapid, individualized evaluation.
6.1. High-dimensional multi-omics and systems integration
Contemporary studies combine proteomics, metabolomics, transcriptomics, including single-cell and spatial, extracellular-vesicle cargo, lipidomics, and cfDNA/mtDNA analytics to map coordinated cascades across coagulation/complement, thrombo-inflammation, endothelial injury, and metabolic reprogramming [218], [219]. In particular, scRNA-seq and chromatin accessibility profiling of trauma patient leukocytes have demonstrated that immune-endotype-specific transcriptional and epigenetic programs are strongly associated with clinical phenotype and outcome, providing a prototype for multi-omic patient classification in polytrauma [81], [82]. Integrated pipelines merge these layers with clinical/physiologic data to support causal inference, risk stratification, and target prioritization. In trauma cohorts, proteo-metabolomic and EV-omic signatures correlate with infection risk, endotheliopathy, and organ dysfunction, while cfDNA/mtDNA refine organ-source attribution and predict trajectories [57], [59], [218], [220], [221]. Coupled with AI-enabled digital-twin frameworks, these datasets inform adaptive triage, timing of immunomodulatory or endothelial-protective therapies, and monitoring of regeneration [222], [223], [224]. Although still in early translation, these tools provide the foundation for clinically actionable, precision-guided trauma panels [225].
6.2. Multi-analyte biomarker panels
Panels that combine classical tissue-injury markers (CK, LDH, myoglobin) with miRNAs, inflammatory cytokines (IL-6, TNF-α), DAMPs, and senescence-associated proteins provide a multidimensional view of patient status [226]. Combining acute-phase cytokines with senescence markers (p16INK4a, SASP factors) provides early insight into maladaptive healing and fibrotic risk [227]. ML models align temporal biomarker dynamics with clinical metadata to refine prognosis and guide intervention [228].
6.3. Real-time monitoring technologies
Wearable and implantable biosensors are extending diagnostics beyond the laboratory, offering continuous monitoring of physiologic and biochemical parameters [229], [230], [231]. These devices track lactate, tissue oxygen saturation (StO₂), perfusion indices, and inflammatory mediators in sweat, saliva, or interstitial fluid, potentially useful for rapid decision-making in both military and civilian trauma care [232], [233]. Such systems hold promise for early detection of systemic inflammation or compartment syndrome, optimizing triage in austere and remote environments.
6.4. Liquid biopsy
Adapted from oncology, liquid biopsy approaches are emerging as minimally invasive, repeatable tools for probing systemic injury and organ-associated pathophysiological responses in trauma [234]. Circulating cfDNA, mtDNA, miRNAs, and EV cargoes represent core liquid biopsy components. These analytes reflect cellular injury, immune activation, metabolic stress, and organ dysfunction, and have demonstrated strong potential for tracking inflammation, fibrosis, and regeneration across the trauma phase [221], [235], [236], [237]. Their serial measurement enables longitudinal profiling of dynamic pathophysiological responses, making them central to emerging trauma liquid biopsy platforms.
Large-scale proteomic and metabolomic profiling can be viewed as liquid-biopsy-like approaches because both approaches quantify circulating proteins, peptides, lipids, and metabolites derived from injured tissues, dysregulated immune cells, activated endothelium, and stressed mitochondria. Proteomic signatures in trauma consistently reveal alterations in coagulation, complement activation, and energy metabolism, while metabolomic profiling identifies shifts in amino-acid, lipid, and mitochondrial-related pathways that correspond to injury severity, early sepsis, and systemic metabolic stress [238], [239]. By capturing these circulating molecular fingerprints through blood sampling, proteomics and metabolomics function as extensions of liquid biopsy, enabling the construction of dynamic network models for clinical risk stratification, precision monitoring, and therapeutic targeting [240], [241], [242].
6.5. Clinical convergence and translation
Integrating multi-omics, multi-analyte panels, and real-time biosensing can enable earlier identification of high-risk patients, personalized treatment selection, and responsive monitoring [243]. Portable, rugged, and cost-effective platforms tailored to trauma-specific biomarkers are key for battlefield and low-resource deployment [244].
7. Technological integration
7.1. Wearables and biosensors
The convergence of wearable devices and biosensors with trauma analytics has demonstrated feasibility and potential to improve early risk detection, physiologic monitoring, and triage efficiency [245]. Evidence from prehospital [246], [247] and simulated mass-casualty environments shows that these technologies can reduce time-to-triage, enhance detection of occult deterioration, and support more accurate resuscitation decisions [248], [249]. Modern devices extend well beyond activity tracking. To begin with, inertial measurement units, electromyography sensors, and optical platforms quantify gait asymmetry, joint loading, and muscle activation to support early functional risk detection and personalized rehabilitation [250], [251]. In addition, physiologic signals, such as heart-rate variability, perfusion indices, and skin temperature, often presage clinical deterioration and can serve as early-warning markers when integrated with continuous monitoring systems [252], [253], [254], [255]. Next-generation biochemical biosensors now enable minimally/non-invasive sampling of sweat, saliva, interstitial fluid, or capillary blood (LDH, CK, cortisol, electrolytes) to flag metabolic imbalance, rhabdomyolysis, or hypovolemia [256], [257]. Importantly, although wearable lactate sensing has been shown to shorten triage times in simulated disaster studies, these same evaluations reveal durability constraints, sensor drift, and incomplete data integration under operational stressors [244]. Adoption barriers, costs, workflow fit, and alarm fatigue remain prominent [253]. In prehospital and battlefield settings, these devices can accelerate triage and guide resuscitation decisions under constrained resources [222].
7.2. Domain-specific AI applications and validation
AI applications in trauma care are rapidly expanding, with several domain-specific use cases showing clinical promise. One major area involves the real-time prediction of hemodynamic decompensation and hemorrhage risk during field evacuation or intensive care monitoring, where algorithms trained on streaming vital signs and sensor telemetry enable early triage and timely intervention [222], [258]. Similarly, AI-driven forecasting of sepsis, MODS, and related deterioration employs models based on physiologic time-series data, laboratory parameters, and, in some studies, metabolomic inputs [259], [260], [261]. Meta-analyses indicate that such early-warning systems can improve recognition of critical deterioration and guide resuscitation strategies [258]. Beyond the acute phase, ML models are increasingly applied to rehabilitation and recovery, using longitudinal biomarker and imaging data to stratify risk for delayed MSK recovery and fibrotic complications after polytrauma, with biologic surrogates such as galectin-3 (a fibrosis-associated marker) supporting model interpretability [204].
Validation efforts are evolving from single-site retrospective studies to multicenter, externally validated models and prospective trials encompassing both military and civilian trauma cohorts [262], [263]. Wearable and biosensor-based AI platforms have demonstrated feasibility in simulated and operational field contexts, though practical constraints in data integration and interoperability persist [244], [258]. These limitations largely reflect the technical challenges of managing high-frequency sensor data under variable environmental and operational conditions. Despite these advances, several failure modes and biases limit generalizability. Overfitting remains a key challenge, particularly given the underrepresentation of female and geriatric populations in training datasets and the predominance of combat injury data [264]. Field-deployed systems also face technical reliability issues, including signal noise, sensor dropout, and intermittent network connectivity, while human-factor barriers such as alarm fatigue, workflow burden, and limited clinician acceptance hinder operational uptake [244], [253], [258]. To address these challenges, emerging frameworks prioritize explainable AI, human-in-the-loop oversight, and privacy-preserving or federated learning approaches to enhance interpretability, data security, and cross-site robustness.
7.3. Military vs. civilian deployment
The deployment of AI-driven trauma diagnostics and monitoring platforms diverges significantly between military and civilian settings due to distinct operational constraints and priorities. In austere or forward military environments, devices must be portable, ruggedized, and require minimal calibration while offering rapid decision support, often within 30 min, to aid triage and evacuation under intermittent connectivity. These systems prioritize speed, robustness, and interpretable outputs suitable for non-specialist users in high-stress conditions [222], [244]. In contrast, civilian hospital and rehabilitation environments benefit from stable infrastructure that supports high-plex assays, advanced imaging modalities, and integration with electronic health records (EHRs). Here, longer processing times are acceptable when offset by higher analytical depth and actionable insights, such as multiplex proteomic or EV analyses [222], [229], [230], [231], [232], [233], [256], [257].
Sample handling and time-to-result differ markedly between these settings. Field diagnostics typically rely on minimally invasive sampling, capillary blood, sweat, or interstitial fluid, paired with on-device analytics to deliver short turnaround times (TAT). However, these approaches remain vulnerable to motion artifacts, temperature fluctuations, and environmental contamination [244], [256], [257]. Civilian hospital workflows utilize venous sampling, refrigerated logistics, and centralized analyzers, allowing longer TAT but achieving superior analytical resolution through multi-analyte or liquid-biopsy workflows [229], [230], [231], [232], [233], [237].
Throughput and workflow design also reflect contextual divergence. Field-deployed platforms emphasize low-plex, high-frequency monitoring with edge analytics optimized for bandwidth efficiency and data compression [222], [244]. Similarly, civilian core laboratories leverage higher throughput, batchable assays, and seamless EHR-integrated decision support to deliver comprehensive, longitudinal data interpretation [222], [229], [230], [231], [232], [233], [256], [257].
Context critically shapes the clinical utility and performance of these systems. At the point of injury, wearable lactate or StO₂ sensors and hemodynamic AI algorithms can substantially improve triage and evacuation prioritization despite lower analytical granularity [222], [231], [244], [258]. In the intensive care or rehabilitation phases, multi-analyte and liquid-biopsy panels, such as those assessing cfDNA, mtDNA, or EV cargo, combined with AI-driven risk modeling, provide enhanced predictive power for sepsis, multi-organ dysfunction, and recovery trajectories, where slightly delayed turnaround is acceptable given the higher clinical impact [57], [221], [235], [236], [237], [265].
7.4. Remote monitoring and telemedicine
Secure data transmission from field and rural locations to centralized command or hospital centers enables a continuous and coordinated approach to trauma care. Rather than functioning as data-integration platforms themselves, telemedicine systems serve as clinical oversight and decision-support channels, allowing specialists to interpret incoming physiologic and biochemical information and provide real-time guidance across all stages of care, from the point of injury through transport, acute management, and rehabilitation [222]. By leveraging remote expertise, these platforms enhance situational awareness, optimize resource allocation, and ensure continuity of care across geographically dispersed military and civilian trauma networks.
7.5. Implementation risks and equity
Despite rapid technological progress, significant implementation challenges remain for integrating wearable biosensors and AI analytics into trauma workflows. Practical barriers include ensuring device ruggedness under extreme or unpredictable conditions, managing high volumes of streaming data without overwhelming providers, and maintaining robust data privacy and cybersecurity safeguards. Additional hurdles involve regulatory and reimbursement uncertainties and the need for targeted training programs to support AI-assisted clinical decision-making [266], [267]. Beyond technical limitations, equity concerns persist, particularly in regions with limited connectivity, maintenance capacity, or workforce readiness [268]. To ensure sustainable adoption, deployment strategies should include provisions for reliable infrastructure, local capacity building, and culturally attuned implementation models that bridge the gap between high-resource and low-resource trauma care settings [244], [253], [258].
8. Future outlook
The global burden of polytrauma with major MSK injury emphasizes the urgent need for transformative, not merely incremental, advances in trauma care. Although major progress has been made in understanding trauma biology, identifying reliable biomarkers, and developing therapeutic interventions, a wide translational disconnect remains between preclinical discovery and clinical application. This gap is particularly evident in regions disproportionately affected by high-energy injuries linked to armed conflict, road traffic collisions, and natural disasters. Addressing these challenges demands coordinated, mechanism-driven, and technology-enabled frameworks that redefine how trauma is investigated, diagnosed, and managed across diverse health systems.
A promising path forward is the establishment of a Global Trauma Initiative modeled after successful multinational consortia such as the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) [269], [270], active across more than 60 countries in Europe, North America, Africa, and Asia, and the International Traumatic Brain Injury Research (InTBIR) initiative. This global coalition would unite military, academic, clinical, and public health stakeholders to develop harmonized trauma registries, longitudinal biobanks, and multi-omics datasets that represent diverse injury profiles, emphasizing inclusion of LMICs. The integration of genomic, transcriptomic, proteomic, and metabolomic data with standardized clinical metadata could generate an equitable evidence base for the advancement of precision trauma medicine.
Within this global framework, the concept of a Precision Trauma Panel illustrates how mechanistic insights could translate into actionable diagnostics for polytrauma patients with significant MSK injury. By combining biomarkers such as FABP3 (muscle injury), IL-6 and IL-10 (inflammatory balance), syndecan-1 (endothelial glycocalyx degradation), and galectin-3 (fibrosis and senescence), these multi-analyte panels could enable early risk stratification and guide personalized interventions. Designed for both advanced laboratories and portable POC platforms, such tools could support triage and longitudinal monitoring across resource settings, whether in austere combat environments or tertiary trauma centers.
AI and ML will be central to managing the complexity of multi-modal trauma data. By integrating biomarker kinetics, physiologic signals, imaging, and contextual metadata, AI-driven systems can generate individualized predictive models. The emerging concept of a Combat Trauma Digital Twin, a real-time computational representation of the injured patient, exemplifies how digital platforms may automate triage, anticipate clinical deterioration, and personalize therapy across both military and civilian contexts.
Realizing this vision requires concurrent strengthening of foundational health-system components. The Global Alliance for MSK Health (G-MUSC) blueprint provides an actionable structure for such efforts, emphasizing adaptable, country-specific implementation strategies [271], [272]. Future initiatives should prioritize embedding biomarker-informed pathways within integrated service models supported by sustainable financing and workforce capacity building. Enhanced surveillance frameworks that link functional recovery metrics with molecular and clinical data will be crucial for benchmarking outcomes and ensuring equitable technology validation between high- and low-resource regions.
To operationalize this vision, priority actions over the next 5 years should include: 1) launching pilot trauma biomarker registries and multi-omics biobanks in diverse cohorts, including LMICs; 2) developing regulatory pathways and standardized qualification pipelines for multi-analyte panels; 3) funding multicenter randomized controlled trials to validate AI-enabled triage systems and digital twin frameworks across heterogeneous trauma populations; 4) establishing global collaborations for equitable biospecimen sharing, data harmonization, and open-access analytics; and 5) conducting interventional trials targeting cellular senescence and the SASP to mitigate chronic inflammation, fibrosis, and long-term disability.
While prototypes such as the Precision Trauma Panel and wearable biosensors show promise, most remain investigational and limited to early validation phases [225], [273], [274]. Broader implementation will depend on rigorous multicenter testing, technical standardization, ethical governance, and equitable access. Through sustained international collaboration and regulatory alignment, trauma care can evolve from reactive management toward predictive, precision-guided, and resilient systems that improve survival and long-term recovery worldwide.
9. Limitations
Although the review emphasized biomarkers and therapeutic pathways most directly linked to acute systemic pathophysiology, including immune dysregulation, endothelial dysfunction, mitochondrial injury, and trauma-induced senescence, this focused scope necessarily excluded several other clinically relevant biomarker domains. Important indicators of MSK remodeling and neurotrophic recovery, such as the myostatin-follistatin axis, brain-derived neurotrophic factor, troponin T, and IGF-1, as well as bone and cartilage turnover markers including osteocalcin, sclerostin, bone-specific alkaline phosphatase, and C-terminal crosslinked telopeptide of type II collagen, were not systematically evaluated. Likewise, broader endocrine and metabolic regulators (vitamin D, dehydroepiandrosterone sulfate, and cortisol), nonspecific inflammatory markers (C-reactive protein and TNF-α), and high-throughput proteomic discovery platforms were outside the scope of this analysis. The exclusion of these domains limits the review’s ability to integrate acute injury biology with the longer-term processes of MSK adaptation, rehabilitation, and chronic recovery. Future reviews that bridge acute mechanistic responses with longitudinal remodeling trajectories will be essential to advancing precision trauma care.
10. Conclusions
Polytrauma with predominant MSK injury, whether caused by battlefield blast exposures or civilian blunt and crush injuries, extends far beyond localized tissue damage. These injuries trigger complex systemic cascades involving immune dysregulation, endothelial dysfunction, metabolic disruption, and premature cellular senescence, profoundly influencing both acute management and long-term recovery. Persistent sequelae such as chronic pain, fibrosis, HO, neuroinflammation, and disability remain prevalent, highlighting the insufficiency of conventional frameworks based on anatomical scoring and nonspecific markers such as CK and myoglobin. These limitations mandate the adoption of next-generation diagnostics that capture the dynamic and evolving molecular landscape of trauma.
Emerging biomarkers, including miRNAs, EVs, FABP3, galectin-3, and muscle- and bone-derived cytokines, are redefining the molecular understanding of trauma by revealing signatures of immune activation, vascular injury, and regenerative potential. When coupled with wearable biosensors, multiplex assays, and liquid biopsy technologies, these biomarkers enable real-time and minimally invasive profiling of injury dynamics. AI and ML further strengthen this model by transforming complex multimodal datasets into predictive, clinically actionable insights. Seminal scRNA-seq and scATAC-seq studies in trauma patients now provide high-resolution immune endotypes that can be integrated into such analytic frameworks, enabling biology-guided patient classification and precision triage. Novel concepts such as biomarker-based trauma scoring systems and “Combat Trauma Digital Twins” exemplify the shift toward proactive and individualized care, bridging the gap between military and civilian trauma contexts.
Parallel therapeutic advances, such as senolytics, endothelial stabilizers, mitochondrial protectants, immunomodulators, glycocalyx-preserving agents, and bio-instructive scaffolds, reflect a transition from symptom control to biological recalibration. These interventions aim to restore vascular integrity, temper chronic inflammation, and accelerate functional regeneration, aligning treatment with the mechanistic roots of trauma pathology.
The future of trauma medicine lies in uniting mechanistic discovery with clinical implementation to create proactive, biology-informed models of recovery. Through sustained international collaboration, equitable access to innovation, and ethical governance of data and technology, the field stands poised to transform trauma care, improving survival, resilience, and long-term quality of life across global populations.
Abbreviations
AKI: Acute kidney injury
AI: Artificial intelligence
ARDS: Acute respiratory distress syndrome
ATP: Adenosine triphosphate
Ca²⁺: Calcium ion
CARS: Compensatory anti-inflammatory response syndrome
cfDNA: Circulating cell-free DNA
CK: Creatine kinase
DAMPs: Damage-associated molecular patterns
ECM: Extracellular matrix
EHR: Electronic health record
EVs: Extracellular vesicles
FABP3: Fatty acid-binding protein 3
FX06: Fibrin-derived peptide 06
HLA-DR: Human leukocyte antigen DR isotype
HMGB1: High-mobility group box 1
HO: Heterotopic ossification
HPA: Hypothalamic-pituitary-adrenal
HSP: Heat shock protein
IFN-γ: Interferon-γ
IGF-1: Insulin-like growth factor 1
IL: Interleukin
LDH: Lactate dehydrogenase
LMICs: Low- and middle-income countries
MAPK: Mitogen-activated protein kinase
MDSC: Myeloid-derived suppressor cell
miRNAs: MicroRNAs
MitoQ: Mitochondria-targeted coenzyme Q10 analogue
ML: Machine learning
MMP: Matrix metalloproteinase
MODS: Multi-organ dysfunction syndrome
MSCs: Mesenchymal stem cells
mtDNA: Mitochondrial DNA
MSK: Musculoskeletal
NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells
NLR: NOD-like receptor
POC: Point-of-care
PRISMA-ScR: Preferred reporting items for systematic reviews and meta-analyses extension for scoping reviews
PRRs: Pattern recognition receptors
P188: Poloxamer 188
RAGE: Receptor for advanced glycation end products
ROS: Reactive oxygen species
SASP: Senescence-associated secretory phenotype
scATAC-seq: Single-cell assay for transposase-accessible chromatin using sequencing
scRNA-seq: Single-cell RNA sequencing
SIRS: Systemic Inflammatory Response Syndrome
SS-31: Elamipretide peptide
StO₂: Tissue oxygen saturation
TAT: Turnaround times
TGF-β: Transforming growth factor-β
TIC: Trauma-induced coagulopathy
TLR: Toll-like receptor
TNF-α: Tumor necrosis factor α
Ethics approval and consent to participate
Not applicable.
Funding
Not applicable.
Acknowledgments
The authors acknowledge the use of Grammarly to assist with grammar correction and to improve the clarity and readability of the manuscript.
Authors’ contributions
RJRST conceptualized, conceived, and initiated the review, developed the first and final manuscript drafts, and designed the figures and tables. Formal literature analysis was conducted by RJRST and PA. MYG, CYP, and PA contributed to the drafting process, critically reviewed, and revised the manuscript. Textual contributions were made by RJRST, MYG, CYP, and PA, while visualization was managed by RJRST and PA. Writing, review, and editing responsibilities were shared by RJRST and PA. All authors read and approved the final manuscript.
Consent for publication
Not applicable.
Competing interests
The authors declared that they have no competing interests.
Contributor Information
Rex Jeya Rajkumar Samdavid Thanapaul, Email: rexjeyarajkumar.samdavidthanapaul.ctr@health.mil, rsamdavidthanapaul@genevausa.org.
Manoj Y. Govindarajulu, Email: manoj.y.govindarajulu.ctr@health.mil.
Chetan Y. Pundkar, Email: chetan.y.pundkar.ctr@health.mil.
Peethambaran Arun, Email: peethambaran.arun.civ@health.mil.
Availability of data and materials
Not applicable.
References
- 1.Blyth F.M., Briggs A.M., Schneider C.H., Hoy D.G., March L.M. The global burden of musculoskeletal pain – where to from here? Am J Public Health. 2019;109(1):35–40. doi: 10.2105/AJPH.2018.304747. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Khorram-Manesh A., Burkle F.M., Goniewicz K., Robinson Y. Estimating the number of civilian casualties in modern armed conflicts – a systematic review. Front Public Health. 2021;9 [Google Scholar]
- 3.Chevalley K., Zimmerman J., Mittendorf A., Sennersten F., Dalman A., Frogh S., et al. Civilian pattern of injuries in armed conflicts – a systematic review. Scand J Trauma Resusc Emerg Med. 2024;32(1):125. doi: 10.1186/s13049-024-01299-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Mock C., Cherian M.N. The global burden of musculoskeletal injuries: challenges and solutions. Clin Orthop Relat Res. 2008;466(10) [Google Scholar]
- 5.Juman L., Schneider E.B., Clifton D., Koehlmoos T.P. Common data elements and databases essential for the study of musculoskeletal injuries in military personnel. Mil Med. 2024;189(910) [Google Scholar]
- 6.Molloy J.M., Pendergrass T.L., Lee I.E., Chervak M.C., Hauret K.G., Rhon D.I. Musculoskeletal injuries and United States Army Readiness Part I: overview of injuries and their strategic impact. Mil Med. 2020;185(910) [Google Scholar]
- 7.Weil Y.A., Mosheiff R. In: The poly-traumatized patient with fractures: a multi-disciplinary approach. Pape H.C., Sanders R., Borrelli Jr. J., editors. Springer; 2016. High-energy injuries caused by penetrating trauma; pp. 329–342. [Google Scholar]
- 8.Howard J.T., Kotwal R.S., Stern C.A., Janak J.C., Mazuchowski E.L., Butler F.K., et al. Use of combat casualty care data to assess the US military trauma system during the Afghanistan and Iraq conflicts, 2001-2017. JAMA Surg. 2019;154(7):600–608. doi: 10.1001/jamasurg.2019.0151. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Lawry L.L., Korona-Bailey J., Kanagaratnam A., Maddox J., Hamm T.E., Janvrin M., et al. Qualitative assessment of point of injury to Role 2+ combat casualty care in Ukraine. Trauma Surg Acute Care Open. 2025;10(2) [Google Scholar]
- 10.Zasiekina L., Duchyminska T., Bifulco A., Bignardi G. War trauma impacts in Ukrainian combat and civilian populations: moral injury and associated mental health symptoms. Mil Psychol. 2024;36(5):555–566. doi: 10.1080/08995605.2023.2235256. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Alsalqawi A., Tahoon K.A., Nijim A., Halimy M., Villar R. A Mass casualty event in a Gaza war hospital. medRxiv. 2024. https://www.medrxiv.org/content/10.1101/2024.11.14.24316980v1.
- 12.Prat D., Braun M., Givon A., Goldman S., Katorza E., Shapira S. How do gunshot and explosive injuries to the lower extremities differ in severity and treatment? A comparative study from the israel-gaza conflict. Clin Orthop Relat Res. 2025;483(11):2037–2043. doi: 10.1097/CORR.0000000000003498. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Remondelli M.H., Remick K.N., Shackelford S.A., Gurney J.M., Pamplin J.C., Polk T.M., et al. Casualty care implications of large-scale combat operations. J Trauma Acute Care Surg. 2023;95(2):S180–S184. doi: 10.1097/TA.0000000000004063. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Gane E.M., Brakenridge C.L., Smits E.J., Johnston V. The impact of musculoskeletal injuries sustained in road traffic crashes on work-related outcomes: a protocol for a systematic review. Syst Rev. 2018;7:202. doi: 10.1186/s13643-018-0869-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Giri S., Risnes K., Uleberg O., Rogne T., Shrestha S.K., Nygaard Ø.P., et al. Impact of 2015 earthquakes on a local hospital in Nepal: a prospective hospital-based study. PLoS One. 2018;13(2) [Google Scholar]
- 16.Temel S., Yuksel R.C., Kaynar A.S., Caliskan M., Demir B., Alkan M., et al. Retrospective analysis of earthquake related crush injurie patients in ICU: 6-February earthquake in Türkiye. Eur J Trauma Emerg Surg. 2025;51(1):116. doi: 10.1007/s00068-025-02771-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Akrivos V.S., Koutalos A., Stefanou N., Koskiniotis A., Arnaoutoglou C. Crush injury and crush syndrome: a comprehensive review. EFORT Open Rev. 2025;10(6):424–430. doi: 10.1530/EOR-2025-0055. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Courtney A., Courtney M. The complexity of biomechanics causing primary blast-induced traumatic brain injury: a review of potential mechanisms. Front Neurol. 2015;6:221. doi: 10.3389/fneur.2015.00221. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Ortega R., Vietor R., Arbelaez C., Feliu D., Nozari A., Ortoleva J. Blast injuries. N Engl J Med. 2024;391(23) [Google Scholar]
- 20.Simon L.V., Lopez R.A., King K.C. StatPearls. StatPearls. Academic; Treasure Island: 2025. Blunt force trauma; pp. 30–38. [Google Scholar]
- 21.Portela R.C., Roney N. Crush injury. Emergency Medical Services. 2021:294–298. 〈https://onlinelibrary.wiley.com/doi/abs/10.1002/9781119756279.ch34〉 [Google Scholar]
- 22.Vourc'h M., Roquilly A., Asehnoune K. Trauma-induced damage-associated molecular patterns-mediated remote organ injury and immunosuppression in the acutely ill patient. Front Immunol. 2018;9:1330. doi: 10.3389/fimmu.2018.01330. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Ye J., Hu X., Wang Z., Li R., Gan L., Zhang M., Wang T. The role of mtDAMPs in the trauma-induced systemic inflammatory response syndrome. Front Immunol. 2023;14 [Google Scholar]
- 24.Srdić T., Đurašević S., Lakić I., Ružičić A., Vujović P., Jevđović T., et al. From molecular mechanisms to clinical therapy: understanding sepsis-induced multiple organ dysfunction. Int J Mol Sci. 2024;25(14):7770. doi: 10.3390/ijms25147770. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Spapen H.D., Jacobs R., Honoré P.M. Sepsis-induced multi-organ dysfunction syndrome – a mechanistic approach. J Emerg Crit Care Med. 2017;1:27. [Google Scholar]
- 26.Adejuyigbe B., Gharpure M., Tilve R., Kakulamarri S., Wang S., Kallini J., et al. Revisiting the OTA-OFC: a systematic review of open fracture classification studies since 2010. OTA Int. 2025;8(2) [Google Scholar]
- 27.Ahmed S.K., Mohammed M.G., Abdulqadir S.O., El‐Kader R.G.A., El‐Shall N.A., Chandran D., et al. Road traffic accidental injuries and deaths: a neglected global health issue. Health Sci Rep. 2023;6(5) [Google Scholar]
- 28.Lord J.M., Midwinter M.J., Chen Y.F., Belli A., Brohi K., Kovacs E.J., et al. The systemic immune response to trauma: an overview of pathophysiology and treatment. Lancet. 2014;384(9952):1455–1465. doi: 10.1016/S0140-6736(14)60687-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Tricco A.C., Lillie E., Zarin W., O’Brien K.K., Colquhoun H., Levac D., et al. PRISMA extension for scoping reviews (PRISMA-ScR): checklist and explanation. Ann Intern Med. 2018;169(7):467–473. doi: 10.7326/M18-0850. [DOI] [PubMed] [Google Scholar]
- 30.Iyengar K.P., Venkatesan A.S., Jain V.K., Shashidhara M.K., Elbana H., Botchu R. Risks in the management of polytrauma patients: clinical insights. Orthop Res Rev. 2023;15:27–38. doi: 10.2147/ORR.S340532. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Cernak I. In: Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects. Kobeissy F.H., editor. CRC Press/Taylor & Francis; Boca Raton (FL): 2015. Blast injuries and blast-induced neurotrauma: overview of pathophysiology and experimental knowledge models and findings. Chapter 45. [Google Scholar]
- 32.Emseih S., Abu-Sittah G.S. Springer; Cham: 2023. Biodynamics of Blast Injury; pp. 17–43. [Google Scholar]
- 33.Hudlicka O., Brown M.D. Adaptation of skeletal muscle microvasculature to increased or decreased blood flow: role of shear stress, nitric oxide and vascular endothelial growth factor. J Vasc Res. 2009;46(5):504–512. doi: 10.1159/000226127. [DOI] [PubMed] [Google Scholar]
- 34.Yin H., Arpino J.M., Lee J.J., Pickering J.G. Regenerated microvascular networks in ischemic skeletal muscle. Front Physiol. 2021;12 [Google Scholar]
- 35.Wang J., Chen J., Zhou J., Qiu J., Yao Y. Springer Nature; 2023. Injuries from Conventional Explosive Weapons; pp. 505–547. [Google Scholar]
- 36.Stenson B.A., Joseph J.W. New Delhi. Elsevier; 2024. Introduction to Explosions and Blasts; pp. 473–480. [Google Scholar]
- 37.Saran S. Biomechanics of blunt force trauma: forensic investigation techniques. J Forensic Biomech. 2024;15(2):488. [Google Scholar]
- 38.Shkrum M.J. Springer; Cham: 2024. Blunt Trauma; pp. 189–232. [Google Scholar]
- 39.Sexton K., Schwab N., Galtés I., Casas A., Armentano N., Brillas P., et al. Osteonal damage patterns from ballistic and blunt force trauma in human long bones. Life. 2024;14(2):220. doi: 10.3390/life14020220. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Janakiram N.B., Valerio M.S., Goldman S.M., Dearth C.L. The role of the inflammatory response in mediating functional recovery following composite tissue injuries. Int J Mol Sci. 2021;22(24):13552. doi: 10.3390/ijms222413552. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Long B., Liang S.Y., Gottlieb M. Crush injury and syndrome: a review for emergency clinicians. Am J Emerg Med. 2023;69:180–187. doi: 10.1016/j.ajem.2023.04.029. [DOI] [PubMed] [Google Scholar]
- 42.Torres P.A., Helmstetter J.A., Kaye A.M., Kaye A.D. Rhabdomyolysis: pathogenesis, diagnosis, and treatment. Ochsner J. 2015;15(1):58–69. [PMC free article] [PubMed] [Google Scholar]
- 43.Danaei B., Sharifi A., Mazloom H., Najafi I., Farhang Ranjbar M., Safari S. Prevalence of compartment syndrome and disseminated intravascular coagulation following rhabdomyolysis; a systematic review and meta-analysis. Arch Acad Emerg Med. 2023;11(1) [Google Scholar]
- 44.Wong Y.R., Pang X., Lim Z.Y., Du H., Tay S.C., McGrouther D.A. Biomechanical evaluation of peripheral nerves after crush injuries. Heliyon. 2019;5(4) [Google Scholar]
- 45.Soares R.O.S., Losada D.M., Jordani M.C., Évora P., Castro-e-Silva O. Ischemia/reperfusion injury revisited: an overview of the latest pharmacological strategies. Int J Mol Sci. 2019;20(20):5034. doi: 10.3390/ijms20205034. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Khan S., Neradi D., Unnava N., Jain M., Tripathy S.K. Pathophysiology and management of crush syndrome: a narrative review. World J Orthop. 2025;16(4) [Google Scholar]
- 47.Relja B., Land W.G. Damage-associated molecular patterns in trauma. Eur J Trauma Emerg Surg. 2020;46(4):751–775. doi: 10.1007/s00068-019-01235-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48.Asim M., Amin F., El-Menyar A. Multiple organ dysfunction syndrome: contemporary insights on the clinicopathological spectrum. Qatar Med J. 2020;2020(1):22. doi: 10.5339/qmj.2020.22. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49.Grazioli S., Pugin J. Mitochondrial damage-associated molecular patterns: from inflammatory signaling to human diseases. Front Immunol. 2018;9:832. doi: 10.3389/fimmu.2018.00832. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 50.Riley J.S., Tait S.W. Mitochondrial DNA in inflammation and immunity. EMBO Rep. 2020;21(4) [Google Scholar]
- 51.Cernak I., Noble-Haeusslein L.J. Traumatic brain injury: an overview of pathobiology with emphasis on military populations. J Cereb Blood Flow Metab. 2010;30(2):255–266. doi: 10.1038/jcbfm.2009.203. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52.Govindarajulu M., Patel M.Y., Wilder D.M., Krishnan J., LaValle C., Pandya J.D., et al. Upregulation of multiple Toll-like receptors in ferret brain after blast exposure: potential targets for treatment. Neurosci Lett. 2023;810 [Google Scholar]
- 53.Samdavid Thanapaul R.J.R., Krishnan J.K.S., Govindarajulu M.Y., Pundkar C.Y., Phuyal G., Long J.B., et al. Differential neuroendocrine responses and dysregulation of the hypothalamic-pituitary-adrenal axis following repeated mild concussive impacts and blast exposures in a rat model. Brain Sciences. 2025;15(8):847. doi: 10.3390/brainsci15080847. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 54.Arun P., Rossetti F., Wilder D.M., Sajja S., Van Albert S.A., Wang Y., et al. Blast exposure leads to accelerated cellular senescence in the rat brain. Front Neurol. 2020;11:438. doi: 10.3389/fneur.2020.00438. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 55.Tu H., Li Y.L. Inflammation balance in skeletal muscle damage and repair. Front Immunol. 2023;14 [Google Scholar]
- 56.Gallo J., Raska M., Kriegova E., Goodman S.B. Inflammation and its resolution and the musculoskeletal system. J Orthop Translat. 2017;10:52–67. doi: 10.1016/j.jot.2017.05.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 57.Thurairajah K., Briggs G.D., Balogh Z.J. The source of cell-free mitochondrial DNA in trauma and potential therapeutic strategies. Eur J Trauma Emerg Surg. 2018;44(3):325–334. doi: 10.1007/s00068-018-0954-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 58.Wang Q., Long G., Luo H., Zhu X., Han Y., Shang Y., et al. S100A8/A9: an emerging player in sepsis and sepsis-induced organ injury. Biomed Pharmacother. 2023;168 [Google Scholar]
- 59.Horner E., Lord J.M., Hazeldine J. The immune suppressive properties of damage associated molecular patterns in the setting of sterile traumatic injury. Front Immunol. 2023;14 [Google Scholar]
- 60.Yao J., Sterling K., Wang Z., Zhang Y., Song W. The role of inflammasomes in human diseases and their potential as therapeutic targets. Sig Transduct Target Ther. 2024;9(1):10. [Google Scholar]
- 61.Wei J., Zhang Y., Li H., Wang F., Yao S. Toll-like receptor 4: a potential therapeutic target for multiple human diseases. Biomed Pharmacother. 2023;166 [Google Scholar]
- 62.Paik S., Kim J.K., Silwal P., Sasakawa C., Jo E.K. An update on the regulatory mechanisms of NLRP3 inflammasome activation. Cell Mol Immunol. 2021;18(5):1141–1160. doi: 10.1038/s41423-021-00670-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 63.Fujimura K., Karasawa T., Komada T., Yamada N., Mizushina Y., Baatarjav C., et al. NLRP3 inflammasome-driven IL-1β and IL-18 contribute to lipopolysaccharide-induced septic cardiomyopathy. J Mol Cell Cardiol. 2023;180:58–68. doi: 10.1016/j.yjmcc.2023.05.003. [DOI] [PubMed] [Google Scholar]
- 64.Poppenborg T., Saljic A., Bruns F., Abu-Taha I., Dobrev D., Fender A.C. A short history of the atrial NLRP3 inflammasome and its distinct role in atrial fibrillation. J Mol Cell Cardiol. 2025;202:13–23. doi: 10.1016/j.yjmcc.2025.02.011. [DOI] [PubMed] [Google Scholar]
- 65.Samdavid Thanapaul R.J.R., Pundkar C., Phuyal G., Govindarajulu M.Y., Menon A., Long J.B., et al. Temporal dynamics of retinal inflammation following blast exposure in a ferret model. Neurotrauma Rep. 2025;6(1):283–290. doi: 10.1089/neur.2024.0127. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 66.Arun P., Rossetti F., Wilder D.M., Wang Y., Gist I.D., Long J.B. Blast exposure causes long-term degeneration of neuronal cytoskeletal elements in the cochlear nucleus: a potential mechanism for chronic auditory dysfunctions. Front Neurol. 2021;12 [Google Scholar]
- 67.Zhang J.M., An J. Cytokines, inflammation, and pain. Int Anesthesiol Clin. 2007;45(2):27. doi: 10.1097/AIA.0b013e318034194e. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 68.Li R., Ye J.J., Gan L., Zhang M., Sun D., Li Y., et al. Traumatic inflammatory response: pathophysiological role and clinical value of cytokines. Eur J Trauma Emerg Surg. 2024;50(4):1313–1330. doi: 10.1007/s00068-023-02388-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 69.Caballero-Sánchez N., Alonso-Alonso S., Nagy L. Regenerative inflammation: when immune cells help to rebuild tissues. FEBS J. 2024;291(8):1597–1614. doi: 10.1111/febs.16693. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 70.Guisasola M.C., Alonso B., Bravo B., Vaquero J., Chana F. An overview of cytokines and heat shock response in polytraumatized patients. Cell Stress Chaperones. 2018;23(4):483–489. doi: 10.1007/s12192-017-0859-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 71.Baddam S., Burns B. Systemic inflammatory response syndrome. In: StatPearls. 2025. 〈https://www.ncbi.nlm.nih.gov/books/NBK547669/〉. Accessed 20 Jun, 2025.
- 72.Rosenthal M.D., Moore F.A. Persistent inflammation, immunosuppression, and catabolism: evolution of multiple organ dysfunction. Surg Infect (Larchmt) 2016;17(2):167–172. doi: 10.1089/sur.2015.184. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 73.Stoecklein V.M., Osuka A., Lederer J.A. Trauma equals danger – damage control by the immune system. J Leukoc Biol. 2012;92(3):539–551. doi: 10.1189/jlb.0212072. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 74.Yang Z., Simovic M.O., Edsall P.R., Liu B., Cancio T.S., Batchinsky A.I., et al. HMGB1 inhibition to ameliorate organ failure and increase survival in trauma. Biomolecules. 2022;12(1):101. doi: 10.3390/biom12010101. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 75.Muire P.J., Mangum L.H., Wenke J.C. Time course of immune response and immunomodulation during normal and delayed healing of musculoskeletal wounds. Front Immunol. 2020;11:1056. doi: 10.3389/fimmu.2020.01056. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 76.Zhang X., Gao Y., Zhang S., Wang Y., Pei X., Chen Y., et al. Mitochondrial dysfunction in the regulation of aging and aging-related diseases. Cell Commun Signal. 2025;23:290. doi: 10.1186/s12964-025-02308-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 77.Simmon J.D., Lee Y.L., Mulekar S., Kuck J.L., Brevard S.B., Gonzalez R.P., et al. Elevated levels of plasma mitochondrial DNA DAMPs are linked to clinical outcome in severely injured human subjects. Ann Surg. 2013;258(4):591–598. doi: 10.1097/SLA.0b013e3182a4ea46. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 78.Nie J., Zhou L., Tian W., Liu X., Yang L., Yang X., et al. Deep insight into cytokine storm: from pathogenesis to treatment. Sig Transduct Target Ther. 2025;10(1):112. [Google Scholar]
- 79.Fu X., Liu Z., Wang Y. Advances in the study of immunosuppressive mechanisms in sepsis. J Inflamm Res. 2023;16:3967–3981. doi: 10.2147/JIR.S426007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 80.Gao X., Cai S., Li X., Wu G. Sepsis-induced immunosuppression: mechanisms, biomarkers and immunotherapy. Front Immunol. 2025;16 [Google Scholar]
- 81.Chen T., Delano M.J., Chen K., Sperry J.L., Namas R.A., Lamparello A.J., et al. A road map from single-cell transcriptome to patient classification for the immune response to trauma. JCI Insight. 2021;6(2) [Google Scholar]
- 82.Chen T., Conroy J., Wang X., Situ M., Namas R.A., Vodovotz Y., et al. The independent prognostic value of global epigenetic alterations: an analysis of single-cell ATAC-seq of circulating leukocytes from trauma patients followed by validation in whole blood leukocyte transcriptomes across three etiologies of critical illness. EBioMedicine. 2022;76 [Google Scholar]
- 83.Maniar D., Keenum M.C., Vantucci C.E., Guyer T., Chatterjee P., Leguineche K., et al. Single-cell transcriptomic analysis identifies systemic immunosuppressive myeloid cells and local monocytes/macrophages as key regulators in polytrauma-induced immune dysregulation. Bone Res. 2025;13(1):69. doi: 10.1038/s41413-025-00444-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 84.Cheng A., Vantucci C.E., Krishnan L., Ruehle M.A., Kotanchek T., Wood L.B., et al. Early systemic immune biomarkers predict bone regeneration after trauma. Proc Natl Acad Sci U S A. 2021;118(8) [Google Scholar]
- 85.Nityashree K.L., Rachitha P., Hanchinmane S., Raghavendra V.B. Advancing precision medicine: uncovering biomarkers and strategies to mitigate immune-related adverse events in immune checkpoint inhibitors therapy. Toxicol Rep. 2025;14 [Google Scholar]
- 86.Cardenas J.C., Dong J.F., Kozar R.A. Injury-induced endotheliopathy: what you need to know. J Trauma Acute Care Surg. 2023;95(4):454–463. doi: 10.1097/TA.0000000000004082. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 87.Patterson E.K., Cepinskas G., Fraser D.D. Endothelial glycocalyx degradation in critical illness and injury. Front Med (Lausanne) 2022;9 [Google Scholar]
- 88.Barry M., Pati S. Targeting repair of the vascular endothelium and glycocalyx after traumatic injury with plasma and platelet resuscitation. Matrix Biol Plus. 2022;14 [Google Scholar]
- 89.Suzuki K., Okada H., Sumi K., Tomita H., Kobayashi R., Ishihara T., et al. Syndecan-1 as a severity biomarker for patients with trauma. Front Med (Lausanne) 2022;9 [Google Scholar]
- 90.Braunstein M., Annecke T., Frey K., Kusmenkov T., Wörnle M., Ney L., et al. Effect on syndecan-1 and hyaluronan levels depending on multiple organ failure, coagulopathy and survival: an observational study in major trauma patients. J Clin Med. 2024;13(22):6768. doi: 10.3390/jcm13226768. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 91.Chalkias A. Shear stress and endothelial mechanotransduction in trauma patients with hemorrhagic shock: hidden coagulopathy pathways and novel therapeutic strategies. Int J Mol Sci. 2023;24(24):17522. doi: 10.3390/ijms242417522. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 92.Aldecoa C., Llau J.V., Nuvials X., Artigas A. Role of albumin in the preservation of endothelial glycocalyx integrity and the microcirculation: a review. Ann Intensive Care. 2020;10(1):85. doi: 10.1186/s13613-020-00697-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 93.Medrano-Bosch M., Simón-Codina B., Jiménez W., Edelman E.R., Melgar-Lesmes P. Monocyte-endothelial cell interactions in vascular and tissue remodeling. Front Immunol. 2023;14 [Google Scholar]
- 94.Chen X., Ji Y., Liu R., Zhu X., Wang K., Yang X., et al. Mitochondrial dysfunction: roles in skeletal muscle atrophy. J Transl Med. 2023;21(1):503. doi: 10.1186/s12967-023-04369-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 95.Dobson G.P., Morris J.L., Letson H.L. Immune dysfunction following severe trauma: a systems failure from the central nervous system to mitochondria. Front Med. 2022;9 [Google Scholar]
- 96.Liu H., Liu X., Zhou J., Li T. Mitochondrial DNA is a vital driving force in ischemia-reperfusion injury in cardiovascular diseases. Oxid Med Cell Longev. 2022;2022 [Google Scholar]
- 97.Sanderson T.H., Reynolds C.A., Kumar R., Przyklenk K., Hüttemann M. Molecular mechanisms of ischemia-reperfusion injury in brain: pivotal role of the mitochondrial membrane potential in reactive oxygen species generation. Mol Neurobiol. 2013;47(1):9–23. doi: 10.1007/s12035-012-8344-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 98.Chandra A., Lagnado A.B., Farr J.N., Doolittle M., Tchkonia T., Kirkland J.L., et al. Targeted clearance of p21‐ but not p16‐positive senescent cells prevents radiation‐induced osteoporosis and increased marrow adiposity. Aging Cell. 2022;21(5) [Google Scholar]
- 99.Liu Y., Dou Y., Sun X., Yang Q. Mechanisms and therapeutic strategies for senescence-associated secretory phenotype in the intervertebral disc degeneration microenvironment. J Orthop Translat. 2024;45:56–65. doi: 10.1016/j.jot.2024.02.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 100.Alum E., Izah S., Uti D., Ugwu O., Betiang P., Basajja M., et al. Targeting cellular senescence for healthy aging: advances in senolytics and senomorphics. Drug Des Devel Ther. 2025;19:8489–8522. [Google Scholar]
- 101.Klaassens E.R. Bouncing back-trauma and the HPA-axis in healthy adults. Eur J Psychotraumatol. 2010;1 [Google Scholar]
- 102.Thanapaul R.J.R.S., Govindarajulu M., Pundkar C., Phuyal G., Eken O., Long J.B., et al. Longitudinal dysregulation of adiponectin and leptin following blast-induced polytrauma in a rat model. Int J Mol Sci. 2025;26(14):6860. doi: 10.3390/ijms26146860. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 103.Mira J.C., Brakenridge S.C., Moldawer L.L., Moore F.A. Persistent inflammation, immunosuppression and catabolism syndrome (PICS) Crit Care Clin. 2017;33(2):245–258. doi: 10.1016/j.ccc.2016.12.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 104.Yin X., Manczak M., Reddy P.H. Mitochondria-targeted molecules MitoQ and SS31 reduce mutant huntingtin-induced mitochondrial toxicity and synaptic damage in Huntington’s disease. Hum Mol Genet. 2016;25(9):1739–1753. doi: 10.1093/hmg/ddw045. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 105.Maurer S., Kirsch V., Ruths L., Brenner R.E., Riegger J. Senolytic therapy combining dasatinib and quercetin restores the chondrogenic phenotype of human osteoarthritic chondrocytes by the release of pro‐anabolic mediators. Aging Cell. 2024;24(1) [Google Scholar]
- 106.Drygała S., Radzikowski M., Maciejczyk M. β-blockers and metabolic modulation: unraveling the complex interplay with glucose metabolism, inflammation and oxidative stress. Front Pharmacol. 2024;15 [Google Scholar]
- 107.Davis C.S., Wilkinson K.H., Lin E., Carpenter N.J., Georgeades C., Lomberk G., et al. Precision medicine in trauma: a transformational frontier in patient care, education, and research. Eur J Trauma Emerg Surg. 2022;48(4):2607–2612. doi: 10.1007/s00068-021-01817-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 108.Briassouli E., Syrimi N., Ilia S. Hyperferritinemia and macrophage activation syndrome in septic shock: recent advances with a pediatric focus (2020–2025) Children. 2025;12(9):1193. doi: 10.3390/children12091193. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 109.Shakoory B., Carcillo J.A., Chatham W.W., Amdur R.L., Zhao H., Dinarello C.A., et al. Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of the macrophage activation syndrome: re-analysis of a prior phase III trial. Crit Care Med. 2016;44(2):275–281. doi: 10.1097/CCM.0000000000001402. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 110.Emery P., Keystone E., Tony H.P., Cantagrel A., van Vollenhoven R., Sanchez A., et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis. 2008;67(11):1516. doi: 10.1136/ard.2008.092932. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 111.Angriman F., Ferreyro B.L., Burry L., Fan E., Ferguson N.D., Husain S., et al. Interleukin-6 receptor blockade in patients with COVID-19: placing clinical trials into context. Lancet Respir Med. 2021;9(6):655–664. doi: 10.1016/S2213-2600(21)00139-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 112.Somers E.C., Eschenauer G.A., Troost J.P., Golob J.L., Gandhi T.N., Wang L., et al. Tocilizumab for treatment of mechanically ventilated patients with COVID-19. Clin Infect Dis. 2021;73(2):e445–e454. doi: 10.1093/cid/ciaa954. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 113.Erkurt M.A., Sarici A., Özer A.B., Kuku I., Biçim S., Aydogan M.S., et al. The effect of HA330 hemoperfusion adsorbent method on inflammatory markers and end-organ damage levels in sepsis: a retrospective single center study. Eur Rev Med Pharmacol Sci. 2022;26(21):8112–8117. doi: 10.26355/eurrev_202211_30165. [DOI] [PubMed] [Google Scholar]
- 114.Li Y., Han M., Yang M., Su B. Hemoperfusion with the HA330/HA380 cartridge in intensive care settings: a state-of-the-art review. Blood Purif. 2025;54(2):122–137. doi: 10.1159/000542469. [DOI] [PubMed] [Google Scholar]
- 115.He M., Bianchi M.E., Coleman T.R., Tracey K.J., Al-Abed Y. Exploring the biological functional mechanism of the HMGB1/TLR4/MD-2 complex by surface plasmon resonance. Mol Med. 2018;24(1):21. doi: 10.1186/s10020-018-0023-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 116.Okuma Y., Liu K., Wake H., Liu R., Nishimura Y., Hui Z., et al. Glycyrrhizin inhibits traumatic brain injury by reducing HMGB1-RAGE interaction. Neuropharmacology. 2014;85:18–26. doi: 10.1016/j.neuropharm.2014.05.007. [DOI] [PubMed] [Google Scholar]
- 117.Yang H., Wang H., Andersson U. Targeting inflammation driven by HMGB1. Front Immunol. 2020;11:484. doi: 10.3389/fimmu.2020.00484. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 118.Zhong H., Li X., Zhou S., Jiang P., Liu X., Ouyang M., et al. Interplay between RAGE and TLR4 regulates HMGB1-induced inflammation by promoting cell surface expression of RAGE and TLR4. J Immunol. 2020;205(3):767–775. doi: 10.4049/jimmunol.1900860. [DOI] [PubMed] [Google Scholar]
- 119.Das N., Dewan V., Grace P.M., Gunn R.J., Tamura R., Tzarum N., et al. HMGB1 activates proinflammatory signaling via TLR5 leading to allodynia. Cell Rep. 2016;17(4):1128–1140. doi: 10.1016/j.celrep.2016.09.076. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 120.Yaqrit Ltd. Phase II, double-blind, randomized, placebo-controlled, multicentre study to evaluate the safety, efficacy, and pharmacokinetics of TAK-242 and (G-CSF) in subjects with (sAH) and (ACLF). 2025. 〈https://clinicaltrials.gov/study/NCT06890039〉. Accessed 1 Sept, 2025.
- 121.Opal S.M., Laterre P.F., Francois B., LaRosa S.P., Angus D.C., Mira J.P., et al. Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial. JAMA. 2013;309(11):1154. doi: 10.1001/jama.2013.2194. [DOI] [PubMed] [Google Scholar]
- 122.Kustermann M., Dasari P., Knape I., Keltsch E., Liu J., Pflüger S., et al. Adoptively transferred in vitro-generated myeloid-derived suppressor cells improve T-cell function and antigen-specific immunity after traumatic lung injury. J Innate Immun. 2022;15(1):78–95. doi: 10.1159/000525088. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 123.Lu H., Wang J., Chen Z., Wang J., Jiang Y., Xia Z., et al. Engineered macrophage membrane-coated S100A9-siRNA for ameliorating myocardial ischemia-reperfusion injury. Adv Sci (Weinh) 2024;11(41) [Google Scholar]
- 124.Ying J., Zhang C., Wang Y., Liu T., Yu Z., Wang K., et al. Sulodexide improves vascular permeability via glycocalyx remodelling in endothelial cells during sepsis. Front Immunol. 2023;14 [Google Scholar]
- 125.Li T., Liu X., Zhao Z., Ni L., Liu C. Sulodexide recovers endothelial function through reconstructing glycocalyx in the balloon-injury rat carotid artery model. Oncotarget. 2017;8(53):91350–91361. doi: 10.18632/oncotarget.20518. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 126.Adam E.H., Schmid B., Sonntagbauer M., Kranke P., Zacharowski K., Meybohm P. Fibrin-derived peptide Bβ15-42 (FX06) as salvage treatment in critically ill patients with COVID-19-associated acute respiratory distress syndrome. Crit Care. 2020;24:574. doi: 10.1186/s13054-020-03293-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 127.Ahrens I., Peter K. FX-06, a fibrin-derived Bbeta15-42 peptide for the potential treatment of reperfusion injury following myocardial infarction. Curr Opin Investig Drugs. 2009;10(9):997–1003. [Google Scholar]
- 128.Assistance publique – Hôpitaux de Paris. FX06 to rescue acute respiratory distress syndrome during COVID-19 pneumonia. 2021. 〈https://clinicaltrials.gov/study/NCT04618042〉. Accessed 13 June 2021.
- 129.Henning D.R. Efficacy of FX06 in the prevention of myocardial reperfusion injury, 2007. 〈https://clinicaltrials.gov/study/NCT00326976〉. Accessed 12 Dec, 2007.
- 130.Wang Z., Zhernovkov V., Dmitrii L., Wu K., Doyle L., Wynne K., et al. The fibrin-derived peptide Bβ15-42 (FX06) protects human pulmonary endothelial cells against COVID-19-triggered cytokines. 2024. 〈http://hdl.handle.net/10197/27872〉. Accessed 2 Sept, 2024.
- 131.Ait-Aissa K., Leng L.N., Lindsey N.R., Guo X., Juhr D., Koval O.M., et al. Mechanisms by which statins protect endothelial cells from radiation-induced injury in the carotid artery. Front Cardiovasc Med. 2023 〈https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2023.1133315/full〉 Accessed 19 June, 2023. [Google Scholar]
- 132.Tan K.C.B., Chow W.S., Tam S.C.F., Ai V.H.G., Lam C.H.L., Lam K.S.L. Atorvastatin lowers C-reactive protein and improves endothelium-dependent vasodilation in type 2 diabetes mellitus. J Clin Endocrinol Metab. 2002;87(2):563–568. doi: 10.1210/jcem.87.2.8249. [DOI] [PubMed] [Google Scholar]
- 133.Zarief E. Could early atorvastatin offer anti-inflammatory effects upon brain in traumatic head injury? A randomized double-blind clinical trial. 2022. 〈https://clinicaltrials.gov/study/NCT04718155〉. Accessed 1 June, 2022.
- 134.Robinson B.D., Isbell C.L., Melge A.R., Lomas A.M., Shaji C.A., Mohan C.G., et al. Doxycycline prevents blood-brain barrier dysfunction and microvascular hyperpermeability after traumatic brain injury. Sci Rep. 2022;12(1):5415. doi: 10.1038/s41598-022-09394-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 135.Vidaurre M.D.P.H., Osborn B.K., Lowak K.D., McDonald M.M., Wang Y.W.W., Pa V., et al. A 3-O-sulfated heparan sulfate dodecasaccharide (12-mer) suppresses thromboinflammation and attenuates early organ injury following trauma and hemorrhagic shock. Front Immunol. 2023;14 [Google Scholar]
- 136.Douin D.J., Fernandez-Bustamante A. Early fibrinogen replacement to treat the endotheliopathy of trauma: novel resuscitation strategies in severe trauma. Anesthesiology. 2023;139(5):675–683. doi: 10.1097/ALN.0000000000004711. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 137.Kwiatkowski T.A., Rose A.L., Jung R., Capati A., Hallak D., Yan R., et al. Multiple poloxamers increase plasma membrane repair capacity in muscle and nonmuscle cells. Am J Physiol Cell Physiol. 2020;318(2):C253–C262. doi: 10.1152/ajpcell.00321.2019. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 138.Rai V., Mathews G., Agrawal D.K. Translational and clinical significance of DAMPs, PAMPs, and PRRs in trauma-induced inflammation. Arch Clin Biomed Res. 2022;6(5):673–685. doi: 10.26502/acbr.50170279. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 139.Wu R., Koduri R., Cho M., Alatrash N., Nomellini V. Effects of poloxamer 188 on traumatic brain injury. Brain Behav Immun Health. 2024;38 [Google Scholar]
- 140.Marks J.D., Pan C.Y., Bushell T., Cromie W., Lee R.C. Amphiphilic, tri‐block copolymers provide potent, membrane‐targeted neuroprotection. FASEB J. 2001;15(6):1107–1109. doi: 10.1096/fj.00-0547fje. [DOI] [PubMed] [Google Scholar]
- 141.Ng R., Metzger J.M., Claflin D.R., Faulkner J.A. Poloxamer 188 reduces the contraction-induced force decline in lumbrical muscles from mdx mice. Am J Physiol Cell Physiol. 2008;295(1):C146–C150. doi: 10.1152/ajpcell.00017.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 142.Houang E.M., Haman K.J., Filareto A., Perlingeiro R.C., Bates F.S., Lowe D.A., et al. Membrane-stabilizing copolymers confer marked protection to dystrophic skeletal muscle in vivo. Mol Ther Methods Clin Dev. 2015;2 [Google Scholar]
- 143.Moloughney J.G., Weisleder N. Poloxamer 188 (P188) as a membrane resealing reagent in biomedical applications. Recent Pat Biotechnol. 2012;6(3):200–211. doi: 10.2174/1872208311206030200. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 144.Houang E.M., Bartos J., Hackel B.J., Lodge T.P., Yannopoulos D., Bates F.S., et al. Cardiac muscle membrane stabilization in myocardial reperfusion injury. JACC Basic Transl Sci. 2019;4(2):275–287. doi: 10.1016/j.jacbts.2019.01.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 145.Chianese M., Screm G., Salton F., Confalonieri P., Trotta L., Barbieri M., et al. Pirfenidone and nintedanib in pulmonary fibrosis: lights and shadows. Pharmaceuticals. 2024;17(6):709. doi: 10.3390/ph17060709. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 146.Babariya H., Gaidhane S.A., Acharya S., Kumar S. Pirfenidone as a cornerstone in the management of fibrotic interstitial lung diseases and its emerging applications: a comprehensive review. Cureus. 2024;16(9) [Google Scholar]
- 147.Wang J., Li K., Hao D., Li X., Zhu Y., Yu H., et al. Pulmonary fibrosis: pathogenesis and therapeutic strategies. MedComm (2020) 2024;5(10) [Google Scholar]
- 148.Islam M.T., Tuday E., Allen S., Kim J., Trott D.W., Holland W.L., et al. Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age. Aging Cell. 2023;22(2) [Google Scholar]
- 149.Shvedova M., Thanapaul R.J.R.S., Ha J., Dhillon J., Shin G.H., Crouch J., et al. Topical ABT-263 treatment reduces aged skin senescence and improves subsequent wound healing. Aging. 2025;17(1):16–32. [Google Scholar]
- 150.Tarantini S., Balasubramanian P., Delfavero J., Csipo T., Yabluchanskiy A., Kiss T., et al. Treatment with the BCL-2/BCL-xL inhibitor senolytic drug ABT263/Navitoclax improves functional hyperemia in aged mice. Geroscience. 2021;43(5):2427–2440. doi: 10.1007/s11357-021-00440-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 151.Chung C.L., Lawrence I., Hoffman M., Elgindi D., Nadhan K., Potnis M., et al. Topical rapamycin reduces markers of senescence and aging in human skin: an exploratory, prospective, randomized trial. Geroscience. 2019;41(6):861–869. doi: 10.1007/s11357-019-00113-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 152.Fitzsimmons R.E.B., Mazurek M.S., Soos A., Simmons C.A. Mesenchymal stromal/stem cells in regenerative medicine and tissue engineering. Stem Cells Int. 2018;2018 [Google Scholar]
- 153.Julien A., Kanagalingam A., Martínez-Sarrà E., Megret J., Luka M., Ménager M., et al. Direct contribution of skeletal muscle mesenchymal progenitors to bone repair. Nat Commun. 2021;12(1):2860. doi: 10.1038/s41467-021-22842-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 154.Yang Q., Teng B.H., Wang L.N., Li K., Xu C., Ma X.L., et al. Silk fibroin/cartilage extracellular matrix scaffolds with sequential delivery of TGF-β3 for chondrogenic differentiation of adipose-derived stem cells. Int J Nanomedicine. 2017;12:6721–6733. doi: 10.2147/IJN.S141888. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 155.Tung C., Varzideh F., Farroni E., Mone P., Kansakar U., Jankauskas S.S., et al. Elamipretide: a review of its structure, mechanism of action, and therapeutic potential. Int J Mol Sci. 2025;26(3):944. doi: 10.3390/ijms26030944. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 156.Ghiam M.K., Patel S.D., Hoffer A., Selman W.R., Hoffer B.J., Hoffer M.E. Drug repurposing in the treatment of traumatic brain injury. Front Neurosci. 2021;15 [Google Scholar]
- 157.Jiang N., Chen Z., Liu L., Yin X., Yang H., Tan X., et al. Association of metformin with mortality or ARDS in patients with COVID-19 and type 2 diabetes: a retrospective cohort study. Diabetes Res Clin Pract. 2021;173 [Google Scholar]
- 158.Jochmans S., Alphonsine J.E., Chelly J., Vong L.V.P., Sy O., Rolin N., et al. Does metformin exposure before ICU stay have any impact on patients’ outcome? A retrospective cohort study of diabetic patients. Ann Intensive Care. 2017;7(1):116. doi: 10.1186/s13613-017-0336-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 159.Reitz K.M., Marroquin O.C., Zenati M.S., Kennedy J., Korytkowski M., Tzeng E., et al. Association between preoperative metformin exposure and postoperative outcomes in adults with type 2 diabetes. JAMA Surg. 2020;155(6) [Google Scholar]
- 160.Saengboonmee C., Abbasi M., Śliwińska A. Editorial: emerging horizons of metformin: exploring recent advances and addressing challenges in research and clinical utilization. Front Pharmacol. 2025;16 [Google Scholar]
- 161.Yang Y., Liu J., Hou Y., Wei Y., Huang L., Wei W. Correlation between metformin use and mortality in acute respiratory failure: a retrospective ICU cohort study. Front Pharmacol. 2025;16 [Google Scholar]
- 162.Kopel J., Brower G.L., Sorensen G., Griswold J. Application of beta-blockers in burn management. Proc (Bayl Univ Med Cent) 2021;35(1):46–50. doi: 10.1080/08998280.2021.2002110. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 163.Strickland B.A., Bakhsheshian J., Emmanuel B., Amar A., Giannotta S.L., Russin J.J., et al. Neuroprotective effect of minocycline against acute brain injury in clinical practice: a systematic review. J Clin Neurosci. 2021;86:50–57. doi: 10.1016/j.jocn.2021.01.005. [DOI] [PubMed] [Google Scholar]
- 164.Brown R.B., Tozer D.J., Loubière L., Harshfield E.L., Hong Y.T., Fryer T.D., et al. MINocyclinE to Reduce inflammation and blood‐brain barrier leakage in small Vessel disease (MINERVA): a phase II, randomized, double‐blind, placebo‐controlled experimental medicine trial. Alzheimers Dement. 2024;20(6):3852–3863. doi: 10.1002/alz.13830. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 165.Scott G., Zetterberg H., Jolly A., Cole J.H., De Simoni S., Jenkins P.O., et al. Minocycline reduces chronic microglial activation after brain trauma but increases neurodegeneration. Brain. 2018;141(2):459–471. doi: 10.1093/brain/awx339. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 166.Angelopoulou E., Pyrgelis E.S., Piperi C. Emerging potential of the phosphodiesterase (PDE) inhibitor ibudilast for neurodegenerative diseases: an update on preclinical and clinical evidence. Molecules. 2022;27(23):8448. doi: 10.3390/molecules27238448. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 167.Ellis A., Wieseler J., Favret J., Johnson K.W., Rice K.C., Maier S.F., et al. Systemic administration of propentofylline, ibudilast, and (+)-naltrexone each reverses mechanical allodynia in a novel rat model of central neuropathic pain. J Pain. 2014;15(4):407–421. doi: 10.1016/j.jpain.2013.12.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 168.Ledeboer A., Liu T., Shumilla J.A., Mahoney J.H., Vijay S., Gross M.I., et al. The glial modulatory drug AV411 attenuates mechanical allodynia in rat models of neuropathic pain. Neuron Glia Biol. 2007;2(4):279–291. [Google Scholar]
- 169.Fluyau D., Mitra P., Jain A., Kailasam V.K., Pierre C.G. Selective serotonin reuptake inhibitors in the treatment of depression, anxiety, and post-traumatic stress disorder in substance use disorders: a Bayesian meta-analysis. Eur J Clin Pharmacol. 2022;78(6):931–942. doi: 10.1007/s00228-022-03303-4. [DOI] [PubMed] [Google Scholar]
- 170.Kozarić-Kovačić D. Psychopharmacotherapy of posttraumatic stress disorder. Croat Med J. 2008;49(4):459–475. doi: 10.3325/cmj.2008.4.459. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 171.Guina J., Rossetter S.R., DeRHODES B.J., Nahhas R.W., Welton R.S. Benzodiazepines for PTSD: a systematic review and meta-analysis. J Psychiatr Pract. 2015;21(4):281. doi: 10.1097/PRA.0000000000000091. [DOI] [PubMed] [Google Scholar]
- 172.Weppner J., Linsenmeyer M., Ide W. Military blast-related traumatic brain injury. Curr Phys Med Rehabil Rep. 2019;7(4):323–332. [Google Scholar]
- 173.Edinoff A.N., Hegefeld T.L., Petersen M., Patterson J.C., Yossi C., Slizewski J., et al. Transcranial magnetic stimulation for post-traumatic stress disorder. Front Psychiatry. 2022;13 [Google Scholar]
- 174.Zhang N., Zhang H., Yu L., Fu Q. Advances in anti-inflammatory treatment of sepsis-associated acute respiratory distress syndrome. Inflamm Res. 202;74(1):74.
- 175.Giamarellos-Bourboulis E.J., Kotsaki A., Kotsamidi I., Efthymiou A., Koutsoukou V., Ehler J., et al. Precision immunotherapy to improve sepsis outcomes: the ImmunoSep Randomized Clinical Trial. JAMA. 2025 [Google Scholar]
- 176.Kravitz M.S., Kattouf N., Stewart I.J., Ginde A.A., Schmidt E.P., Shapiro N.I. Plasma for prevention and treatment of glycocalyx degradation in trauma and sepsis. Crit Care. 2024;28(1):254. doi: 10.1186/s13054-024-05026-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 177.Zha D., Wang S., Monaghan-Nichols P., Qian Y., Sampath V., Fu M. Mechanisms of endothelial cell membrane repair: progress and perspectives. Cells. 2023;12(22):2648. doi: 10.3390/cells12222648. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 178.Ammendolia D.A., Bement W.M., Brumell J.H. Plasma membrane integrity: implications for health and disease. BMC Biology. 2021;19(1):71. doi: 10.1186/s12915-021-00972-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 179.Bittel D.C., Chandra G., Tirunagri L.M.S., Deora A.B., Medikayala S., Scheffer L., et al. Annexin A2 mediates dysferlin accumulation and muscle cell membrane repair. Cells. 2020;9(9):1919. doi: 10.3390/cells9091919. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 180.Huang H.L., Grandinetti G., Heissler S.M., Chinthalapudi K. Cryo-EM structures of the membrane repair protein dysferlin. Nat Commun. 2024;15(1):9650. doi: 10.1038/s41467-024-53773-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 181.Pomella S., Cassandri M., Antoniani F., Crotti S., Mediani L., Silvestri B., et al. Heat shock proteins: important helpers for the development, maintenance and regeneration of skeletal muscles. Muscles. 2023;2(2):187–203. doi: 10.3390/muscles2020014. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 182.Li Z., Shaw G.S. Role of calcium-sensor proteins in cell membrane repair. Biosci Rep. 2023;43(2) BSR20220765. [Google Scholar]
- 183.Gielecińska A., Kciuk M., Kontek R. The impact of calcium overload on cellular processes: exploring calcicoptosis and its therapeutic potential in cancer. Int J Mol Sci. 2024;25(24):13727. doi: 10.3390/ijms252413727. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 184.Cai W., Zhang H., Li Z., Cai M., Yu S., Chen P., et al. Tissue fibrosis decoded via cellular senescence: mechanisms, treatments, and emerging technologies. Aging Dis. 2025 [Google Scholar]
- 185.Kubat G.B., Picone P., Tuncay E., Aryan L., Girgenti A., Palumbo L., et al. Biotechnological approaches and therapeutic potential of mitochondria transfer and transplantation. Nat Commun. 2025;16(1):5709. doi: 10.1038/s41467-025-61239-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 186.Wyles S.P., Tchkonia T., Kirkland J.L. Targeting cellular senescence for age-related diseases: path to clinical translation. Plast Reconstr Surg. 2022;150:20S–26SS. [Google Scholar]
- 187.Simmons E.C., Scholpa N.E., Schnellmann R.G. Mitochondrial biogenesis as a therapeutic target for traumatic and neurodegenerative CNS diseases. Exp Neurol. 2020;329 [Google Scholar]
- 188.Jayaraman S.P., Anand R.J., DeAntonio J.H., Mangino M., Aboutanos M.B., Kasirajan V., et al. Metabolomics and precision medicine in trauma: the state of the field. Shock. 2018;50(1):5–13. doi: 10.1097/SHK.0000000000001093. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 189.Kim M.J., Oh C.J., Hong C.W., Jeon J.H. Comprehensive overview of the role of mitochondrial dysfunction in the pathogenesis of acute kidney ischemia-reperfusion injury: a narrative review. J Yeungnam Med Sci. 2024;41(2):61–73. doi: 10.12701/jyms.2023.01347. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 190.Veenker C.G.H., Redzhebov B.B., Hoeks S.E., Van Eijk L.T., Struys M.M.R.F., De Hon O., et al. Effects of growth hormone and anabolic steroids, in critically ill patients admitted to the intensive care unit: a systematic review and meta-analysis. Sci Rep. 2025;15(1) [Google Scholar]
- 191.Neigh G.N., Ali F.F. Co-morbidity of PTSD and immune system dysfunction: opportunities for treatment. Curr Opin Pharmacol. 2016;29:104–110. doi: 10.1016/j.coph.2016.07.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 192.Ren W., Xue X., Liu L., Huang J. AI applications in depression detection and diagnosis: bibliometric and visual analysis of trends and future directions. JMIR Ment Health. 2025;12 [Google Scholar]
- 193.Assanangkornchai N., Akaraborworn O., Kongkamol C., Kaewsaengrueang K. Characteristics of creatine kinase elevation in trauma patients and predictors of acute kidney injury. J Acute Med. 2017;7(2):54–60. doi: 10.6705/j.jacme.2017.0702.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 194.Nielsen F.E., Cordtz J.J., Rasmussen T.B., Christiansen C.F. The association between rhabdomyolysis, acute kidney injury, renal replacement therapy, and mortality. Clin Epidemiol. 2020;12:989–995. doi: 10.2147/CLEP.S254516. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 195.Rajagopalan S. Crush injuries and the crush syndrome. Med J Armed Forces India. 2010;66(4):317–320. doi: 10.1016/S0377-1237(10)80007-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 196.Brigic L., Mušija E., Kadić F., Halilčević M., Durak-Nalbantic A., Dervišević L., et al. Role of lactate dehydrogenase as a biomarker of early cardiac remodeling: a cross-sectional study. Cureus. 2024;16(9) [Google Scholar]
- 197.Tarazona V., Figueiredo S., Hamada S., Pochard J., Haines R.W., Prowle J.R., et al. Admission serum myoglobin and the development of acute kidney injury after major trauma. Ann Intensive Care. 2021;11(1):140. doi: 10.1186/s13613-021-00924-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 198.Siracusa J., Koulmann N., Sourdrille A., Chapus C., Verret C., Bourdon S., et al. Phenotype-specific response of circulating miRNAs provides new biomarkers of slow or fast muscle damage. Front Physiol. 2018;9:684. doi: 10.3389/fphys.2018.00684. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 199.Yang L., Wang B., Zhou Q., Wang Y., Liu X., Liu Z., et al. MicroRNA-21 prevents excessive inflammation and cardiac dysfunction after myocardial infarction through targeting KBTBD7. Cell Death Dis. 2018;9(7):769. doi: 10.1038/s41419-018-0805-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 200.Khan N.A., Asim M., El-Menyar A., Biswas K.H., Rizoli S., Al-Thani H. The evolving role of extracellular vesicles (exosomes) as biomarkers in traumatic brain injury: clinical perspectives and therapeutic implications. Front Aging Neurosci. 2022;14 [Google Scholar]
- 201.Pritt M.L., Hall D.G., Recknor J., Credille K.M., Brown D.D., Yumibe N.P., et al. Fabp3 as a biomarker of skeletal muscle toxicity in the rat: comparison with conventional biomarkers. Toxicol Sci. 2008;103(2):382–396. doi: 10.1093/toxsci/kfn042. [DOI] [PubMed] [Google Scholar]
- 202.Yi Y., Tae M., Shin S., Choi S.I. Predicting acute kidney injury in trauma using an extreme gradient boosting model. Clin Kidney J. 2025;18(4) [Google Scholar]
- 203.Zamzam A., Syed M.H., Rotstein O.D., Eikelboom J., Klein D.J., Singh K.K., et al. Validating fatty acid binding protein 3 as a diagnostic and prognostic biomarker for peripheral arterial disease: a three-year prospective follow-up study. EClinicalMedicine. 2022;55 [Google Scholar]
- 204.Cullinane A.R., Yeager C., Dorward H., Carmona-Rivera C., Wu H.P., Moss J., et al. Dysregulation of galectin-3. Implications for Hermansky-Pudlak syndrome pulmonary fibrosis. Am J Respir Cell Mol Biol. 2014;50(3):605–613. doi: 10.1165/rcmb.2013-0025OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 205.Zhang J., Gao Y., Yan J. Roles of myokines and muscle-derived extracellular vesicles in musculoskeletal deterioration under disuse conditions. Metabolites. 2024;14(2):88. doi: 10.3390/metabo14020088. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 206.Working Z.M., Czachor M.E., Nelson A.L., O’Hara K.M., Lancaster K., Hellwinkel J.E., et al. Efficacy of biomarkers in the endochondral phase of fracture repair and healing in long bones: a clinical observational studys. PLoS Med. 2025;22(8) [Google Scholar]
- 207.Coghlan R.F., Oberdorf J.A., Sienko S., Aiona M.D., Boston B.A., Connelly K.J., et al. A degradation fragment of type X collagen is a real-time marker for bone growth velocity. Sci Transl Med. 2017;9(419) [Google Scholar]
- 208.Baur A., Saiz A.M. Translating biomarker research into clinical practice in orthopaedic trauma: a systematic review. J Clin Med. 2025;14(4):1329. doi: 10.3390/jcm14041329. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 209.Zhang Y., Zhou F., Wu Z., Li Y., Li C., Du M., et al. Timing of tocilizumab administration under the guidance of IL-6 in CAR-T therapy for R/R acute lymphoblastic leukemia. Front Immunol. 2022;13 [Google Scholar]
- 210.Vantucci C.E., Guyer T., Leguineche K., Chatterjee P., Lin A., Nash K.E., et al. Systemic immune modulation alters local bone regeneration in a delayed treatment composite model of non-union extremity trauma. Front Surg. 2022;9 [Google Scholar]
- 211.Beyer C.A., Burmeister D.M., Gómez B.I., Tercero J., Babcock E., Walker L.E., et al. Point-of-care urinary biomarker testing for risk prediction in critically injured combat casualties. J Am Coll Surg. 2019;229(5):508–515. doi: 10.1016/j.jamcollsurg.2019.07.003. e1. [DOI] [PubMed] [Google Scholar]
- 212.David J., Fairburn S., Fogle H., Dulin N., Day R. End-of-life care in the austere military environment. Mil Med. 2025 usaf436. [Google Scholar]
- 213.de Melo Bezerra Cavalcante C.T., Castelo Branco K.M., Pinto Júnior V.C., Meneses G.C., de Oliveira Neves F.M., de Souza N.M., et al. Syndecan-1 improves severe acute kidney injury prediction after pediatric cardiac surgery. J Thorac Cardiovasc Surg. 2016;152(1):178–186.e2. doi: 10.1016/j.jtcvs.2016.03.079. [DOI] [PubMed] [Google Scholar]
- 214.Diaz-Arrastia R. Performance of diagnostic biomarkers for traumatic brain injury within the first hour – expanding their clinical utility. JAMA Netw Open. 2024;7(9) [Google Scholar]
- 215.Rashidi H.H., Makley A., Palmieri T.L., Albahra S., Loegering J., Fang L., et al. Enhancing military burn- and trauma-related acute kidney injury prediction through an automated machine learning platform and point-of-care testing. Arch Pathol Lab Med. 2021;145(3):320–326. doi: 10.5858/arpa.2020-0110-OA. [DOI] [PubMed] [Google Scholar]
- 216.Garcia-Davis S., Hlaing W.M., Vidot D.C., Feaster D.J., Hansen J., Brintz B.J., et al. The epidemiology of the long-term care needs and unmet needs of older veterans in the United States. JCM. 2025;14(12):4219. doi: 10.3390/jcm14124219. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 217.Song Y.H., Song J.L., Delafontaine P., Godard M.P. The therapeutic potential of IGF-I in skeletal muscle repair. Trends Endocrinol Metab. 2013;24(6):310–319. doi: 10.1016/j.tem.2013.03.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 218.Wu J., Vodovotz Y., Abdelhamid S., Guyette F.X., Yaffe M.B., Gruen D.S., et al. Multi-omic analysis in injured humans: patterns align with outcomes and treatment responses. Cell Rep Med. 2021;2(12) [Google Scholar]
- 219.Li S.R., Moheimani H., Herzig B., Kail M., Krishnamoorthi N., Wu J., et al. High-dimensional proteomics identifies organ injury patterns associated with outcomes in human trauma. J Trauma Acute Care Surg. 2023;94(6):803–813. doi: 10.1097/TA.0000000000003880. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 220.Coleman J.R., D’Alessandro A., LaCroix I., Dzieciatkowska M., Lutz P., Mitra S., et al. A metabolomic and proteomic analysis of pathologic hypercoagulability in traumatic brain injury patients after dura violation. J Trauma Acute Care Surg. 2023;95(6):925–934. doi: 10.1097/TA.0000000000004019. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 221.Seim R.F., Willis M.L., Wallet S.M., Maile R., Coleman L.G. Extracellular vesicles as regulators of immune function in traumatic injuries and sepsis. Shock. 2023;59(2):180–189. doi: 10.1097/SHK.0000000000002023. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 222.Stallings J.D., Laxminarayan S., Yu C., Kapela A., Frock A., Cap A.P., et al. Appraise-HRI: an artificial intelligence algorithm for triage of hemorrhage casualties. Shock. 2023;60(2):199–205. doi: 10.1097/SHK.0000000000002166. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 223.Halpern G.A., Nemet M., Gowda D.M., Kilickaya O., Lal A. Advances and utility of digital twins in critical care and acute care medicine: a narrative review. J Yeungnam Med Sci. 2025;42:9. doi: 10.12701/jyms.2024.01053. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 224.Cannon J.W., Gruen D.S., Zamora R., Brostoff N., Hurst K., Harn J.H., et al. Digital twin mathematical models suggest individualized hemorrhagic shock resuscitation strategies. Commun Med. 2024;4(1):113. doi: 10.1038/s43856-024-00535-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 225.Huie J.R., Diaz-Arrastia R., Yue J.K., Sorani M.D., Puccio A.M., Okonkwo D.O., et al. Testing a multivariate proteomic panel for traumatic brain injury biomarker discovery: a TRACK-TBI pilot study. J Neurotrauma. 2019;36(1):100–110. doi: 10.1089/neu.2017.5449. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 226.Ren B., Li R., Lin C.Y., Park C., Wang S., Suen A.O., et al. Nucleotide motif-guided selection of plasma microRNA biomarkers for organ injury prediction in trauma. medRxiv. 2025;28(10) [Google Scholar]
- 227.Wagner K.D., Wagner N. The senescence markers p16INK4A, p14ARF/p19ARF, and p21 in organ development and homeostasis. Cells. 2022;11(12):1966. doi: 10.3390/cells11121966. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 228.Zhao Q., Zhang C., Zhang W., Zhang S., Liu Q., Guo Y. Applications and challenges of biomarker-based predictive models in proactive health management. Front Public Health. 2025;13 [Google Scholar]
- 229.Ghazizadeh E., Naseri Z., Deigner H.P., Rahimi H., Altintas Z. Approaches of wearable and implantable biosensor towards of developing in precision medicine. Front Med (Lausanne) 2024;11 [Google Scholar]
- 230.Yogev D., Goldberg T., Arami A., Tejman-Yarden S., Winkler T.E., Maoz B.M. Current state of the art and future directions for implantable sensors in medical technology: clinical needs and engineering challenges. APL Bioeng. 2023;7(3) [Google Scholar]
- 231.Cheng C., Ganguly S., Li P., Tang X. Detecting hypoxia through the non-invasive and simultaneous monitoring of sweat lactate and tissue oxygenation. Biosensors (Basel) 2024;14(12):584. doi: 10.3390/bios14120584. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 232.Badillo-Ramírez I., Carreón Y.J.P., Rodríguez-Almazán C., Medina-Durán C.M., Islas S.R., Saniger J.M. Graphene-based biosensors for molecular chronic inflammatory disease biomarker detection. Biosensors (Basel) 2022;12(4):244. doi: 10.3390/bios12040244. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 233.David B.E., Madhurantakam S., Karnam J.B., Muthukumar S., Prasad S. Electrochemical profiling of vWFA2 for systemic inflammatory state detection. ACS Meas Sci Au. 2024;4(6):721–728. doi: 10.1021/acsmeasuresciau.4c00060. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 234.Wang B., Wöhler A., Greven J., Salzmann R.J.S., Keller C.M., Tertel T., et al. Liquid biopsy in organ damage: small extracellular vesicle chip-based assessment of polytrauma. Front Immunol. 2023;14 [Google Scholar]
- 235.van der Pol Y., Moldovan N., Ramaker J., Bootsma S., Lenos K.J., Vermeulen L., et al. The landscape of cell-free mitochondrial DNA in liquid biopsy for cancer detection. Genome Biol. 2023;24:229. doi: 10.1186/s13059-023-03074-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 236.Peng F., Wang S., Feng Z., Zhou K., Zhang H., Guo X., et al. Circulating cell-free mtDNA as a new biomarker for cancer detection and management. Cancer Biol Med. 2024;21(2):105–110. [Google Scholar]
- 237.Jansen F., Li Q., Pfeifer A., Werner N. Endothelial- and immune cell-derived extracellular vesicles in the regulation of cardiovascular health and disease. JACC Basic Transl Sci. 2017;2(6):790–807. doi: 10.1016/j.jacbts.2017.08.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 238.Feng K., Dai W., Liu L., Li S., Gou Y., Chen Z., et al. Identification of biomarkers and the mechanisms of multiple trauma complicated with sepsis using metabolomics. Front Public Health. 2022;10 [Google Scholar]
- 239.Schaid T.R., LaCroix I., Cohen M.J., Hansen K.C., Moore E.E., Sauaia A., et al. Metabolomic and proteomic changes in trauma-induced hypocalcemia. Shock. 2023;60(5):652–663. doi: 10.1097/SHK.0000000000002220. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 240.Karasu E., Nilsson B., Köhl J., Lambris J.D., Huber-Lang M. Targeting complement pathways in polytrauma- and sepsis-induced multiple-organ dysfunction. Front Immunol. 2019;10:543. doi: 10.3389/fimmu.2019.00543. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 241.Huber‐Lang M.S., Ignatius A., Köhl J., Mannes M., Braun C.K. Complement in trauma – traumatised complement? Br J Pharmacol. 2021;178(14):2863–2879. doi: 10.1111/bph.15245. [DOI] [PubMed] [Google Scholar]
- 242.Huang P., Liu Y., Li Y., Xin Y., Nan C., Luo Y., et al. Metabolomics- and proteomics-based multi-omics integration reveals early metabolite alterations in sepsis-associated acute kidney injury. BMC Med. 2025;23(1):79. doi: 10.1186/s12916-025-03920-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 243.Moon G.Y., Dalkiran B., Park H.S., Shin D., Son C., Choi J.H., et al. Dual biomarker strategies for liquid biopsy: integrating circulating tumor cells and circulating tumor DNA for enhanced tumor monitoring. Biosensors (Basel) 2025;15(2):74. doi: 10.3390/bios15020074. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 244.Mathias Q., De Malleray H., Nguyen C., Weghel L.L., Boussen S., Bordes J. Enhancing combat casualty care in military medicine: the potential of early warning systems and wearable biosensors in large-scale warfare. BMJ Mil Health. 2025 military-2025-002977. [Google Scholar]
- 245.Lemarquand A., Jannot P., Kammerlocher L., Lissorgues G., Behr M., Arnoux P.J., et al. A new trauma severity scoring system adapted to wearable monitoring: a pilot study. PLoS One. 2025;20(3) [Google Scholar]
- 246.Gathright R., Mejia I., Gonzalez J.M., Hernandez Torres S.I., Berard D., Snider E.J. Overview of wearable healthcare devices for clinical decision support in the prehospital setting. Sensors (Basel) 2024;24(24):8204. doi: 10.3390/s24248204. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 247.Schmollinger M., Gerstner J., Stricker E., Muench A., Breckwoldt B., Sigle M., et al. Evaluation of an app-based mobile triage system for mass casualty incidents: within-subjects experimental study. J Med Internet Res. 2024;26 [Google Scholar]
- 248.Marsden M.E.R., Perkins Z.B., Pisirir E., Marsh W., Kyrimi E., Rossetto A., et al. Early clinical evaluation of a machine-learning system for risk prediction of trauma-induced coagulopathy in the prehospital setting. Emerg Med J. 2025;42(10):654–661. doi: 10.1136/emermed-2024-214396. [DOI] [PubMed] [Google Scholar]
- 249.Neumann J., Vogel C., Kießling L., Hempel G., Kleber C., Osterhoff G., et al. TraumaFlow-development of a workflow-based clinical decision support system for the management of severe trauma cases. Int J Comput Assist Radiol Surg. 2024;19(12):2399–2409. doi: 10.1007/s11548-024-03191-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 250.Lobo P., Morais P., Murray P., Vilaça J.L. Trends and innovations in wearable technology for motor rehabilitation, prediction, and monitoring: a comprehensive review. Sensors (Basel) 2024;24(24):7973. doi: 10.3390/s24247973. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 251.Celik Y., Wall C., Moore J., Godfrey A. Better understanding rehabilitation of motor symptoms: insights from the use of wearables. Pragmat Obs Res. 2025;16:67–93. doi: 10.2147/POR.S396198. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 252.Runkle J.D., Cui C., Fuhrmann C., Stevens S., Del Pinal J., Sugg M.M. Evaluation of wearable sensors for physiologic monitoring of individually experienced temperatures in outdoor workers in Southeastern U.S. Environ Int. 2019;129:229–238. doi: 10.1016/j.envint.2019.05.026. [DOI] [PubMed] [Google Scholar]
- 253.Roos L.G., Slavich G.M. Wearable technologies for health research: opportunities, limitations, and practical and conceptual considerations. Brain Behav Immun. 2023;113:444–452. doi: 10.1016/j.bbi.2023.08.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 254.Li K., Cardoso C., Moctezuma-Ramirez A., Elgalad A., Perin E. Heart rate variability measurement through a smart wearable device: another breakthrough for personal health monitoring? Int J Environ Res Public Health. 2023;20(24):7146. doi: 10.3390/ijerph20247146. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 255.Spinelli J.C., Suleski B.J., Wright D.E., Grow J.L., Fagans G.R., Buckley M.J., et al. Wearable microfluidic biosensors with haptic feedback for continuous monitoring of hydration biomarkers in workers. NPJ Digit Med. 2025;8(1):76. doi: 10.1038/s41746-025-01466-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 256.Bhide A., Ganguly A., Parupudi T., Ramasamy M., Muthukumar S., Prasad S. Next-generation continuous metabolite sensing toward emerging sensor needs. ACS Omega. 2021;6(9):6031–6040. doi: 10.1021/acsomega.0c06209. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 257.Song Z., Zhou S., Qin Y., Xia X., Sun Y., Han G., et al. Flexible and wearable biosensors for monitoring health conditions. Biosensors (Basel) 2023;13(6):630. doi: 10.3390/bios13060630. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 258.Yuan S., Yang Z., Li J., Wu C., Liu S. AI-powered early warning systems for clinical deterioration significantly improve patient outcomes: a meta-analysis. BMC Med Inform Decis Mak. 2025;25:203. doi: 10.1186/s12911-025-03048-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 259.Peng J., Li Y., Liu C., Mao Z., Kang H., Zhou F. Predicting multiple organ dysfunction syndrome in trauma-induced sepsis: nomogram and machine learning approaches. J Intensive Med. 2025;5(2):193–201. doi: 10.1016/j.jointm.2024.12.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 260.She H., Du Y., Du Y., Tan L., Yang S., Luo X., et al. Metabolomics and machine learning approaches for diagnostic and prognostic biomarkers screening in sepsis. BMC Anesthesiol. 2023;23(1):367. doi: 10.1186/s12871-023-02317-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 261.Zhou L., Shao M., Wang C., Wang Y. An early sepsis prediction model utilizing machine learning and unbalanced data processing in a clinical context. Prev Med Rep. 2024;45 [Google Scholar]
- 262.Hall A., Qureshi I., Glaser J., Bulger E.M., Scalea T., Shackelford S., et al. Validation of a predictive model for operative trauma experience to facilitate selection of trauma sustainment military-civilian partnerships. Trauma Surg Acute Care Open. 2019;4(1) [Google Scholar]
- 263.Lokerman R.D., Van Der Sluijs R., Waalwijk J.F., Verleisdonk E.J.M.M., Haasdijk R.A., Van Deemter M.M., et al. Development and validation of prediction models for prehospital triage of military trauma patients. BMJ Mil Health. 2025;171(e1):e56–e62. [Google Scholar]
- 264.Jumreornvong O., Perez A.M., Malave B., Mozawalla F., Kia A., Nwaneshiudu C.A. Biases in artificial intelligence application in pain medicine. J Pain Res. 2025;18:1021–1033. doi: 10.2147/JPR.S495934. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 265.Baues M., Dasgupta A., Ehling J., Prakash J., Boor P., Tacke F., et al. Fibrosis imaging: current concepts and future directions. Adv Drug Deliv Rev. 2017;121:9–26. doi: 10.1016/j.addr.2017.10.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 266.Benjamens S., Dhunnoo P., Meskó B. The state of artificial intelligence-based FDA-approved medical devices and algorithms: an online database. NPJ Digit Med. 2020;3(1):118. doi: 10.1038/s41746-020-00324-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 267.Ibrahim H., Liu X., Rivera S.C., Moher D., Chan A.W., Sydes M.R., et al. Reporting guidelines for clinical trials of artificial intelligence interventions: the SPIRIT-AI and CONSORT-AI guidelines. Trials. 2021;22(1):11. doi: 10.1186/s13063-020-04951-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 268.Schwalbe N., Wahl B. Artificial intelligence and the future of global health. Lancet. 2020;395(10236):1579–1586. doi: 10.1016/S0140-6736(20)30226-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 269.Maas A.I.R., Menon D.K., Steyerberg E.W., Citerio G., Lecky F., Manley G.T., et al. Collaborative European neurotrauma effectiveness research in traumatic brain injury (CENTER-TBI): a prospective longitudinal observational study. Neurosurgery. 2015;76(1):67–80. doi: 10.1227/NEU.0000000000000575. [DOI] [PubMed] [Google Scholar]
- 270.Maas A.I.R., Menon D.K., Adelson P.D., Andelic N., Bell M.J., Belli A., et al. Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research. Lancet Neurol. 2017;16(12):987–1048. doi: 10.1016/S1474-4422(17)30371-X. [DOI] [PubMed] [Google Scholar]
- 271.G-MUSC - Global Alliance for Musculoskeletal Health. 2000. 〈https://gmusc.com/〉. Accessed Jan 2000.
- 272.Briggs A.M., Schneider C.H., Slater H., Jordan J.E., Parambath S., Young J.J., et al. Health systems strengthening to arrest the global disability burden: empirical development of prioritised components for a global strategy for improving musculoskeletal health. BMJ Glob Health. 2021;6(6) [Google Scholar]
- 273.Thelin E., Al Nimer F., Frostell A., Zetterberg H., Blennow K., Nyström H., et al. A serum protein biomarker panel improves outcome prediction in human traumatic brain injury. J Neurotrauma. 2019;36(20):2850–2862. doi: 10.1089/neu.2019.6375. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 274.Jović M., Prim D., Paciotti G., Pfeifer M.E. Engineering a diagnostic platform based on a spatially resolved electrochemiluminescence immunoassay for low-plex biomarker detection at point-of-care: mild traumatic brain injury and cardiac applications. Lab Chip. 2025;25(21):5428–5438. doi: 10.1039/d5lc00360a. [DOI] [PubMed] [Google Scholar]
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Data Availability Statement
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