Search Results (880)

Acute coronary syndromes (ACS) remain time-critical clinical emergencies in which early diagnosis and accurate risk stratification determine management and outcomes. Although symptoms, electrocardiography, and high-sensitivity cardiac troponin (hs-cTn) provide a reliable framework for detecting myocardial injury, they offer limited insight into plaque instability, thromboinflammatory activity, vascular repair, and post-infarction remodeling. In this narrative review, we examine the biological rationale and current clinical evidence supporting brain-derived neurotrophic factor (BDNF) as a candidate biomarker in ACS, with particular attention to pre-analytical, analytical, and phenotypic sources of heterogeneity. Available studies show that circulating BDNF concentrations vary substantially according to biological matrix, timing of sampling, ACS subtype, and assay methodology, which likely contributes to inconsistent findings across cohorts. Overall, current evidence does not support BDNF as a diagnostic alternative to hs-cTn in rule-in or rule-out pathways. However, BDNF may have value in biological phenotyping and risk stratification by reflecting platelet activation, endothelial dysfunction, inflammatory signaling, and remodeling processes after ACS. Further progress will require standardized pre-analytical procedures, separate assessment of mature BDNF and proBDNF, serial sampling, and validation in large multicenter studies. Full article

Background/Objectives: Chronic wounds that fail to respond to standard wound care (SWC) remain a major clinical challenge. Platelet-rich plasma (PRP) is an advanced regenerative therapy that delivers platelet-derived growth factors involved in angiogenesis and tissue repair. However, clinical data in Asian populations and evidence regarding ulcers associated with vasculitis or microangiopathic ischemia remain limited. This study evaluated the efficacy, safety, and treatment frequency of autologous PRP gel prepared using the newly approved AutoloGel System^® in Japan. Methods: This single-center retrospective study included 20 patients with chronic ulcers unresponsive to ≥28 days of conventional therapy by a wound specialist. PRP gel was applied weekly for up to eight sessions under current insurance coverage. Primary outcomes were wound healing rate at 12 weeks after PRP initiation and healing duration. Healing time during specialist-directed conventional therapy was compared with that following PRP using the Wilcoxon signed-rank test. Results: Twenty patients (mean age 60 ± 15 years) with diverse refractory ulcers—including diabetic foot ulcers, chronic limb-threatening ischemia, vasculitic ulcers, venous leg ulcers, pressure ulcers, and surgical site infections—were analyzed. All wounds achieved complete epithelialization within 12 weeks. Healing time decreased significantly from 87.2 ± 77.1 days during conventional therapy to 47.9 ± 28.5 days after PRP initiation (median 60 vs. 44 days, p = 0.0107). No treatment-related adverse events were observed. Conclusions: Weekly autologous PRP gel therapy prepared using the AutoloGel System^® was associated with improved healing outcomes in refractory chronic wounds. Favorable outcomes were observed in traditionally difficult-to-treat conditions, including vasculitis-associated and microangiopathic ischemic ulcers. These findings suggest the potential role of PRP in promoting angiogenesis and improving microcirculatory perfusion in wounds associated with microvascular dysfunction. Full article

Tumor-associated Tie2-expressing monocytes/macrophages (TEMs) have been implicated in promoting angiogenesis and metastasis in colorectal cancer (CRC), yet the molecular mechanisms linking TEMs infiltration to tumor metastasis and progression remain incompletely defined. This study investigated the distribution of TEMs in CRC and their association with gene expression profiles, microvessel density (MVD), and clinical outcomes. Immunohistochemistry on 30 formalin-fixed paraffin-embedded (FFPE) primary CRC samples revealed that TEMs, which characteristically express tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 2 (Tie2) receptor and CD14, preferentially localize to perivascular regions and are associated with higher histological grade, tumor size, lymph node metastasis, and increased MVD. However, Tie2⁻/CD14⁺ macrophages and CD68⁺ tumor-associated macrophages (TAMs) showed uniform stromal distribution. Gene set enrichment analysis (GSEA) of in silico transcriptomic datasets of metastatic CRC (mCRC) identified enrichment of pathways related to cell–cell recognition, calcium signaling, transcription regulation, and metalloexopeptidase activity in Tie2⁺/CD14⁺ tumors. Subsequent qRT-PCR validation on FFPE primary CRC samples confirmed significant upregulation of C-C chemokine receptor 7 (CCR7), platelet-derived growth factor A (PDGFRA), CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 2 (CITED2), and carboxypeptidase E (CPE) in TEMs⁺ regions. Notably, angiopoietin1 (Ang1), but not angiopoietin2 (Ang2), was significantly elevated in TEMs⁺ primary tumors. Kaplan–Meier analysis on 1336 CRC patients indicated that high expression of CITED2, CPE, and Ang2 is associated with reduced overall survival. Collectively, these findings suggest that TEM infiltration is linked to transcriptional regulation, biological processes, and enzymatic programs in CRC, potentially contributing to tumor progression and poor prognosis, and highlight CCR7, PDGFRA, CITED2, CPE, and Ang1 as candidate biomarkers for further mechanistic exploration. Full article

Objectives: Soft tissue sarcomas (STS) are biologically heterogeneous malignancies with unpredictable clinical behavior. Although tumor size, histological grade, and surgical margin status remain the main determinants of prognosis, additional biomarkers that integrate tumor biology and host-related factors are needed. The hemoglobin × albumin × lymphocyte/platelet (HALP) score reflects systemic inflammation and nutritional status. This study aimed to evaluate the association between preoperative HALP score and oncological as well as surgical outcomes in patients undergoing curative resection for STS. Materials and Methods: A retrospective cohort study was conducted including 46 consecutive patients who underwent surgery for STS between 2017 and 2025. HALP scores were calculated using preoperative laboratory parameters, and patients were stratified into low- and high-HALP groups according to the cohort median (24.9). Overall survival (OAS) and disease-free survival (DFS) were analyzed using the Kaplan–Meier method and Cox proportional hazards models. Surgical margin status and postoperative complications were also compared. Results: Patients with low HALP scores had significantly larger tumors, higher rates of non-R0 resection, and increased major complications (p < 0.05). Recurrence and mortality were more frequent in the low-HALP group. Kaplan–Meier analysis demonstrated significantly shorter OAS (log-rank p = 0.0034) and DFS (log-rank p = 0.0318) in patients with low HALP scores. In univariate Cox analysis, HALP was significantly associated with survival outcomes; however, in multivariate analysis, histological grade and surgical margin status remained independent prognostic factors, while HALP lost independent significance. Conclusions: A low preoperative HALP score is associated with aggressive tumor characteristics, increased surgical morbidity, and poorer survival in STS patients. Although HALP did not retain independent significance in multivariable analysis, its strong association with tumor aggressiveness and survival suggests that it may reflect the systemic manifestation of high-risk tumor biology. As a simple and cost-effective biomarker derived from routine laboratory parameters, HALP may support preoperative risk stratification and help identify patients with biologically aggressive disease. Full article

Background: Venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism, is increasingly recognized as a thromboinflammatory disorder involving coagulation, innate immunity, endothelial dysfunction, and vascular homeostasis. Emerging evidence suggests that gut microbiome-related inflammatory and metabolic signals may influence pathways potentially relevant to VTE through intestinal barrier dysfunction, microbial translocation, and microbiome-derived metabolites. This review critically examines the direct and indirect evidence relating gut dysbiosis to mechanisms potentially relevant to venous thrombogenesis. Methods: A structured literature search of PubMed, Scopus, and Web of Science was conducted from database inception to February 2026. Observational, translational, experimental, preclinical, and selected genetic studies were narratively synthesized across heterogeneous evidence types. Results: Available evidence suggests that intestinal barrier dysfunction and microbial translocation may increase systemic exposure to lipopolysaccharide and other microbial products, potentially contributing to inflammatory signaling and procoagulant responses. Proposed downstream effects include tissue factor (TF) activation, platelet reactivity, neutrophil extracellular traps (NETs) formation, complement signaling, endothelial perturbation, and impaired balance of anticoagulant and fibrinolytic pathways. Microbiome-derived metabolites, including trimethylamine N-oxide (TMAO), phenylacetylglutamine (PAGln), bile acids, and short-chain fatty acids (SCFAs), have been linked, mainly in experimental or non-VTE settings, to thrombosis-related biology. However, most evidence remains indirect, associative, or experimental, whereas direct human VTE-specific evidence is limited and heterogeneous. Conclusions: The gut microbiome–VTE axis is biologically plausible and supported mainly by mechanistic and indirect evidence, but current data are insufficient to support strong causal conclusions. Further longitudinal, well-phenotyped, mechanistically informed studies are needed to determine whether microbiome-related pathways have measurable clinical relevance in human VTE. Full article

Platelet-rich plasma (PRP) therapies are increasingly used in musculoskeletal and regenerative medicine; however, substantial variability in reported outcomes persists even when similar preparation protocols are employed. In quantitative terms, PRP preparation can be interpreted as a stochastic process in which uncertainty propagates through multiple biological and technical inputs. Herein we propose a probabilistic framework to quantify variability in the platelet dose delivered (PDD) using Monte Carlo simulations. The platelet dose was formulated as a random variable defined by a multiplicative model involving the platelet count (modeled as a normal distribution), concentration factor (log-normal), injected volume (uniform), and processing efficiency (beta). Input parameters were represented by probability distributions derived from ranges reported in the literature, and uncertainty propagation was explored through 100,000 Monte Carlo iterations. The resulting simulations revealed a wide dispersion in PDD, characterized by a right-skewed distribution with a median of 3.1 × 10⁹ platelets and an interquartile range of 1.9 × 10⁹ platelets, yielding a coefficient of variation exceeding 50%. Sensitivity analysis based on variance-based global sensitivity measures (Sobol indices) identified the injected volume and concentration factor as the dominant contributors to output variability, with substantial interaction effects between these parameters accounting for a considerable portion of total variance. The baseline platelet count and processing efficiency had comparatively smaller effects. These results demonstrate how probabilistic modeling can clarify the sources of variability in PRP preparation and provide a generalizable framework for uncertainty quantification in multiplicative biomedical systems. Full article

Purinergic signaling plays a critical role in several inflammatory diseases, including acute lung injury, inflammatory bowel disease, coronary artery diseases, and various cancers. Purine and its derivatives, specifically adenosine and ATP, exhibit a critical regulatory axis that bridges platelet activation, vascular thrombosis, and sterile inflammation. Myocardial infarction (MI) initiates a complex pathophysiological cascade characterized by profound hypoxia, inflammation response, reduced coronary blood flow, and increased oxidative stress, which leads to myocardial cell death and apoptosis. Reperfusion therapy remains a primary strategy for restoring coronary blood flow and maximally limiting infarct size; increased infarct size further exacerbates ischemic injury, making it myocardial ischemic/reperfusion injury (MIRI). In this review, we delineate the mechanistic “triad axis”, comprising adenosine signaling, hypoxia-inducible factor (HIF) stabilization, and reactive oxygen species (ROS) homeostasis; this axis serves as a pivotal determinant of cardiomyocyte death during MIRI. We further examine the cell-specific roles of adenosine signaling in modulating immune cell infiltration and function within the ischemic milieu. Finally, we highlight the emerging role of mitochondrial ROS (mtROS) and HIF-dependent signaling in circadian regulation, suggesting that the chronotherapeutic approaches targeting these pathways may offer transformative opportunities for the treatment of ischemic heart disease (IHD). Full article

Background/Objectives: Platelet-rich plasma (PRP) is an autologous blood-derived biologic enriched in platelets and bioactive mediators. In urology and sexual medicine, PRP has been promoted for erectile dysfunction (ED) and a growing range of urogenital disorders on the premise that it may support angiogenesis, neuroregeneration, immune modulation, and tissue remodeling. However, clinical uptake has outpaced high-quality evidence, while heterogeneity in PRP preparation, characterization, and delivery limits interpretability and reproducibility. This structured narrative review aims to critically integrate mechanistic, preclinical, and clinical evidence regarding PRP use in ED, Peyronie’s disease (PD), stress urinary incontinence (SUI), interstitial cystitis/bladder pain syndrome (IC/BPS), and selected emerging indications. We further aim to identify sources of heterogeneity and propose an actionable minimum reporting framework (PRP-Uro Checklist) to guide future research. Methods: A structured search of PubMed/MEDLINE was conducted for studies published between 2021 and 2025. The relevant literature on PRP use in ED, PD, SUI, IC/BPS, and related indications was included for critical narrative synthesis. Emphasis was placed on PRP classification and preparation variables, outcome measure validity, and sources of heterogeneity across studies. Results: Mechanistic and preclinical evidence supports PRP’s potential to modulate nerve repair, angiogenesis, extracellular matrix remodeling, and immune polarization through a complex secretome of growth factors, cytokines, and extracellular vesicles (EVs). Clinical evidence suggests that intracavernosal PRP may improve erectile function in selected populations, but effect size, durability, and superiority over placebo remain uncertain due to small trials, substantial placebo effects, short follow-up, and incomplete biologic characterization. Evidence for PRP in PD, SUI, and IC/BPS remains preliminary and is derived largely from small cohorts, proof-of-concept studies, or uncontrolled designs, although early findings suggest potential symptom benefit and acceptable short-term tolerability. Across indications, inconsistent PRP reporting, particularly the absence of absolute platelet dose, leukocyte quantification, activation method, and standardized treatment protocols, represents a major barrier to reproducibility and evidence synthesis. Conclusions: PRP is biologically plausible and appears broadly safe, but its role in urology and sexual medicine remains investigational and is not yet supported by guideline-level evidence. To enhance reproducibility and interpretation, we propose a Minimum PRP Reporting Checklist for Urology and Sexual Medicine Trials (PRP-Uro Checklist). Future progress requires rigorous standardized reporting, indication-specific biologic characterization, rigorously designed sham-controlled trials, clinically meaningful endpoints, and longer-term follow-up. Full article

Background: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening condition resulting from a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS13) deficiency, leading to the accumulation of ultra-large von Willebrand factor (vWF) multimers and widespread microvascular thrombosis. While therapeutic plasma exchange and immunosuppression have significantly improved response, refractory and relapsed disease are significant challenges. N-acetylcysteine (NAC) has emerged as a biologically plausible adjunctive therapy due to its potential to reduce disulfide bonds in vWF multimers. However, its clinical role is unclear. This systematic review aimed to evaluate the clinical evidence regarding the efficacy and safety of N-acetylcysteine in patients with immune-mediated TTP. Methods: We performed a systematic review in accordance with the PRISMA guidelines. PubMed/MEDLINE, Google Scholar, and ClinicalTrials.gov were searched until January 2026. Studies involving patients with immune-mediated TTP treated with NAC were included. Case reports, case series, and observational studies involving patients with immune-mediated TTP treated with NAC were included. Risk of bias was evaluated using adapted quality assessment tools. Results: Sixteen studies encompassing 69 patients met the inclusion criteria. Most reports were case reports or small case series; two were larger observational cohorts. NAC was predominantly used as adjunctive therapy in relapsed or refractory TTP. Dose regimens varied. Platelet recovery following NAC was reported within 1–15 days in responding cases. Predominantly positive haematological responses were observed in small series. Significant heterogeneity in patient populations, timing of initiation, concomitant therapies, and outcome reporting limited causal inference. Conclusions: The current evidence suggests that NAC has a biologically rational and potentially adjunctive value in TTP, particularly in refractory disease or resource-constrained settings. However, current data are largely heterogeneous and derived from low-level evidence. Well-designed prospective studies and randomized controlled trials are needed to determine whether NAC provides significant clinical benefit beyond standard therapy. Full article

Elevated levels of platelet-derived growth factor (PDGF) isoforms in fibrosis are implicated in driving a dysfunctional profibrotic fibroblast phenotype. This study investigated the differential effects of the five PDGF isoforms (AA, AB, BB, CC, and DD) in inducing neonatal dermal and fetal lung fibroblast contraction, proliferation, cytokine production, myofibroblast differentiation, and extracellular matrix (ECM) deposition. All PDGF isoforms, except PDGF-AA, increased contraction of 3-dimensional collagen I gels by dermal (p < 0.01) and lung fibroblasts (p < 0.05) compared to media control. PDGF-AB, BB, and CC enhanced proliferation only in dermal fibroblasts (p < 0.05). PDGF-BB induced profibrotic IL-11 cytokine release in dermal and lung fibroblasts (p < 0.0001) and IL-6 cytokine release in dermal fibroblasts (p < 0.05) compared to media control. None of the PDGF isoforms affected ECM synthesis or myofibroblast differentiation. Dermal fibroblasts exhibited elevated PDGF Receptor-β (PDGFRβ) expression (p < 0.01) and increased basal ERK1/2 phosphorylation (p < 0.05) compared to lung fibroblasts. In summary, PDGF modulates fibroblast functions in a tissue-specific manner, with PDGF-BB driving profibrotic processes in dermal fibroblasts through high PDGFRβ expression and ERK1/2 signalling. Further research is needed to explore the benefit of tissue and isoform-specific PDGF inhibition strategies in skin and lung fibrosis. Full article

Background/Objectives: Natural killer (NK) cells are key innate lymphoid cells that restrict tumour progression by secreting proinflammatory cytokines and directly lysing malignant cells, with their activity tightly regulated by a balance of activating and inhibitory surface receptors. The natural cytotoxicity receptor NKp44 is induced on NK cells following stimulation with IL-2 or IL-15 and recognizes platelet-derived growth factor D (PDGF-DD) as a ligand. Mechanistic interpretation of NKp44 signalling upon PDGF-DD engagement is confounded by the existence of three distinct NKp44 isoforms (NKp44-1, -2, and -3), each capable of initiating divergent intracellular signalling cascades. Unlike NKp44-2 and -3, NKp44-1 encodes a cytoplasmic tyrosine residue (Y238) that conforms to a putative immunoreceptor tyrosine-based inhibition motif (ITIM) and has been reported to suppress NK cell effector functions in some contexts. However, it remains unclear whether the NKp44 isoforms are translated and expressed in NK cells, and formal evidence defining NKp44-1 signalling in response to engagement by PDGF-DD is lacking. Methods: In this study, we used C-terminal targeting monoclonal antibodies (mAbs) and a NFAT-GFP reporter system to define the expression and signalling properties of NKp44 isoforms in response to PDGF-DD. Results: We demonstrate protein expression of NKp44-1 and NKp44-2-/3 receptors in IL-2 expanded NK cells. We further show that NKp44-1 transduces activating rather than inhibitory signals when engaged by PDGF-DD ligand, albeit weaker than NKp44-3. Intriguingly, we find that Y238 is dispensable for NKp44-1 activating signalling and instead functions as a YXXΦ internalisation motif. Conclusions: Collectively, these findings provide the first evidence that the NKp44-1 and NKp44-2/3 isoforms are expressed in NK cells and establish that PDGF-DD activates signalling through NKp44-1 independently of Y238. This work lays the foundations for future studies investigating how PDGF-DD sensing by the different NKp44 isoforms shapes immune functions in different physiological and pathological contexts. Full article

Background: Recombinant human growth hormone (rhGH) replacement therapy, administered to children with growth hormone deficiency (GHD), exerts pleiotropic effects on growth, metabolism, and tissue functions. Extracellular vesicles (EVs) are emerging mediators of inter-organ communication, but the effects of rhGH therapy on EV release in humans have not yet been investigated. Methods: In a preliminary prospective clinical study, children with GHD (n = 10; F/M = 5/5; age: 11.0 ± 2.7 years) were treated with rhGH for 6 months. Plasma samples were collected at baseline (T0) and after treatment (T6) to characterize the size distribution and tissue-derived composition of circulating EVs. Total EVs and EV subpopulations derived from monocytes/macrophages (CD14+), adipose tissue (FABP+), skeletal muscle (SCG+), endothelium (CD62E+), and platelets (CD42A+) were analyzed. Clinical, auxological/auxometric, and biochemical/metabolic parameters were assessed in parallel. Statistical methods included longitudinal analyses, interaction models, and adjustments for relevant covariates, including insulin-like growth factor 1 (IGF-1) and osteocalcin. Results: After 6 months of rhGH therapy, significant improvements in height velocity (cm/year and SDS) were observed, accompanied by increased circulating IGF-1 and osteocalcin levels. Hormone therapy induced no size-dependent changes in (total) EVs. Significant increases in CD14+ and FABP+ EVs were observed after treatment, without affecting the other tissue-derived EVs. Interaction analyses revealed that children with more severe GHD exhibited a stronger vesiculogenic response to rhGH. Furthermore, specific tissue-derived EVs were associated with metabolic/biochemical and auxological/auxometric parameters, including lipids, insulin resistance, and growth-related measures. Conclusions: When administered for six months, rhGH therapy seems to selectively change tissue-derived composition of circulating EVs in GHD children, particularly those derived from immune cells and adipose tissue. These preliminary findings suggest that EVs might represent an adjunctive component of GH-dependent inter-organ communication and might serve as biomarkers of treatment response and disease severity in pediatric endocrinology. Full article

Neutrophil extracellular traps (NETs) critically influence thrombosis by promoting platelet aggregation, fibrin formation, and thrombus stabilisation. However, primary human neutrophils present experimental limitations, including short lifespan ex vivo and ethical concerns. In this article, we discuss the available data on PLB-985 cells, a neutrophil-like model with potential to replace human neutrophils in research. Additionally, we present novel structural comparisons showing that both PLB-985- and human neutrophil-derived NETs significantly increased fibrin fibre thickness compared to thrombin-only controls, with similar fibre morphology across conditions. Notably, we also see spherical particles resembling microvesicles within PLB-985-derived NETs, suggesting potential additional procoagulant effects via microvesicle-associated tissue factor level in these cells. New and existing data presented in this article suggest that differentiated PLB-985 cells are able to effectively replicate key structural and functional aspects of human neutrophil NETs. These observations support the use of PLB-985 cells as an ethical, reproducible, and practical alternative for in vitro studies of NETs. Further characterisation is required to determine differences between human neutrophils and neutrophil-like models in macrovesicle formation and implication in NET-related thrombosis research. Full article

The role of platelet-derived growth factor D (PDGFD) in mesenchymal cells is well-established, but its specific function in skeletal muscle generation remains unknown. This study reveals for the first time PDGFD’s dual regulatory role in myogenesis: it acts both as a “guardian” maintaining the myoblast pool and as an “initiator” driving myogenic differentiation. Through single-cell RNA sequencing analysis of skeletal muscle from Jiangquan Black pigs, we identified PDGFD as a common candidate gene for both muscle and fat development. In the C2C12 cell model, PDGFD knockdown significantly inhibited cell proliferation and promoted apoptosis, while overexpression enhanced viability and inhibited apoptosis, indicating its critical role in maintaining myoprogenic precursor cell homeostasis. Further studies revealed that PDGFD interference downregulated key myogenic differentiation markers MyoD and MyoG, inhibiting differentiation. Its expression peaked during mid-differentiation (D5), suggesting temporal regulation of differentiation. Interestingly, although PDGFD primarily acts through the PI3K/Akt pathway downstream of PDGFR-β, PDGFD knockdown did not show significant synergistic effects with PI3K/Akt pathway activation in inhibiting differentiation. This suggests PDGFD may specifically regulate myogenic differentiation via an independent or parallel signaling axis. This study not only expands the known functions of PDGFD in muscle biology but also provides new insights into the mechanisms by which growth factors coordinate cell fate decisions. Full article

Platelet-rich gel (PRG) is a fibrin-based biobased biomaterial generated by activating platelet-rich plasma (PRP), yet its biological characterization has commonly relied on univariate measurements of isolated mediators. This study aimed to define the multivariate biological organization of PRG and related hemocomponents (PRP, chemically induced platelet lysate (CIPL), and plasma) in a canine model under single exposure to non-steroidal anti-inflammatory drugs (NSAIDs). In a randomized crossover design (n = 6 dogs), hemocomponents were produced at baseline (0 h) and 6 h after administration of carprofen or firocoxib. Platelet and white blood cell (WBC) counts, growth factors (platelet-derived growth factor-BB (PDGF-BB) and transforming growth factor beta-1 (TGF-β1)), and cytokines (tumor necrosis factor alpha (TNF-α), interleukin-1 beta, and interleukin-10) were integrated using linear mixed-effects modeling, principal component analysis (PCA), and hierarchical clustering. PRG was derived from a leukocyte-poor PRP precursor with moderate platelet enrichment (~1.6-fold vs. whole blood) and a marked WBC reduction (~8–9-fold). In mixed-effects modeling, hemocomponent type significantly influenced the PDGF-BB:TNF-α log-ratio, with PRG (estimate −1.12; 95% CI −1.34 to −0.90) and plasma (−2.06; 95% CI −2.28 to −1.84) lower than PRP, while CIPL did not differ. Time and NSAID effects were not supported. PCA identified two orthogonal axes explaining 61.3% of total variance (PC1 = 43.7%, PC2 = 18.6%), separating a platelet/trophic dimension (log(PDGF-BB), log(TGF-β1), platelet count, PDGF-BB:TNF-α log-ratio) from an inflammatory dimension (log(TNF-α), log(IL-1β)). Overall, hemocomponent composition emerged as the primary determinant of mediator organization, supporting the interpretation of PRG as a structured, biomaterial defined by coordinated mediator networks. Full article