Search Results (188)

Background/Objectives: Diabetic Foot Ulceration (DFU) is one of the most debilitating and costly complications of diabetes mellitus, representing a significant cause of morbidity, disability, and healthcare burden worldwide. Refractory non-healing ulcers that fail to respond to conventional therapies require novel adjuvant treatment modalities. This clinical audit aimed to evaluate the long-term clinical outcomes of an autologous, bioactive platelet-rich fibrin (PRF) matrix combined with topical gentamicin in patients with chronic, non-healing DFUs. Methods: A retrospective observational audit was conducted, involving eleven patients with refractory DFUs who underwent adjunctive treatment with a PRF matrix (Arthrozheal^®) and co-applied gentamicin. Patients were followed at three-week intervals using standardised wound imaging (Silhouette^® 3D) to assess healing parameters. Long-term follow-up data, evaluating healing durability and complications, is presented. Results: All patients completed the treatment protocol, with significant reductions in mean wound area (87.9%), perimeter, depth, and volume (all p < 0.05). Epithelialised tissue increased from 24.7% to 82.8%. At 12 months, 81.8% of patients maintained complete ulcer healing. Two patients experienced complications: one ulcer recurrence requiring surgical debridement and one unrelated amputation due to osteomyelitis. Conclusions: The combination of autologous PRF matrix and gentamicin demonstrated promising results in promoting sustained healing of refractory DFUs with minimal complications. These findings support further investigation in larger, controlled studies to validate this biologic-antimicrobial approach as a safe, effective, and durable therapy for complex diabetic wounds. Full article

Meniscal preservation is increasingly recognized as a critical determinant of long-term knee joint health, yet successful repair remains challenging due to the meniscus’s limited intrinsic healing capacity. The adult meniscus is characterized by restricted vascularity, low cellularity, a dense extracellular matrix, complex biomechanical loading, and a hostile post-injury intra-articular inflammatory environment—factors that collectively impair meniscus healing, particularly in the avascular zones. Over the past several decades, a wide range of biologic augmentation strategies have been explored to overcome these barriers, including synovial abrasion, fibrin clot implantation, marrow stimulation, platelet-derived biologics, cell-based therapies, scaffold coverage, and emerging biologic and biophysical interventions. This review summarizes the biological basis of meniscal healing, critically evaluates current and emerging biologic augmentation techniques, and integrates these approaches within a unified framework of vascular, cellular, matrix, biomechanical, and immunologic targets. Understanding and modulating the cellular and molecular mechanisms governing meniscal degeneration and repair may enable the development of more effective, mechanism-driven strategies to improve healing outcomes and reduce the risk of post-traumatic osteoarthritis. Full article

Background/Objectives: Autologous dentin matrix (ADM) has been suggested as a biologically plausible biomaterial for alveolar bone regeneration after tooth extraction. However, clinical evidence regarding its biological activity and early healing outcomes is limited. This exploratory, randomized controlled pilot study aimed to descriptively assess early alveolar healing patterns and bone morphogenetic protein 4 (BMP4) expression following tooth extraction using ADM compared with other grafting approaches. Methods: Patients requiring tooth extraction were allocated to one of four groups: ADM, xenograft, ADM combined with platelet-rich fibrin, and a graft-free control group. Histological and immunohistochemical analyses were performed four months after extraction to descriptively assess cellular features of healing and BMP4 expression. The trial was registered at the Brazilian Registry of Clinical Trials (ReBEC; RBR-24mdgrf) and conducted under prior ethics committee approval. Results: BMP4 expression was detected in 67.9% of the analyzed histological fields, predominantly localized in osteocytic, osteoblastic, and medullary areas. Although descriptive differences in BMP4-positive fields were observed among the groups, no statistically significant differences were identified between the groups. Histological evaluation revealed an active cellular environment across all treatment modalities, consistent with early post-extraction healing. No adverse events related to surgical procedures or grafting materials were reported during the study period. Conclusions: Within the limitations of this pilot randomized clinical trial, ADM exhibited consistent biological behavior during early post-extraction alveolar healing. The observed BMP4 expression likely reflects a general physiological healing response rather than a material-specific effect. This finding supports the biological plausibility of dentin-derived grafts as osteoconductive biomaterials. These findings are hypothesis-generating, and larger, adequately powered randomized clinical trials with standardized molecular and histological assessments are required to determine their clinical relevance. Full article

Mesothelial cells line serosal cavities and internal organs, playing a vital role in maintaining serosal integrity and homeostasis. Their remarkable plasticity and ability to undergo mesothelial-to-mesenchymal transition (MMT) position them as key regulators of tissue repair. However, when normal repair processes fail, mesothelial cells can acquire a profibrotic phenotype. They actively contribute to all stages of fibrosis development, including inflammation, fibrin accumulation, myofibroblast differentiation, and extracellular matrix (ECM) remodeling. Fibrotic progression involves multiple cell types, and communication among them is essential for its perpetuation. Mesothelial cells are implicated in bidirectional crosstalk with fibroblasts, macrophages, lymphocytes, and endothelial cells of the serosal microenvironment through direct contact, paracrine signaling, and extracellular vesicle exchange. These interactions regulate immune cell recruitment, cytokine balance, endothelial permeability, and ECM deposition, while, in turn, immune and endothelial cells modulate mesothelial activation, proliferation, and transition. Understanding this complex network of intercellular communication provides new insights into fibrosis pathogenesis and reveals promising targets for antifibrotic therapies. Full article

Fibrin hydrogels are biocompatible but often lack instructive cues needed to sustain chondrocyte phenotype and cartilage-like matrix formation; therefore, we investigated whether a tricomposite fibrin hydrogel incorporating decellularized articular cartilage matrix (dACM) and decellularized amniotic membrane matrix (dAMM) enhances human articular chondrocyte performance in vitro. Human articular chondrocytes were encapsulated in tricomposite or fibrin-only hydrogels and cultured for 28 days, evaluating degradation kinetics, viability and cell density, histological remodeling (H&E, Masson’s trichrome, Safranin O), immunohistochemistry for type II collagen, aggrecan, and type I collagen, and qPCR of SOX9, COL2A1, ACAN, RUNX2, COL1A2, and COL10A1. The tricomposite remained cytocompatible (~99% viability), supported marked cell expansion (~250% by day 28), and degraded more slowly than fibrin controls. It increased chondrogenic gene expression (SOX9 >3-fold vs. control by day 28; sustained COL2A1 at 1.5–2-fold; early ACAN at 3–5-fold) while attenuating off-target transcriptional programs (RUNX2 ~50% of control, reduced COL1A2, and negligible COL10A1). Consistently, histology showed progressive lacuna-like morphology and proteoglycan-rich matrix accumulation, accompanied by strong type II collagen and aggrecan immunoreactivity and reduced type I collagen. Overall, adding dACM and dAMM to fibrin improved hydrogel biofunctionality and promoted hyaline-like extracellular matrix assembly, supporting further evaluation of this cell-instructive platform for focal articular cartilage repair. Full article

Fibrinolysis is a natural component of hemostasis in which a no-longer-needed clot is gradually dissolved to restore blood flow. Under pathological thrombotic conditions, this process can be pharmacologically enhanced to promote clot removal. However, thrombolytic therapy has limited efficacy and is associated with a risk of bleeding complications, including intracranial hemorrhage. Fibrinolysis targets only the fibrin-rich part of the thrombus, whereas a substantial fraction of the clot is enriched with non-fibrin components such as extracellular DNA, von Willebrand factor, and extracellular matrix proteins, including collagen, fibronectin, and laminin. These structural regions, which may constitute half or more of the clot volume, remain resistant to classical fibrinolytic agents. To overcome these limitations, recent therapeutic strategies aim to degrade these non-fibrin elements to improve thrombolytic efficacy and reduce adverse effects. In this review, we summarize current trends in pharmacological clot dissolution, discuss novel agents in clinical use and development, and outline how targeting non-fibrin components may influence the future of thrombolytic therapy. Full article

Articular cartilage possesses limited intrinsic healing capacity due to its avascular and aneural nature, posing a significant challenge for treating focal chondral defects. While regenerative strategies employing biomaterials and stem cells have progressed, their mechanistic evaluation is hindered by the lack of physiologically relevant in vitro models. This study aimed to establish and characterize a human ex vivo osteochondral explant model to assess cellular and extracellular matrix responses to cartilage repair strategies. Osteochondral explants (10 mm diameter, n = 61) were harvested from femoral condyles of patients undergoing knee arthroplasty. Standardized full-thickness chondral defects (4 mm) were created and assigned to six treatment groups: native control, untreated defect, fibrin glue, collagen type I hydrogel (ChondroFiller^®), fibrin glue + MSCs, and ChondroFiller^® + MSCs. Explants were cultured for 7, 14, or 21 days, followed by metabolic, biochemical, and histological assessments. Explants remained viable for 21 days. Notably, the ChondroFiller^® group showed a 2.4-fold increase in DNA content by day 14, while MSC-treated groups enhanced collagen deposition and GAG production. Significant correlations between DNA and collagen levels were observed in scaffold-based treatments. This ex vivo model offers a reproducible and translational platform to investigate cartilage regeneration with temporal resolution, supporting preclinical testing of emerging therapeutic approaches. Full article

Dural tear (DT) and cerebrospinal fluid (CSF) leakage, though uncommon complications, represent a potentially serious risk of anterior cervical spine surgery, particularly in patients with ossification of the posterior longitudinal ligament (OPLL). While the incidence in routine anterior cervical discectomy and fusion (ACDF) or corpectomy (ACCF) is typically below 0.5%, it rises sharply to 4–32% in OPLL cases. Furthermore, it exceeds 60% when dural ossification (DO) is present. Adhesion and ossification obliterate the normal epidural plane, creating a fragile osteofibrotic interface that is highly susceptible to tearing during decompression. This review synthesizes current evidence on the pathophysiology of DT and CSF leakage in anterior cervical spine surgery, provides a framework for risk stratification, and outlines evolving techniques for successful repair and management. Intraoperative management has shifted from direct resection toward dura-preserving floating decompression and biologically reinforced multilayer repair using fascia, collagen matrix, fibrin adhesives, and polyethylene glycol (PEG) hydrogel sealants. Postoperative care emphasizes controlled CSF pressure regulation, sterile wound management, and early ambulation. Most DTs achieve successful closure with timely recognition and standardized treatment. However, persistent leakage may require escalation to composite reconstruction, epidural blood patch, or vascularized flap reinforcement. Emerging technologies such as bioactive hydrogels, 3D-printed dural scaffolds, and artificial intelligence–assisted imaging offer potential future improvements, although clinical adoption remains limited. This review summarizes current evidence on the mechanisms, risk factors, diagnostic predictors, repair strategies, and postoperative management of DT and CSF leakage, with specific attention to OPLL-related DO. A more apparent distinction between established clinical practice and emerging investigational technologies is provided to guide evidence-based decision-making. Full article

Background/Objectives: Plasma fibronectin (pFN) supports lung metastasis by promoting tumor cell invasion and survival in the context of blood clotting. Here, we set out to test if myeloid cells reiterate the clot-invasive mechanisms that have been established for tumor cells. Methods: We analyzed lung tissue sections from transgenic pFN-deficient mice for the co-localization of intravenously injected B16F1 tumor cells and the surrounding fibrin with myeloid cells, granulocytes, and macrophages. We also tested the role of pFN for macrophage differentiation and invasion in a three-dimensional fibrin matrix. Results: B16F1 melanoma cells, entrapped in the lungs of pFN-competent C57BL/6-Fn(fl/fl)Mx-Cre⁻ mice, were surrounded by a fibrin matrix, CD11b-positive myeloid cells, and Gr-1-positive granulocytes within 1 h of intravenous injection, while homing F4/80-positive macrophages to lung-born tumor cells occurred within 16 h. Compared to pFN-competent C57BL/6-Fn(fl/fl)Mx-Cre⁻ mice, the co-localization of CD11b⁺, Gr-1⁺, and F4/80⁺ cells with B16F1 cells was significantly reduced in the lungs of pFN-deficient C57BL/6-Fn(fl/fl)Mx-Cre⁻ mice. Mechanistically, we found that fibrin–fibronectin complexes promoted macrophage adhesion, differentiation, and invasion in clotted plasma. The pro-invasive function of fibrin–fibronectin depended on the upregulation of integrin β3 and Tie2 expression in macrophages and was reversed after knocking-down integrin β3 and Tie2 with siRNA. Conclusions: Our results suggest that blood clotting plays an important role in the recruitment of macrophages to circulating tumor cells and that the underlying mechanism of macrophage recruitment involves fibrin–fibronectin complexes, integrin β3, and Tie2. Full article

Platelet-rich plasma (PRP) is an autologous blood-derived concentrate increasingly utilized in regenerative medicine for its ability to accelerate healing and tissue repair. PRP is broadly classified by leukocyte content, fibrin architecture, and platelet concentration, with classification systems developed to standardize characterization. Preparation methods, including single- or double-spin centrifugation and buffy coat techniques, influence the final composition of PRP, determining the relative proportions of platelets, leukocytes, plasma proteins, and extracellular vesicles. These components act synergistically, with platelets releasing growth factors (e.g., VEGF, PDGF, TGF-β) that stimulate angiogenesis and matrix synthesis, leukocytes providing immunomodulation, plasma proteins facilitating scaffolding, and exosomes regulating intercellular signaling. Mechanistically, PRP enhances tissue repair through four key pathways: platelet adhesion molecules promote hemostasis and cell recruitment; immunomodulation reduces pro-inflammatory cytokines and favors M2 macrophage polarization; angiogenesis supports vascular remodeling and nutrient delivery; and serotonin-mediated pathways contribute to analgesia. These processes establish a regenerative microenvironment that supports both structural repair and functional recovery. Clinically, PRP has been applied across multiple specialties. In orthopedics, it promotes tendon, cartilage, and bone healing in conditions such as tendinopathy and osteoarthritis. In dermatology, PRP enhances skin rejuvenation, scar remodeling, and hair restoration. Gynecology has adopted PRP for ovarian rejuvenation, endometrial repair, and vulvovaginal atrophy. In dentistry and oral surgery, PRP accelerates wound closure and osseointegration, while chronic wound care benefits from its angiogenic and anti-inflammatory effects. PRP has also favored gingival recession coverage, regeneration of intrabony periodontal defects, and sinus grafting. Although preparation heterogeneity remains a challenge, PRP offers a versatile, biologically active therapy with expanding clinical utility. Full article

Background: Gingival recession (GR) is defined as the exposure of the root surface due to the gingival margin shifting apically from the cemento-enamel junction. Current effective management of defects related to GR relies on root coverage periodontal plastic surgery (RCPPS), using the Modified Coronally Advanced Flap (mCAF) with an envelope design. Recent literature also reported the association of different biomaterials to the mCAF procedure. In light of these considerations, a systematic review (SR) was conducted to determine and compare the efficacy of all mCAF adjunctive techniques for the treatment of multiple adjacent GR-type (MAGR) defects. Methods: An electronic search was conducted in 2025 on studies published between 2013 and 2025, using PubMed, Scopus, Web of Science, and Cinahl Complete, to address the focused question: “which is the efficacy of different mCAF adjunctive techniques for the treatment of multiple adjacent GR-type defects, in terms of root coverage (RC), esthetic outcomes, and keratinized tissue (KT) augmentation?”. Randomized controlled trials with a minimum follow-up of 6 months with ≥ 5 patients treated for coverage of MAGR were included. Risk of bias was assessed with RoB 2 Tool. A meta-analysis was performed using RevMan5.4 software and the level of evidence of included studies was analyzed with GRADEPro GDT. Results: A total of 17 studies were included in the SR, 9 of which evaluating mCAF + sCTG (subepithelial connective tissue graft) vs. mCAF adjunctive techniques [Collagen Matrix (CM), xenogeneic acellular dermal matrix (XADM), Platelet-Rich Fibrin (PRF), Enamel Matrix Derivatives (EMD), sCTG harvested double blade scalpel] were then included in the meta-analysis. The primary outcomes of complete root coverage (CRC) and keratinized tissue width variation (ΔKTW) were statistically significant ([CRC: Odds Ratio (OR) 1.70; 95% CI (confidence interval) 1.18, 2.44; p = 0.004]; [ΔKTW: SMD (standardized mean difference) 0.37; 95% CI 0.11, 0.63; p = 0.005]) in favor of mCAF + CTG. Meanwhile, no statistically significant difference was observed in terms of RES. The certainty assessment highlighted relevant results: despite the lack of evidence in the long-term, a high level of evidence showed that sCTG was more effective than XADM in terms of CRC (p = 0.002) and ΔKTW (p = 0.0001). A low level of evidence revealed that sCTG achieved a greater ΔKTW compared to CM (p = 0.0006). Although no significant differences were observed, a low level of evidence suggested that mCAF + EMD and mCAF + sCTG (DBS) may provide good results. To date, only one RCT showed long-term stable results of CTG in terms of RC. Conclusions: The association of sCTG to mCAF demonstrated better results in terms of RC and KTW augmentation in short- and medium-term follow-ups. Long-term studies are needed to confirm the efficacy of the other mCAF adjunctive techniques, considering limitations due to heterogeneity in follow-ups, distribution of techniques analyzed, and different study designs. Registration in PROSPERO (International prospective register of systematic reviews) was performed with ID CRD420251085823. Full article

Background and Objective: The aim of this study was to evaluate the effects of enamel matrix protein, platelet-rich fibrin (PRF), and bone graft on new bone formation beyond the skeletal system by creating calvarial bone defects in rats. The effects were assessed using histopathological and immunohistochemical analyses. Materials and Methods: In this study, calvarial bone defects were created in male Sprague Dawley rats weighing 500–550 g. The animals were randomly divided into seven groups: Control (n = 13), Emdogain (EMD, n = 13), Emdogain + Bone Graft (EMD + BG, n = 13), Platelet-Rich Fibrin (PRF, n = 13), PRF + Bone Graft (PRF + BG, n = 13), Bone Graft (BG, n = 13), and PRF + Emdogain + Bone Graft (PRF + EMD + BG, n = 13). An additional group of 36 rats was used for PRF preparation. Titanium domes were placed on the calvarial bone defects, and the animals were sacrificed after three months. Bone samples were evaluated histopathologically for new bone formation, numbers of osteoblasts and osteoclasts, angiogenesis, and fibrosis. Immunohistochemical analysis of bone formation was performed using OPG and RANKL staining kits. Data were analyzed statistically. Results: The PRF group showed a significantly higher level of moderate new bone formation compared with the PRF + BG, EMD + BG, and PRF + EMD + BG groups (p ≤ 0.05). No significant differences were observed among the groups in terms of fibrosis or angiogenesis (p > 0.05). Similarly, OPG and RANKL levels, as well as the OPG/RANKL ratio, did not differ significantly between groups (p > 0.05). Conclusions: Based on the findings of this study, the combined use of Emdogain, PRF, and bone graft appears to have beneficial effects on enhancing bone formation in calvarial defects. Full article

Dynamic compression (DC) bioreactors are widely used to mimic joint loading and study how human mesenchymal stem cells (hMSCs) respond to mechanical cues. However, it remains unclear whether DC alone is sufficient to induce chondrogenesis or how such cues interact during construct maturation. In this study, hMSCs were encapsulated in fibrin hydrogels at different cell densities and subjected to DC without, during, or after TGF-β3-mediated chondrogenic induction. DC alone modestly increased SOX9 expression but failed to upregulate key cartilage matrix genes such as ACAN and COL2A1, indicating that mechanical stimulation alone is insufficient to initiate chondrogenesis. When mechanical stimulation was coupled with TGF-β3, a more mature chondrogenic phenotype was observed for high cell seeding densities (HD). To simulate a post-implantation scenario, we applied DC following growth factor withdrawal and observed marked downregulation of SOX9, ACAN, and COL2A1 in low-density (LD) constructs. This reduction was not observed in HD constructs, which maintained a more stable chondrogenic phenotype under loading. These findings show that construct maturation critically influences mechanoresponsiveness and suggest that immature grafts may not tolerate mechanical stimulation. DC bioreactors may therefore serve not only to support cartilage engineering but also to predict in vivo graft performance. Full article

Background: The growing interest in the field of platelet-rich fibrins has led to the development of novel generations of these concentrates, with one of the newest additions being advanced platelet-rich fibrin plus (A-PRF+). The updated centrifuge protocol utilized for the preparation of A-PRF+ has been shown to provide blood clots with more white blood cells and growth factors trapped in the fibrin matrix, presenting a more homogenous distribution. The objective of this study was to assess the available randomized clinical trials (RCTs), in order to evaluate the effects that the addition of A-PRF+ can have on postoperative quality of life and soft tissue healing after dental surgery. Materials and Methods: To perform a systematic review based on high-quality results, only RCTs were taken into consideration. The search included articles published between 1 January 2014 and 31 December 2024, indexed in the PubMed, Cochrane, Library, Embase, Scopus, and Google Scholar databases. Nine full texts were finally acquired after the screening of articles, from which relevant data were extracted. Results: A-PRF+ positively influenced the postoperative quality of life in patients. The subjective analysis of pain and its management via painkiller intake indicated that, in general, the addition of A-PRF+ into protocols results in less pain, pain that lasts for a shorter time, and pain that is more easily managed through medication, as a lower number of pills was needed to restore comfort. Furthermore, the occurrence of facial swelling and trismus was also reported to be lower in the A-PRF+ groups. As for soft tissue healing, A-PRF+ significantly enhanced the epithelialization process, total wound area reduction, and inflammation in the surrounding tissues. This positive effect was most noticeable at 7- and 14-day follow-ups. The addition of A-PRF+ also had a positive effect on postoperative bleeding by significantly reducing the bleeding time, providing benefits for patients undergoing antiplatelet drug therapy in particular. Conclusions: The addition of A-PRF+ into the surgical protocol can positively enhance the patient’s quality of life, reduce the need for postoperative medication, and improve the patient’s confidence by reducing potential swelling and trismus. A-PRF+ also positively influences soft tissue wound healing, further enhancing the postoperative well-being of patients, and provides an excellent hemostatic effect even in patients that are on antiplatelet drug therapy. Full article

Ischemic stroke is one of the leading causes of morbidity and mortality worldwide, with carotid atherosclerosis being its key etiological factor. MicroRNA-21 (miR-21) regulates intracellular signal pathways responsible for vascular changes and ischemic brain injury, and is recognized as a potential diagnostic and prognostic biomarker. It modifies the activity of macrophages (MΦ) and vascular smooth muscle cells, causing inflammation and affecting the stability of atherosclerotic plaques. A deficiency of miR-21 in macrophages stimulates the inflammatory response and plaque growth. It promotes both the synthesis of extracellular matrix, stabilizing the plaque, and the degradation of the fibrin cap, which leads to plaque instability. The effect of miR-21 on endothelial cells differs: it stimulates both NO· synthesis and inflammation. During ischemic stroke, miR-21 demonstrates neuroprotective effects by modulating post-ischemic inflammation and protecting the integrity of the blood–brain barrier. Therapy targeting miR-21 shows potential in experimental models, but it requires cell-specific delivery and precise timing. Further research efforts should focus on the effects of miR-21 on different cell types, as well as the development of new technologies for diagnostic and therapeutic applications. Full article