Search Results (1,123)

Hyaluronic acid (HA) is a glycosaminoglycan that is found within the body and has both structural and signaling functions in the extracellular matrix. HA is biocompatible and biodegradable; it has a high water content and binds directly to certain cell-surface proteins. Due to these characteristics, it is considered a promising component for the design of biomaterials for regenerative wound healing. This review covers the most recent findings on the use of HA-based biomaterials in soft tissue repair, while also incorporating earlier, foundational studies relevant to the field, focusing on HA’s characteristics, cellular interactions, design, and preclinical and clinical results. The physicochemical characteristics of HA and their influence on cellular responses and tissue regeneration are discussed to show how material properties can be adjusted for specific therapeutic purposes. There have been great advances in chemically modified composite scaffolds and HA matrices, which offer better mechanical stability and controlled degradation. At the same time, new delivery systems have been built using HA, from nanoparticles to gene delivery platforms and growth factors, and these have given the material an active role as a therapeutic agent rather than just a passive one. This narrative review covers the clinical evidence for the effectiveness of commercial products for acute and diabetic wounds, as well as burns and chronic wounds, and discusses where their use is indicated. In the end, the current limitations of the research and future applications and directions are discussed. Full article

Background: Ligamentum flavum hypertrophy (LFH) is a major structural contributor to lumbar spinal stenosis and is characterized by extracellular matrix (ECM) remodeling with an increasingly recognized immune-associated component. However, the regulatory architecture linking disease-associated microRNA (miRNA) dysregulation to LFH transcriptomic remodeling remains incompletely defined. Methods: Public Gene Expression Omnibus datasets were analyzed using an integrated mRNA–miRNA transcriptomic framework. Single-cell RNA sequencing (GSE294458) was used to characterize the cellular landscape of hypertrophic and non-hypertrophic ligamentum flavum, whereas bulk transcriptomic analysis (GSE113212) identified LFH-associated differentially expressed genes. Differentially expressed miRNAs from an ossified ligamentum flavum dataset (GSE106256) were integrated with LFH-associated mRNA profiles through inverse miRNA–mRNA regulatory filtering. Functional enrichment, STRING protein–protein interaction (PPI) analysis, cytoHubba hub gene prioritization, LASSO regression, ROC analysis, remodeling-signature scoring, DGIdb, ChEA, and database-supported miRNA–target annotation were subsequently performed. Results: Single-cell analysis supported fibroblast-, myofibroblast-, and ECM-associated remodeling in hypertrophic ligamentum flavum. Bulk analysis identified nine significant differentially expressed genes, and integration with 33 dysregulated miRNAs generated 651 inverse-regulated core genes. Enrichment analyses highlighted ECM organization, proteoglycan/glycosaminoglycan (GAG) biology, immune cell differentiation, antigen presentation, and NF-κB/Wnt-related pathways. The STRING network included 650 nodes and 547 edges, with significant PPI enrichment (p = 2.04 × 10⁻¹⁴). LASSO prioritized PABPC1 and RPL4 as exploratory candidate hub features showing apparent discovery-cohort discrimination (AUC = 1.00); supplementary uncertainty, internal-stability, and separation-aware sensitivity analyses supported interpretation of this finding as a discovery-cohort signal rather than as independent diagnostic validation. Remodeling-signature analyses showed increased ECM fibrosis and proteoglycan/GAG scores, with inverse associations involving PABPC1 and RPL4. Multi-layer prioritization identified hsa-miR-708-5p as the leading candidate, followed by hsa-miR-23b-3p, hsa-miR-191-5p, hsa-miR-181a-5p, and hsa-miR-653-5p. Conclusions: This integrated mRNA–miRNA transcriptomic analysis delineated a coordinated fibrotic–immune remodeling landscape in LFH and prioritized experimentally testable miRNA candidates linked to network-central regulatory pathways. Full article

Background: Bone metastasis is a frequent and debilitating complication of advanced cancer, particularly in breast and prostate cancer, and is driven by complex interactions among tumor cells, bone-resident cells, immune populations, vascular components, and the extracellular matrix. Within this specialized microenvironment, proteoglycans have emerged as key molecular regulators of tumor–bone crosstalk, matrix remodeling, metastatic niche formation, dormancy, and therapeutic resistance. Methods: We conducted a narrative review using targeted searches of PubMed and Google Scholar for studies published through 31 May 2026. Search terms included combinations of proteoglycan- and glycosaminoglycan-related concepts, including “proteoglycans,” “glycosaminoglycans,” “heparan sulfate proteoglycans,” “hyaluronan,” “heparanase,” “syndecans,” “glypicans,” “perlecan/HSPG2,” “versican,” and “decorin,” with disease- and process-related terms such as “bone metastasis,” “extracellular matrix,” “tumor–bone crosstalk,” “breast cancer,” “prostate cancer,” “metastatic niche,” “osteolytic metastasis,” “osteoblastic metastasis,” “dormancy,” “reactivation,” “immune regulation,” and “therapy resistance.” Original studies, reviews, and translational reports were selected according to their relevance to cell-surface, pericellular, and extracellular proteoglycans in bone metastatic progression. Results: Proteoglycans and associated GAG/ECM axes are implicated in multiple processes involved in skeletal metastasis, including growth factor availability, extracellular matrix organization, osteolytic and osteoblastic niche formation, angiogenesis, immune evasion, metastatic dormancy, reactivation, and therapy resistance. These functions are highly context-dependent and are influenced by proteoglycan localization, core protein structure, glycosaminoglycan composition, sulfation patterns, proteolytic processing, and cellular source. Conclusions: Proteoglycans represent critical molecular nodes in the bone metastatic microenvironment and hold potential as biomarkers, therapeutic targets, and tools for stratifying metastatic niche heterogeneity. Their clinical translation will require validation in human bone metastasis samples, improved models that reproduce the mineralized and immune-rich bone niche, and a clearer distinction between causal mechanisms and correlative associations. Future studies should integrate matrisome profiling, spatial proteomics, single-cell and spatial transcriptomics, glycosaminoglycan omics, degradomics, and three-dimensional bone niche models to define actionable proteoglycan-dependent mechanisms and improve therapeutic targeting of metastatic bone disease. Full article

The escalating prevalence of bacterial infections has intensified the search for innovative antimicrobial strategies, particularly for infected wound management. Chondroitin sulfate (CS), a naturally occurring glycosaminoglycan with established biocompatibility, presents an attractive scaffold for developing metal ion-functionalized biomaterials. This study reports the fabrication of chondroitin sulfate–copper complex (CSCu) and chondroitin sulfate–zinc complex (CSZn) through an ion exchange method, wherein Cu²⁺ and Zn²⁺ ions bind to the groups of carboxylate, sulfate, or N-acetyl from the CS backbone. The resulting complexes exhibited copper or zinc loading capacities of about 6.6% and demonstrated potent antibacterial activity against E. coli and S. aureus. The integration of CSCu or CSZn with sodium alginate yielded a hydrogel system with a higher apparent viscosity, possessing injectability and spreadability on the skin surface and a porous three-dimensional internal structure conducive to wound healing applications. In a murine model of S. aureus-infected full-thickness wounds, topical application of CSCu and CSZn hydrogels substantially accelerated wound closure, achieving 97.46% and 98.11% healing, respectively, by day 10. Additionally, treatment with CSCu or CSZn hydrogels significantly attenuated systemic inflammatory responses, as reflected in lowered serum TNF-α, IL-1β, and IL-6 alongside increased IL-10. Histological evaluation confirmed enhanced re-epithelialization and stratum spinosum formation in treated wounds. These findings establish CSCu and CSZn as a promising bioactive agent for addressing bacterial wound infections through a dual mechanism of direct antibacterial action and immunomodulatory effects, offering a valuable alternative to conventional antibiotic therapies. Full article

Background: Rheumatoid arthritis (RA) is influenced by environmental exposures. High humidity has been clinically associated with worsened joint symptoms, but the microbial and metabolic mechanisms remain unclear. We investigated whether a gut microbiota–metabolism axis contributes to humidity-associated aggravation of collagen-induced arthritis (CIA). Methods: CIA mice were maintained under normal or high relative humidity. We integrated 16S rRNA and metagenomic sequencing, liquid chromatography–tandem mass spectrometry metabolomics, and intestinal barrier assessments. Fecal microbiota transplantation (FMT) was performed to evaluate microbiota dependency. Based on multi-omics findings, we quantified chondroitin sulfate (CS) and conducted functional experiments involving Prevotella stercorea (P. stercorea) supplementation, CS administration, and in vitro degradation assays. Results: High humidity aggravated arthritis severity and systemic inflammation, including increased interleukin-6, interleukin-17A, and granulocyte colony-stimulating factor, and was accompanied by impaired intestinal barrier integrity. FMT supported a microbiota-dependent contribution. Metagenomic analysis identified enrichment of P. stercorea and glycosaminoglycan degradation pathways under high humidity. CS abundance was reduced in articular cartilage, P. stercorea degraded CS in vitro and was associated with cartilage CS loss in vivo, and CS supplementation attenuated arthritis under high humidity and reduced the arthritis-promoting effects associated with P. stercorea. Conclusions: High humidity is associated with microbiota-dependent functional remodeling, enhanced CS degradation, and aggravated arthritis in CIA mice. These findings suggest that humidity-associated alterations in microbial CS metabolism may link environmental exposure to cartilage disruption and joint inflammation. Full article

Heparin, the naturally occurring, highly sulfated glycosaminoglycan drug, acts as a regulator of diverse biological processes by interacting with diverse specific proteins through a variety of sulfated structural motifs with varying degrees of affinity. Despite its rarity, 3-O-sulfation of glucosamine plays a key role in several biological activities, especially anticoagulant activity mediated by interaction with antithrombin (AT), a mechanism that has been extensively studied. The present work primarily focuses on sequences containing 3-O-sulfated glucosamine that are not involved in anticoagulant activity, analysing their relative abundance and structural environments in heparins derived from distinct animal origins. Three heparin samples derived from bovine, ovine and porcine intestinal mucosa (BMH, OMH and PMH) were fractionated by affinity chromatography on AT-Sepharose into no affinity (NA) and high affinity (HA) fractions. Parent heparins and derived NA and HA fractions were enzymatically depolymerised using either a cocktail of heparinases I, II and III or heparinase II alone, and the resulting mixtures of di- and oligosaccharides were analysed by liquid chromatography coupled with mass spectrometry. Digestion with heparinase II, which preserves heparin sequences containing 3-O-sulfated glucosamine, produced a series of 3-O-sulfated trisaccharides containing two glucosamine residues either side of a uronic acid, located at the non-reducing end (NRE) of heparin chains. Treatment with a heparinase cocktail, which cleaves these trisaccharides, released NRE glucosamine monosaccharides, including 3-O-sulfated species. Notably, both the number of NRE trisaccharide species and the overall proportion of 3-O-sulfated monosaccharides were markedly higher in OMH compared to BMH or PMH. Using ¹H/¹³C bi-dimensional nuclear magnetic resonance spectroscopy, the higher proportion of NRE 3-O-sulfated glucosamine in ovine heparin relative to bovine and porcine heparins was found to be preferentially located in chains lacking affinity for AT. These results offer new insights into the localisation of most 3-O-sulfated heparin sequences that are not associated with anticoagulant activity and, importantly, also reveal a possible structural marker that indicates the ovine origin of heparin. Additionally, a tetrasaccharide species was detected that may be indicative of a highly sulfated AT-binding site in BMH. Full article

Chronic wounds are associated with long-standing inflammation, impaired angiogenesis, oxidative stress, microbial load and defective remodelling of the extracellular matrix, impairing tissue repair. Conventional dressings offer protection and moisture regulation but do not sufficiently address the biological failures. Electrospun nanofibrous wound dressings offer a more active regenerative platform due to their architecture, which resembles the extracellular matrix, allowing cell adhesion and migration and facilitating the localised delivery of therapeutic agents. Marine-derived polysaccharides, such as alginate, chitosan, carrageenan, fucoidan, glycosaminoglycans, and ulvan, are particularly attractive in this area due to their biocompatibility, biodegradability, sustainability, and intrinsic haemostatic, antimicrobial, anti-inflammatory, antioxidant, and immunomodulatory properties. This review critically discusses the mechanistic and translational relevance of marine polysaccharide-based nanofibres in wound healing with a focus on inflammation resolution, polarisation of macrophages, responses of keratinocytes and fibroblasts, angiogenesis, collagen deposition, redox balance and matrix remodelling. Biofabrication strategies, especially electrospinning and related nanofibre-forming strategies, are reviewed from the aspects of scaffold architecture, drug-loading capacity, controlled release, and wound microenvironment modulation. The review also discusses current shortcomings such as heterogeneity in the composition of marine polymers, mechanical fragility, sterilisation and storage issues, scalability, regulatory uncertainty and limited translation from preclinical models to clinical evidence. Overall, marine-derived polysaccharide nanofibers are a promising class of multifunctional wound dressings, but their clinical translation needs stronger standardisation, comparative in vivo evidence, safety validation and manufacturable designs. Full article

Micro-fragmented adipose tissue (mFAT) is a promising autologous biologic in regenerative medicine because it provides a mechanically processed adipose-derived product that preserves native extracellular matrix architecture and a cellular milieu rich in mesenchymal stem cells, pericytes, growth factors, cytokines, and extracellular vesicles. Mechanistically, mFAT is hypothesized to act largely through paracrine signaling that dampens inflammation, supports vascular stabilization, and promotes cartilage and soft-tissue repair; in vitro data suggest modulation of osteoarthritic synovial macrophage signaling, including reductions in chemokines such as CCL2 and CCL3. Preparation involves liposuction harvest followed by closed, sterile mechanical processing without enzymatic digestion or cell expansion, aligning with “minimal manipulation” concepts relevant to regulatory frameworks. Preclinical animal studies generally demonstrate favorable effects on synovial inflammation and cartilage matrix markers (e.g., glycosaminoglycan content) with limited adverse events. Clinically, the strongest body of evidence is in knee osteoarthritis, where multiple prospective and retrospective studies report improvements in pain and function from months to several years after single injections, though response rates vary and study designs are heterogeneous. Evolving data support potential benefit in hip osteoarthritis and select tendon conditions, but cohorts remain small. Overall, mFAT appears safe and potentially effective, yet larger, standardized, long-term randomized controlled trials and comparative studies versus platelet-rich plasma and bone marrow aspirate concentrates are needed to clarify indications, dosing, durability, and mechanisms in vivo. Full article

Proteoglycans (PGs) and their glycosaminoglycan (GAG) chains play key roles in corneal epithelial physiology and host–microbe interactions. Although bacterial exposure has been shown to alter PG and GAG biosynthesis, the contribution of specific bacterial-derived signals remains unclear. In this study, reconstructed human corneal epithelia (QobuR) were exposed to bacterial extracellular vesicles (BEVs) from Pseudomonas aeruginosa and Staphylococcus epidermidis, as well as to lipopolysaccharide, peptidoglycan, and lipoteichoic acid. The expression of 72 genes involved in PG and GAG biosynthesis and remodeling was analyzed by quantitative real-time PCR. Only 22 genes showed significant transcriptional alterations, indicating a highly selective response. Most changes affected enzymes involved in the generation of heparan sulfate (HS) and chondroitin sulfate (CS) fine structure, particularly sulfotransferases. Notably, HS3ST4 and HS3ST5 were consistently upregulated under all experimental conditions, suggesting that modulation of HS 3-O-sulfation represents a conserved corneal epithelial response to bacterial-derived stimuli. Whereas microbial-associated molecular patterns induced broader transcriptional responses, BEVs elicited more restricted and species-dependent effects. Overall, these findings demonstrate that bacterial-derived signals selectively remodel GAG biosynthetic pathways and provide new insights into the molecular mechanisms underlying host–microbe interactions at the ocular surface. Full article

Equine osteoarthritis (OA) is a major cause of lameness and economic loss in horses. While platelet-rich plasma (PRP) has clinical potential, the biological effects of fresh PRP (F-PRP) and freeze-dried PRP (FD-PRP) remain insufficiently defined. This pilot study compared 25% and 50% F-PRP and FD-PRP in an interleukin-1β-induced equine cartilage-synovium explant co-culture model. PRP treatments reduced inflammatory responses, with significant downregulation of COX-2 and PGE2 expression, and 25% F-PRP showed the most consistent inhibition of nitric oxide production. PRP also significantly reduced glycosaminoglycan release and altered matrix-related gene expression; however, FD-PRP significantly upregulated MMP13, indicating a potential pro-catabolic response. Untargeted LC/MS metabolomics showed that F-PRP and FD-PRP were associated with changes in glucose, purine, amino acid, lipid, and nucleotide metabolism. Growth factor analysis further showed lower PDGF and TGF-β1 concentrations in FD-PRP than in F-PRP. Overall, F-PRP showed more consistent anti-inflammatory and matrix-protective effects, whereas FD-PRP requires further optimization and safety validation before clinical application. Full article

Glycosaminoglycans (GAGs) are the carbohydrate portion of proteoglycans (PGS), a family of complex biomacromolecules ubiquitously found in the extracellular matrix and on cell surfaces that play critical roles in a plethora of physiological and pathological processes. In the present work, chondroitin sulfate (CS) and dermatan sulfate (DS) were extracted and purified from the head (GCB) and skin (GDB) of blue runner fish (Caranx crysos) to explore their structural features and biological properties. GCB and GDB were purified by ion-exchange chromatography with yields of 0.82% and 0.61%, respectively. Chemical and structural analysis showed that GCB and GDD demonstrated quite similar sulfation degrees (4.45% and 4.24%, respectively). The molecular weight values obtained for GCB and GDB as estimated by high-performance size exclusion chromatography coupled with a triple detector array (HP-SEC-TDA) were 48.9 and 28.54 KDa, respectively. Structural features were elucidated using FT-IR and 2D NMR spectroscopy. GCB was mainly identified as chondroitin sulfate, containing 82% GlcA and minor proportions of IdoA and IdoA2S (scoring 18% dermatan-like structures). In contrast, GDB was predominantly dermatan sulfate, with a higher unsulfated IdoA content (54%) and a lower GlcA percentage (17%). In vitro anticoagulant activity, evaluated using APTT and PT assays, demonstrated that both GAGs exhibit significant anticoagulant potential. In addition, both fractions exhibited no antiplatelet activity, suggesting that the isolated glycosaminoglycans selectively target the coagulation cascade without affecting platelet aggregation. Furthermore, hemolytic assays confirmed that neither GCB nor GDB showed any hemolytic activity at the tested concentrations. Cytotoxicity assessment in HEK293 and HUVEK cell lines further confirmed the absence of detectable toxicity even at high concentration. Overall, these marine-derived GAGs present promising therapeutic potential as a source of anticoagulant drugs. Full article

The vascular endothelial glycocalyx (EGX) is a gel-like, negatively charged mesh of membrane-bound proteoglycans, glycosaminoglycans, glycoproteins and adsorbed plasma proteins that covers the luminal surface of the endothelium and orchestrates vascular homeostasis through regulation of permeability, leukocyte trafficking, mechanotransduction and anti-thrombotic signalling. Progressive thinning, heterogeneous remodelling and accelerated shedding of the EGX are now recognised as hallmarks of vascular ageing and early drivers of age-related cardiovascular disease. Here, we synthesise current evidence linking EGX integrity to biological ageing, with emphasis on age-dependent remodelling of heparan-sulfate proteoglycans, endothelial progenitor-cell dysfunction, and the heightened susceptibility of the aged EGX to oxidative, inflammatory and infectious insults. We discuss signalling pathways driving EGX shedding—including the IQGAP1/PAR1-2/PI3K/Akt axis—and clinical correlates such as vulnerable coronary plaque in older patients with coronary artery disease and microvascular endotheliopathy in severe COVID-19. Finally, we review emerging anti-ageing strategies targeting the EGX, including direct oral anticoagulants, glycocalyx-mimetic and nitric-oxide-releasing biomaterials, bioinspired antithrombogenic surfaces and microbiome-based modulation, and consider their translational potential for extending cardiovascular healthspan. Full article

Mucopolysaccharidoses (MPS) are severe, inherited metabolic diseases, classified among lysosomal storage diseases (LSDs). The presence of pathological variants of genes coding for enzymes involved in the degradation of glycosaminoglycans (GAGs) is a primary cause of each MPS type, and accumulation of these compounds is a characteristic feature of MPS. Depending on the kind of defective enzyme and the type of stored GAG(s), 12 classical types are distinguished, and a few other related diseases, whose classification is unclear. Although there is no fully effective cure for MPS, several kinds of therapeutic approaches have been proposed to treat these diseases, and some of them have been introduced into clinical practice. In this review article, we present and discuss very recent advances in developing various therapies for MPS, also indicating problems and limitations. This paper focuses on enzyme replacement therapy (ERT), cell- and gene-based therapies (including hematopoietic stem cell transplantation and gene therapy), inhibition of GAG synthesis, and some other newly developed therapeutic approaches. Perspectives on MPS therapies are also discussed. Full article

Polysaccharide–peptide conjugates are modular biomaterials that combine hydrated carbohydrate frameworks with peptide domains capable of mediating molecular recognition, degradability, antimicrobial activity, and biological signaling. In this review, we discuss how covalent, bioorthogonal, and enzymatic conjugation strategies regulate peptide density, orientation, accessibility, and stability within polysaccharide-based matrices. These chemical choices are analyzed in relation to network architecture, viscoelasticity, ligand presentation, degradation behavior, and cell–material interactions. Representative systems based on hyaluronic acid, alginate, chitosan, dextran, cellulose, and glycosaminoglycans are examined to illustrate how peptide functionalization can transform otherwise passive scaffolds into adhesive, degradable, antimicrobial, or therapeutically responsive platforms. We further highlight dynamic and enzyme-responsive materials, localized drug delivery systems, antimicrobial coatings, and antibiofilm interfaces as key biomedical applications of these conjugates. The review also addresses translational challenges associated with structural heterogeneity, stability, immunogenicity, sterilization, batch-to-batch reproducibility, and clinical feasibility. Taken together, the evidence discussed here indicates that the performance of polysaccharide–peptide conjugates depends on reproducible structure–function relationships linking conjugation chemistry, macromolecular architecture, and biological activity under application-relevant conditions. Full article

Glycolic acid is the most widely used alpha-hydroxy acid (AHA), largely because of its small molecular size (76 Da), which allows more efficient skin penetration than larger AHAs such as lactic acid (90 Da) or mandelic acid (152 Da). Its efficacy depends on concentration and formulation pH relative to its pKa (~3.8), which determines the amount of free acid available for skin interaction. At pH 3.8, approximately 50% of glycolic acid is present as free acid; at pH 4.5, this fraction falls to approximately 18%. In an 8% formulation, about 4% is free acid at pH 3.8, compared with about 1.4% at pH 4.5. This review examines how formulation design influences the penetration, irritation, and therapeutic outcomes of glycolic acid in professional peels and daily use products. Low-pH, high-concentration professional peels (20–70%, pH approximately 1.0–2.5) promote rapid penetration, calcium chelation-mediated corneodesmosome disruption, and controlled exfoliation, but they also increase irritation and transient transepidermal water loss (TEWL). In contrast, buffered daily use formulations (5–15%, pH 3.5–4.5) provide gradual exfoliation, improved tolerability, and longer-term benefits in skin texture, pigmentation, collagen, and glycosaminoglycan synthesis. Overall, the safety and efficacy of glycolic acid are highly formulation-dependent, so different design strategies are needed for daily products and professional peels. Full article