Functionalized graphene oxide triggers the neurogenic potential on neuroblastoma cell line (SH-SY5Y) and human amniotic fluid stem cells (hAFSCs).

Lactobacillus gasseri-derived postbiotics promote osteogenic differentiation in BMSCs via ameliorating mitochondrial oxidative stress.

Development and evaluation of a 3D-engineered neural co-culture system: Impacts on oxidative stress, pentose phosphate pathway, trace element and mineral metabolisms.

Injectable hydrogels utilizing gelatin methacrylate and oxidized sodium alginate-curcumin conjugate for treating diseased bone defects

Background and Objectives: Corneal opacity is the fifth global cause of blindness and moderate-to-severe visual impairment due to scar tissue formation. The purpose of this study is to provide an integrated overview of the current state of corneal engineering strategies focused on the comparison with healthy corneas. It aims to identify engineering strategies that would result in functional corneas, providing real alternatives to donor corneal transplants. Materials and Methods: systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and according to the protocol with the ID: CRD420250654641 at the PROSPERO database. The focus question, prompted by considering the shortage of human corneal grafts, was: what is the performance of bioengineered corneal grafts in experimental animal models when compared with healthy eyes in the restoration of corneal anatomy and function? Results: Incorporating human corneal epithelial cells w/ or w/o human corneal stromal stem cells into a gelatin methacrylate and polyethylene glycol diacrylate matrix emerges as the leading option for epithelial layer regeneration. Human and bovine decellularized corneas, porcine corneal ECM in Gelatin methacrylate, dual layered collagen vitrigel and tissue-engineered human anterior hemi-corneas have shown promise for simultaneous regeneration of the corneal stromal and epithelial layers. Corneal stromal tissue regeneration could be positively impacted by transplantation with grafts derived from aligned self-lifting analogous tissue equivalents and collagen-based hydrogels. Finally, scaffolds of silk fibroin and human purified type I collagen represent promising approaches for corneal endothelial regeneration, though their effectiveness is contingent upon integration with endothelial cells. Conclusions: Collectively, these findings contribute to the growing body of evidence supporting the potential of tissue-engineered corneal substitutes as viable therapeutic options for corneal blindness and vision impairment. Assessing the optical and functional properties of the regenerated cornea should be a cornerstone in all studies aiming to evaluate their clinical effectiveness.

This study focuses on the design, production and testing of a micropatterned PDMS surface, featuring micropillars and microchannels to study the regeneration of individual axons of PC12 nerve cells after injury. Micropillar organization on the surface was designed to restrict the PC12 cell bodies while axons were guided into microchannels, allowing observation of individual axons. Surfaces were coated with poly(L-lysine) to improve cell attachment and proliferation. Netrin-1, a chemoattractant molecule and axonal elongation enhancer, was introduced in a gelatin methacrylate (GelMA) hydrogel carrier at the opposite end of the channels. Schwann cells (SC) were co-cultured with PC12 cells to enhance axon extension. MTT and Live-Dead assays showed 90% viability of the PC12 and Schwann cells on surfaces. The average PC12 axon length in the channels was 51 ± 19 μm; which increased to 75 ± 16 μm and 177 ± 31 μm upon co-culture with Schwann cells and Netrin-1 incorporation along with co-culturing, respectively, showing their synergistic effect on axon elongation. To study axon damage and regeneration processes, PC12 axons extended into the microchannels were cut using a microtome blade. An increase in the expression of injury markers ATF3, GFAP and S100β was observed after the injury with confocal microscopy, and their decrease from days 14 to 21 indicated the initiation of axon regeneration. The platform consisting of patterned PDMS surface, Schwann cells and Netrin-1 holds potential as a valuable tool for nerve damage and repair studies, and for in vitro testing of novel nerve tissue engineering strategies.

Recreating physiologically relevant spinal cord models in vitro requires not only appropriate cell types but also structural and topographical cues that mimic native tissue. While 2D cultures fail to reproduce the spatial complexity of the central nervous system, 3D bioprinting strategies enable more realistic neural microenvironments. We aim to develop a 3D spinal cord model by combining murine cell lines or human stem cell–derived neural progenitors with a multi-material scaffold system. Murine neuronal/astrocytic (NE-4C) and motor neuron-like (NSC-34) cells were embedded in gelatin methacrylate (GelMA) hydrogels and layered on aligned polycaprolactone (PCL) microfibers produced by Melt Electrowriting via extrusion-based bioprinting. The matrix supported long-term viability, proliferation, and differentiation: neuronal (MAP2, βIII-tubulin) and glial (GFAP) markers increased progressively over 14-21-28 days in vitro (DIV), confirmed by immunofluorescence and western blot, and spontaneous network activity was detected through calcium imaging. In parallel, human neural progenitor cells (NPCs) derived from induced pluripotent stem cells (iPSCs) were successfully differentiated and later cultured within a composite hydrogel composed of GelMA and Geltrex for 7, 10, and 14 DIV. The NPCs expressed SOX2 and nestin, confirming their neural progenitor identity, and exhibited a characteristic rosette- like morphological organization, indicative of early neuroepithelial architecture. Over time, they showed high viability and progressive neuronal maturation, with MAP2, βIIItubulin, and synapsin expression suggesting neuronal interconnection and emerging network formation. This preliminary 3D system might represent a versatile and biomimetic platform for modeling spinal cord structure and function, with translational potential for studies on spinal cord injury, neurodegeneration, and physiologically relevant drug screening. The work was supported by Fondazione CRT and the European Union – Next Generation EU within the PRIN 2022 program (D.D. 104 – 02/02/2022, Ministero dell’Università e della Ricerca).

Soft tissue management is essential in periodontal, orthodontic, and implant therapies, yet autologous grafts remain limited by donor-site morbidity, inconsistent tissue quality, and restricted availability. To address these challenges, we developed an active gingival hydrogel (AGH) composed of gelatin methacrylate (GelMA), chondroitin sulfate methacrylate (ChsMA), and gingival fibroblasts, which was fabricated into cell-laden hydrogels using extrusion-based 3D bioprinting. The AGH exhibited excellent rheological performance, print fidelity, and interconnected porous microstructures that supported nutrient diffusion and cell migration. Gingival fibroblasts cocultured with AGH showed robust adhesion, proliferation, and collagen matrix deposition, accompanied by significant upregulation of fibronectin (FN) and type I collagen (COL1). Mechanistic studies revealed that these effects were mediated through activation of the Wnt/β-catenin and TGF-β/Smad signaling pathways, which synergistically regulate extracellular matrix remodeling and epithelial keratinization. In vivo experiments demonstrated that AGH implantation significantly enhanced gingival thickness, collagen density, and neovascularization while reducing inflammatory infiltration, as verified by MRI, histological, and immunohistochemical analyses. Furthermore, co-culture with gingival epithelial cells promoted upregulation of KRT10 and KRT14, indicating improved epithelial differentiation. Collectively, this study establishes a 3D bioprinted active gingival hydrogel as a biomimetic and functional substitute for autologous grafts, offering a promising strategy for periodontal and peri-implant soft tissue regeneration.

Diabetic wound healing is critically impaired by dysregulated macrophage polarization, compromised endothelial angiogenic function, and diminished fibroblast proliferation/migration under persistent hyperglycemia. Current therapies, predominantly focused on single-cell targeting, lack coordinated modulation across these key cellular components. We developed a novel triple-targeting core-shell nanoparticle (miR-RPC) leveraging the shared integrin αvβ3 receptor on macrophages, endothelial cells, and fibroblasts to address this limitation. miR-RPC features an RGD/phosphatidylserine (PS)-modified lipid shell encapsulating a chitosan/​​miR-146a-5p​​ core. This miRNA was selected as a model RNA because of its widely recognized beneficial role in three key cell types in wound healing. The RGD peptide enables specific αvβ3-mediated triple-targeting. The anionic lipid PS facilitates core-shell assembly via electrostatic interaction with the cationic chitosan/RNA core and mimics apoptotic signals to enhance macrophage phagocytosis and phenotypic transition. miR-RPC effectively reprogrammed macrophages towards the M2 phenotype, restored endothelial angiogenic capacity under high glucose, and stimulated fibroblast proliferation, migration, and collagen secretion. Incorporated into a gelatin methacrylate (GelMA)/oxidized hyaluronic acid (OHA) double cross-linked hydrogel (GelO), miR-RPC@GelO significantly accelerated diabetic wound healing in rat models, demonstrating reduced inflammation, increased vascular density, and enhanced collagen deposition. This innovative triple-targeting system achieves coordinated diabetic wound repair through synergistic “immunomodulation-angiogenesis-collagen deposition” mechanisms, offering a promising therapeutic approach. Furthermore, the successful preparation of miR-RPC expands the application of anionic lipids in RNA delivery systems and highlights its potential as a versatile gene delivery vector.Graphical Supplementary InformationThe online version contains supplementary material available at 10.1186/s12951-025-03786-0.

The initiation of bone repair inherently involves inflammation, a key regulator of the healing cascade. However, uncontrolled or excessive inflammation can hinder the natural bone repair process. By modulating the immune response, focusing particularly on macrophage recruitment and polarization, the injury microenvironment can be transformed by facilitating conditions more conducive to rapid bone regeneration. Thus, we developed a composite scaffold comprising biocompatible gelatin methacrylate incorporated with lipopolysaccharide (LPS) and an oligomeric proanthocyanidin (OPC)-loaded polylactic acid scaffold. This novel design leverages the release of LPS from gelatin, rapidly attracting macrophages and transforming them into the M1 phenotype. Subsequently, OPC facilitates the polarization of macrophages from the M1 to the M2 phenotype, leading to the release of anti-inflammatory factors that promote the proliferation and differentiation of bone marrow mesenchymal stem cells. Furthermore, the strong antioxidant properties of OPC effectively mitigate the generation of reactive oxygen species at the injury site, facilitating an environment more conducive to healing. In vivo experiments showed significantly increased expression of osteogenic factors 8 weeks after scaffold implantation, promoting neovascularization and bone regeneration via immune regulation. These findings highlight the substantial potential of leveraging macrophage recruitment and immune modulation as an innovative therapeutic strategy for bone defect repair.

Abstract Incontinence‐associated dermatitis (IAD) leads to persistent tissue damage, antibiotic‐resistant infections, and neurogenic inflammation, greatly impairing patients' quality of life. Current therapies fail to simultaneously eliminate resistant bacterial biofilms, neutralize alkaline conditions, and break the cycle of ammonia (NH 3 ) regeneration. Here, a piezoelectric gas therapy strategy based on platinum‐decorated bismuth molybdate load in gelatin methacrylate (GelMA) hydrogel (Pt@BMO‐Gel) is introduced. Under ultrasound excitation, Pt@BMO generates high piezoelectric potential to improve charge separation, selectively adsorbs NH 3 on BMO (001) crystal facets, efficiently degrades NH 3 to normalize pH, and enables sustained release of H 2 and NO for dual antibacterial and anti‐inflammatory effects. Mechanistic insights from theoretical calculations show that the Pt (111) and BMO (001) surfaces lower energy barriers for H 2 formation and N─H bond cleavage, conducive to the generation of NO and H 2 . Transcriptomic profiling reveals downregulation of key nitrogen metabolism genes (arcC/hutH) in methicillin‐resistant Staphylococcus aureus (MRSA) and disruption of the (p)ppGpp‐mediated stringent response, effectively eradicating bacterial persistence via metabolic reprogramming. This study establishes Pt@BMO as an efficient piezoelectric catalyst for wound therapy, presenting a novel approach in medicine that transforms harmful NH 3 into therapeutic H 2 and NO, offering a promising treatment paradigm for infected wounds, such as incontinence‐associated dermatitis.

Customizable glucose-responsive gelatin methacryloyl-based hydrogel microneedle patches for antibacterial therapy and promoted diabetic wound healing.

Mesenchymal stem cell-laden double-network hydrogel nerve guidance conduits for peripheral nerve injury repair.

Zwitterionic hydrogels as antibiofouling, adhesive coatings: Effects of gelatin methacrylate crosslinking on physicochemical, mechanical, and adhesive properties

Background: Chronic wounds, especially in diabetic patients, pose a significant clinical challenge due to current treatment limitations and an increasingly affected population. A major issue is the stalled inflammatory phase, which prevents proper healing. This study developed a novel co-delivery system to address the deficiency of growth factors and persistent inflammation in chronic wounds. Methods: Gelatin nanoparticles (NPs) were synthesized to carry curcumin, an anti-inflammatory compound. These curcumin-loaded NPs (NP/Curc) were then incorporated into gelatin methacrylate (GelMA) hydrogels to form a hierarchical delivery construct, nanoparticles encased within a hydrogel. These hydrogels were then cryogenically milled into microparticles (MPs) to carry human mesenchymal stem cells (hMSCs). The viability and growth of hMSCs on the surface of curcumin-loaded MPs were evaluated. The release of curcumin from various MP configurations was analyzed. The anti-inflammatory effects of the MPs were assessed by measuring pro-inflammatory cytokine expression in human monocyte THP-1 cells. Results: Curcumin directly loaded into hydrogels showed a rapid burst release within three days. In contrast, NP/Curc had a more sustained release profile. Curcumin incorporation did not adversely affect the cell-carrier functions of MPs. Conditioned media from hMSCs cultured on the plain MPs demonstrated anti-inflammatory effects in THP-1 cells. Low doses of curcumin released from the MPs also showed anti-inflammatory activity. The combination of hMSCs and curcumin exhibited an additive effect in reducing IL-8 expression by 4× in THP-1 cells. Conclusions: This study demonstrates the feasibility of co-delivering cells and curcumin without compromising the cell viability of hMSCs. Using gelatin nanoparticles as a carrier prolongs curcumin release, offering a sustained therapeutic effect. This strategy of hierarchical delivery of curcumin and co-delivery of cells represents a promising approach for treating chronic wounds by simultaneously providing growth factors and reducing inflammation.

Skin-inspired phototherapeutic cryogel ameliorates infected wound healing by orchestrating mechanotransduction and immunomodulation

BackgroundHepatocellular carcinoma (HCC) is associated with one of the highest cancer-related mortality rates worldwide and remains therapeutically challenging. There is an urgent need for innovative treatment strategies. Although Newcastle disease virus (NDV) has demonstrated potent oncolytic activity in vitro and in animal models, free virions administered intravenously are rapidly neutralized by pre-existing antibodies and exhibit poor tumor tropism, significantly limiting their clinical translation (Shalhout et al., Nat Rev Clin Oncol 20(3):160-177, 2023).ObjectivesThis study aimed to develop porous gelatin methacrylate (GelMA) microneedles (MNs) for encapsulating Newcastle disease virus (NDV) and to evaluate their antitumor efficacy against HCC.MethodsGelMA microneedles were fabricated and screened across a concentration gradient for biocompatibility and degradability. The optimal NDV-loaded formulation was subsequently evaluated for safety and therapeutic efficacy in HCC models using in vitro assays and a subcutaneous HCC xenograft model in nude mice.ResultsMicroneedles prepared with 10% (w/v) GelMA exhibited excellent biocompatibility and degradability. 10% GelMA MNs loaded with an NDV–gelatin mixture sustained NDV release for over 24 h. Compared with the free virus, they induced significantly stronger inhibition of proliferation, migration, and invasion, and promoted greater apoptosis in HCC cells. In mice bearing subcutaneous HCC xenografts, NDV encapsulated in 10% GelMA MNs markedly suppressed tumor growth without significant changes in body weight or histological damage to major organs. Histological analysis further confirmed reduced proliferation and increased apoptosis in the treated group.ConclusionGelMA-encapsulated NDV microneedles represent a novel, promising and well-tolerated therapeutic strategy for HCC.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13036-025-00582-0.

The article presents a comprehensive analysis of current trends in the research and application of "smart" biologically active hydrogels - innovative polymer materials capable of changing their physicochemical properties in response to external stimuli. Such hydrogels are key components in the development of biomedical technologies, in particular in targeted drug delivery, tissue engineering, chemotherapy, biosensing and 3D bioprinting. The paper considers the classification of "smart" hydrogels by type of crosslinking (chemical and physical), origin (natural or synthetic), as well as by type of external stimuli - physical (temperature, light, electric or magnetic field) and chemical (pH, ionic strength, concentration of substances). Special attention is paid to thermosensitive hydrogels, which demonstrate phase transitions depending on temperature, which allows them to be used as carriers for controlled release of medicinal substances. The mechanisms of transition between soluble and insoluble states are described, in particular when the lower critical solution temperature (LCST) or upper critical solution temperature (UCT) is reached. The article provides an example of creating a diagnostic and therapeutic system based on a thermosensitive terpolymer, which includes acrylamide, N-isopropylacrylamide and N-acryloyloxyphthalimide, with immobilized enzyme trypsin. Such a system allows localizing the medicinal substance in the diseased organ due to the temperature-induced phase transition, which provides not only a therapeutic effect, but also a diagnostic function. A separate section is devoted to the use of "smart" hydrogels in 3D bioprinting. The main types of materials used as bioinks are considered: GelMa (gelatin methacrylate), sodium alginate, Pluronic F-127, modified forms of gelatin and extracellular matrices (dECM). Their biocompatible, mechanical and structural properties are determined, allowing the creation of complex tissue constructs with a high degree of accuracy and functionality. The prospects for the use of "smart" hydrogels in the pharmaceutical industry are summarized, in particular for prolonged drug delivery, reducing toxicity, increasing the effectiveness of therapy and creating feedback systems. The importance of further research in the direction of developing multifunctional hydrogel systems with high biostability, adaptability and the possibility of large-scale production is emphasized.

Wearable sensors that combine high precision with conformability and skin adhesion are crucial for reliable and highly unobtrusive physiological monitoring. In this context, increasing efforts are directed toward next‐generation miniaturized self‐adhesive sensors employing different sensing technologies. Herein, for the first time a self‐adhesive sensor is developed for real‐time detection of physiological and biomechanical strain signals, by embedding a fiber Bragg grating (FBG) sensor into a soft, biomimetic, flexible matrix. This hydrogel‐based matrix, composed of gelatin methacrylate, xanthan gum, and glycerol, is engineered to balance fiber–matrix mechanical coupling and skin adhesion. The encapsulated FBG sensor exhibits stable optical response, reduced signal attenuation, and retains good sensitivity to both strain (0.07 nm mε −1 ) and temperature (0.01 nm °C −1 ). Preliminary on‐skin tests on a healthy volunteer demonstrate the ability to capture subtle physiological signals such as breathing and heartbeats, as well as limb motion. Notably, the self‐adhesive properties of the matrix enable firm skin contact without additional tapes, enhancing signal reliability, and reducing motion artifacts. This approach offers a robust, biocompatible, and scalable solution for wearable sensing, opening new opportunities in health monitoring, rehabilitation, and human–machine interfaces.

Gradient hydrogels are an emerging strategy in tissue engineering to mimic the heterogeneity in native tissues. Herein, the metal‐thiolate complexation mechanism is exploited by allowing diffusion of silver ions (Ag+) through a cysteine‐rich human hair keratin (HHK) solution to produce a novel gradient hydrogel. This one‐step approach enables the combined benefits of a sustainable material with an established antimicrobial agent. Herein, the gelation kinetics, physical, mechanical, and biochemical properties of the gradient hydrogel are correlated over a range of thiol:Ag ratios. The presence of a porosity gradient within a single construct, along with dissimilar top and bottom surface morphologies, is shown. Disk diffusion tests against Staphylococcus aureus verified the antibacterial activity of this Ag‐loaded hydrogel. Additionally, hydrogels at 1.25 thiol:Ag ratio supported > 95% viability and proliferation of human dermal fibroblasts (HDFs), comparable to collagen hydrogels. These HDFs produce fibronectin, collagen III, and express alpha‐smooth muscle actin within the gradient hydrogels. In an in vivo full‐thickness wound healing mouse model, the 1.25 hydrogel evoke minimal host tissue response, support reepithelialization more than the uniform Gelatin Methacrylate (GelMA) hydrogel, and promote the most collagen deposition. These findings demonstrate the practicality of metal‐thiolate complexation in producing biomimetic gradient hydrogels for tissue regeneration.