The therapeutic management of inflammatory bowel disease (IBD) remains challenging by poor drug bioavailability, limited mucosal targeting, and chronic immune dysregulation. In this study, we report the synthesis and characterization of hyaluronic acid (HA)-decorated polyamidoamine (PAMAM) dendrimers as a multifunctional nanoplatform for targeted delivery of 5-aminosalicylic acid (5ASA), with concurrent antioxidant and immunomodulatory benefits. PAMAM dendrimers (G1.0-G4.0) were synthesized via the Tomalia method and conjugated to HA. Characterization by dynamic light scattering, zeta potential, and electron microscopy showed nanoscale size, stability, and successful functionalization. HA decoration enhanced biocompatibility, reduced hemolysis, and promoted CD44-mediated uptake in macrophages and colonic epithelial cells. The conjugates displayed strong ROS scavenging and polarized macrophages toward an anti-inflammatory M2 phenotype. HA-modified dendrimers improved 5ASA solubility and colonic accumulation, confirmed by FITC biodistribution. In vivo, the PAMAM G4-HA+5ASA complex outperformed free 5ASA in TNBS-induced colitis, reducing inflammation, promoting mucosal repair, and showing favorable pharmacokinetics. While unmodified dendrimers had slightly higher drug loading, HA conjugates offered superior targeting, immune modulation, and safety without systemic toxicity. These results highlight HA-decorated PAMAM dendrimers as promising carriers for site-specific drug delivery and immunotherapy in chronic inflammation.

Bio-based elastomers have emerged as a sustainable alternative to petroleum-derived synthetic polymers across a wide range of applications. Despite substantial progress in the development of bio-derived materials, achieving bio-based elastomers with inherent degradability and competent mechanical performance as of commercial elastomers remains a significant challenge. To this end, this report presents a novel bio-based elastomers exhibiting various traits of conventional silicones yet degradable when desired. Epoxidized castor oil was polymerized with maleic acid to obtain flexible and biocompatible elastomeric materials. Material properties such as glass transition temperature and Young’s modulus can be modulated with the variation in epoxy content. The prepared elastomers showed appreciable swelling in organic solvents and excellent hydrophobicity as measured via contact angle measurements. The potential for food‑packaging applications was demonstrated by using the prepared elastomers as a coating on paper backing material. Besides, the MTT assay (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) was demonstrated to show their biocompatibility and potential of these elastomers in biomedical applications. Finally, aiming towards a suitable end-of-life solution, the degradation of the elastomers in aqueous sodium hydroxide was demonstrated. Overall, the presented bio-based elastomers prepared using castor oil provide a promising sustainable alternative to conventional, nonrecyclable elastomers for applications such as adhesives and packaging materials.

Purines and their receptors play a role in the regulation of stem cell survival, proliferation, and differentiation. They are responsible for the osteogenic differentiation of stem cells by activating many signaling pathways and enhancing the expression of different osteogenic factors, including bone morphogenetic proteins, runt-related transcription factor 3, alkaline phosphatase (ALP), etc. Here, a 2,6,9-trisubstituted adenine derivative is reported, with negligible cytotoxicity and potent osteogenic potential as demonstrated with mouse myoblast (C2C12 cells) and murine preosteoblasts (MC3T3E1 cells). Osteogenic activity of the derivative (Compound 1 ) is supported by increased expression of ALP and enhanced calcium deposition observed with alizarin staining within cells. Thus, the reported adenine derivatives can serve as potential therapeutics for bone fractures as an injectable therapeutic opening avenue for cell-free therapy.

Chronic diabetic foot ulcers (DFUs) are marked by persistent inflammation, oxidative stress and hypoxia, leading to impaired healing and limited treatment success. While extracellular vesicles (EVs) are promising in modulating the immune microenvironment and promoting regeneration, their clinical use is constrained by instability and loss of function over storage. Alternatively, scaffolds that deliver oxygen have shown regenerative potential and can act as a delivery system for EVs. Here, we report a multifunctional Bioactive Oxygenated Off-the-Shelf EV Therapy (BOOST) that integrates lyophilized EVs, oxygen release and immunomodulatory function within a single cryogel scaffold. BOOST synergistically orchestrates immunomodulatory reprogramming, driving macrophages from a pro-inflammatory M1 to a pro-regenerative M2 phenotype while concurrently driving angiogenesis and collagen remodelling. As an off-the-shelf therapy, BOOST preserved EV bioactivity for over 6 months, delivered sustained oxygen and reduced ROS with accelerated wound closure in diabetic wounds. BOOST reprogrammed macrophage polarization and upregulated anti-inflammatory IL10 levels, directing angiogenesis (VEGF, CD31), collagen synthesis (COL1A and COLIIIA) and promoting hair follicle regeneration while mitigating oxidative stress (8-OHdG). This work presents a clinically relevant strategy that merges EV therapy with oxygen delivery and immune modulation to address multiple pathophysiological barriers, offering a potent off-the-shelf therapeutic solution for DFUs.

Around 100 million individuals with diabetes in India are at risk of developing diabetic wounds in their lifetime. These wounds cause severe reductions in the quality of life of patients due to increased economic burden and risk of limb amputations. Indigenous wound dressings offer cost-effective solutions for the management and healing of such wounds. Loading of bioactive formulations in passive dressing material has led to successful intervention in hampered wound healing cascades. The role of traditional wound healing formulations, such as aloe vera, turmeric, and cinnamon oil extracts loaded in hydrogels, hydrocolloids, sponges and other dressing materials, has been reported earlier. Tamra Bhasma and Yasad Bhasma are two types of Ayurvedic formulations (Bhasmas) cited in the Indian traditional medicinal text “Rasa-shastra”. These Bhasmas have been studied in isolation and show beneficial attributes, such as free radical scavenging, hepatoprotective activity and anti-inflammatory effects. The present work is aimed at studying the combinatorial effect of Tamra Bhasma and Yasad Bhasma in conjunction with the potent anti-microbial “cinnamaldehyde nanoemulsion (NE)” loaded in two different forms of a polyvinyl alcohol (PVA) matrix: hydrogel and sponge. In vitro studies on three cell lines, NIH 3T3, HaCaT and HuVECs, showed sustained release of these Bhasmas and NE, leading to enhanced cell proliferation, cell migration, free radical scavenging and collagen formation. Compared with the PVA hydrogel and sponge controls, the developed bioactive wound dressing shows promise for the healing and management of infected diabetic wounds.

Ulcerative colitis remains challenging to treat due to the need for localized control of inflammation, restoration of mucosal integrity, and avoidance of systemic toxicity. Here, we report a rectally administered, sprayable, thermo-responsive hyaluronic acid-based copolymer platform for the localized co-delivery of probiotic-derived extracellular vesicles (ProEVs) and 5-aminosalicylic acid. This system enables enhanced retention and sustained presentation of therapeutics at inflamed colonic sites. The combined formulation demonstrates improved therapeutic efficacy compared to individual treatments, promoting mucosal recovery and intestinal homeostasis. Mechanistically, the platform modulates inflammatory responses, supports epithelial barrier function, and contributes to microbiota rebalancing. Notably, extracellular vesicles provide a more effective and consistent therapeutic modality compared to live probiotics. Importantly, the formulation is designed for clinical translation, offering localized administration, minimal toxicity, and stability upon lyophilization, enabling off-the-shelf use. These findings highlight the potential of integrating extracellular vesicles with biomaterial-based delivery systems as a multifunctional therapeutic strategy for inflammatory bowel disease.

Delayed and impaired wound healing remains a significant clinical challenge, often associated with hypoxia, excessive oxidative stress, insufficient angiogenesis, and impaired tissue repair. Current therapeutic approaches are often inadequate to address these complex and interrelated factors. In the present study, a dual-layer macromolecular scaffold incorporating small extracellular vesicles (sEVs), calcium peroxide (CP), and nitric oxide (NO) (GC-CP-NO-sEV) was developed using solvent casting and cryogelation techniques. The upper layer was designed to provide a controlled microenvironment through sustained release of oxygen and nitric oxide, while the lower layer functioned as a reservoir for sEVs to facilitate cellular infiltration and tissue regeneration. The physicochemical properties of the scaffold, including biodegradability, swelling behavior, and release kinetics, were systematically evaluated. Biocompatibility and proliferative effects were assessed using NIH/3T3 fibroblasts and HaCaT keratinocytes. Furthermore, in vivo wound-healing efficacy was investigated using a full-thickness excisional wound model in rats. The fabricated scaffold exhibited desirable biodegradability and generated non-cytotoxic degradation products. Sustained and controlled release of oxygen, nitric oxide, and sEVs was observed over an 8-day period. In vitro studies demonstrated excellent cytocompatibility and enhanced cellular proliferation. In vivo results revealed that the GC-CP-NO-sEV scaffold significantly improved wound closure and was associated with enhanced collagen deposition, improved tissue organization, elevated expression of wound-healing associated genes, and histological features consistent with advanced tissue remodeling. Collectively, these findings suggest that the dual-layer GC-CP-NO-sEV scaffold provides a multifunctional wound-healing microenvironment that supports multiple aspects of the repair process and represents a promising platform for wound management. However, because individual-component control groups were not included, the specific contributions of the scaffold, oxygen, NO, and sEVs to the observed effects could not be independently determined.

3D printed scaffolds have revolutionized the field of regenerative medicine by overcoming the lacunas such as precision, customization, and reproducibility observed through traditional methods of scaffold preparation such as freeze-drying, electrospinning, etc. Combining the advantages of 3D printed scaffolds along with bioactive cues such as signaling molecules can be an effective treatment approach. In the present study, cellulose nanocrystals (CNCs) along with gelatin, in different ratios, were used for scaffold preparation through the direct ink writing technique and thoroughly characterized. The scaffolds showed porous microstructure, high swelling ratio (∼390 to 590), degradability and porosity (∼65 %). In vitro biocompatibility assays showed high biocompatibility and no toxicity through live-dead, proliferation and hemolysis assay. Further, the optimum formulation was functionalized with nitric oxide (NO)-releasing modified gelatin to enhance the scaffold's biomedical applicability. Functionality assays with this formulation, scratch, and neurite outgrowth showed positive effects of NO on cell migration and neurite length. The study presents the fabrication, modification, and biomedical applicability of the aforementioned inks, which paves new pathways in the field of 3D printing of scaffolds with significant potential for biomedical applications, soft tissue engineering, and wound dressing, for example.

Treatment of large-size bone defects is difficult, and acquiring autografts may be challenging due to limited availability. A synthetic patient-specific bone substitute can be developed by using 3D printing technologies in such cases. In the present study, we have developed photocurable composite resins with poly(trimethylene carbonate) (PTMC) containing a high percentage of biodegradable bioactive strontium-substituted nanohydroxyapatite (SrHA, size 30-70 nm). These photocurable resins have then been employed to develop high-surface-area 3D-printed bone substitutes using the digital light processing (DLP) technique. To enhance the surface area of the 3D-printed substitute, cryogels alone and functionalized with bioactive components of bone morphogenetic protein (BMP) and zoledronic acid (ZA) were filled within the 3D-printed scaffold/substitute. The scaffolds were tested in vitro for biocompatibility and functionality in vivo in two therapeutically relevant rat models with large bone defects (4 mm). The porosities of 3D printed scaffolds were found to be 60.1 ± 0.9%, 72.9 ± 0.5%, and 74.3 ± 1.6% for PTMC, PTMC-HA, and PTMC-SrHA, respectively, which is in the range of cancellous bone (50-95%). The thermogravimetric analysis demonstrated the fabrication of 3D printed composites with HA and SrHA concentrations of 51.5 and 57.4 wt %, respectively, in the PTMC matrix. The tensile Young's modulus (E), compressive moduli, and wettability increased post incorporation of SrHA and HA in the PTMC matrix. In vitro and in vivo results revealed that SrHA integrated into the PTMC matrix exhibited good physicochemical and biological properties. Furthermore, the osteoactive molecule-functionalized 3D printed composite scaffolds were found to have an adequate osteoconductive and osteoinductive surface that has shown increased bone regeneration and defect repair in both tibial and cranial bone defects. Our findings thus support the use of PTMC-SrHA composites as next-generation patient-specific synthetic bioactive biodegradable bone substitutes.

Wound healing represents a complex biological process crucial for tissue repair and regeneration. In recent years, biomaterial-based scaffolds loaded with bioactive compounds have emerged as promising therapeutic strategies to accelerate wound healing. In this study, we investigated the properties and wound healing effects of cryogels loaded with calcium peroxide (CP) and berberine (BB). The cryogels were synthesized through a cryogenic freezing technique and displayed pore diameters of 83 +/- 39 mu m, with porosity exceeding 90%. Following 20 days of degradation, the percentage of remaining weight for GPC and GPC-CP-BB cryogels was determined to be 12.42 +/- 2.45% and 10.78 +/- 2.08%, respectively. Moreover, the swelling ratios after 3 minutes for GPC and GPC-CP-BB were found to be 22.10 +/- 0.05 and 21.00 +/- 0.07, respectively. In vitro investigations demonstrated the cytocompatibility of the cryogels, with sufficient adhesion and proliferation of fibroblast (NIH-3T3) cells observed on the scaffolds, along with their hemocompatibility. Furthermore, the cryogels exhibited sustained release kinetics of both calcium peroxide and berberine, ensuring prolonged therapeutic effects at the wound site. In vivo assessment using a rat model of full-thickness skin wounds demonstrated accelerated wound closure rates in animals treated with the GPC-CP-BB scaffold compared to controls. Histological analysis revealed enhanced granulation tissue formation, re-epithelialization, and collagen deposition in the GPC-CP-BB group. Overall, our findings suggest that the scaffold loaded with CP and BB holds great promise as a therapeutic approach for promoting wound healing. Its multifaceted properties offer a multifunctional platform for localized delivery of therapeutic agents while providing mechanical support and maintaining a favorable microenvironment for tissue regeneration. This study explores cryogels, loaded with CP and berberine BB for wound healing. The cryogels exhibited high porosity, biocompatibility, and sustained release of CP and BB. The scaffolds accelerated wound closure and improved healing in a rat model.

Drug toxicity is an important cause of chronic liver damage, which in the long term can lead to impaired bone homeostasis through an imbalance in the liver-bone axis. For instance, non-steroidal anti-inflammatory drugs (e.g., diclofenac), which are commonly used to control pain during orthopaedic interventions, are known to reduce bone quality and are the most prevalent causes of drug-induced liver damage. Therefore, we used human cell lines to produce a stable, reproducible, and reliable in vitro liver-bone co-culture model, which mimics the impaired bone homeostasis seen after diclofenac intake in vivo. To provide the best cell culture conditions for the two systems, we tested the effects of supplements contained in liver and bone cell culture medium on liver and bone cell lines, respectively. Additionally, different ratios of culture medium combinations on bone cell scaffolds and liver spheroids’ viability and function were also analysed. Then, liver spheroids and bone scaffolds were daily exposed to 3–6 µM diclofenac alone or in co-culture to compare and evaluate its effect on the liver and bone system. Our results demonstrated that a 50:50 liver:bone medium combination maintains the function of liver spheroids and bone scaffolds for up to 21 days. Osteoclast-like cell activity was significantly upregulated after chronic exposure to diclofenac only in bone scaffolds co-cultured with liver spheroids. Consequently, the mineral content and stiffness of bone scaffolds treated with diclofenac in co-culture with liver spheroids were significantly reduced. Interestingly, our results show that the increase in osteoclastic activity in the system is not related to the main product of diclofenac metabolism. However, osteoclast activation correlated with the increase in oxidative stress and inflammation associated with chronic diclofenac exposure. In summary, we established a long-term stable liver-bone system that represents the interaction between the two organs, meanwhile, it is also an outstanding model for studying the toxicity of drugs on bone homeostasis.

While self-healing silicones are required for many practical applications, conventional methods of incorporating self-healability in silicones involve generation of bond-forming moieties within the backbone of the oligomer itself. Such processes involve multiple synthesis steps that turn the silicone expensive and less amenable for scale-up. In contrast, hydrogels can be made self-healing by different simple yet robust chemical routes. Hydrogels however lack mechanical strength, necessary for most engineering applications. To meet the above need, we have introduced here a novel two-phase material, consisting of self-healing hydrogel droplets embedded as microscopic healers inside the continuous matrix of silicone. The hydrogel phase, consisting of starch and polyvinyl alcohol (PVA) as the oligomers and multivariate borate ion as the crosslinker is dispersed in silicone oligomer mixed with the curing agent and both phases are allowed to crosslink. Controlled fracture tests on the resultant crosslinked material show that two cut surfaces of it get joined instantaneously with the tensile failure stress reaching as high as 35 kPa; this material remains healable also over ten cycles of incision and reattachment. The hydrogel can act also as an external glue to heal two incised surfaces of the two-phase composite to achieve durable fracture strength and thereby help forming different polygonal structures with angled joints. We have demonstrated also bio-compatibility of the two-phase material thereby opening up its possible use in large variety of biomedical applications.

Treatment of critical-size osteochondral (OC) injuries at load-bearing sites has remained a major clinical challenge in orthopedic surgery. This is due to the anisotropic characteristics of OC tissue and the stratified structure of the cartilage. Here, we developed a multilayered OC scaffold by employing cryogelation technology. Gelatin, chitosan, and chondroitin sulfate were utilized for designing three distinct, 2425 ± 120 μm thick layers of cartilage having different alignments, while nanohydroxyapatite and gelatin were used for the subchondral bone layer. Exosomes derived from articular chondrocytes in the range of 60-110 nm were used to promote chondrogenesis. The biocompatibility and cartilage formation potential of the scaffold and exosomes were initially evaluated in rat OC defects. The application of exosome-loaded scaffolds was then investigated in a critical-size OC injury (8 × 10 mm) created in the goat knee. Artificial synovial fluid was designed and utilized as a carrier for exosomes for a booster dose administered as an intra-articular injection. X-ray imaging and micro-CT analysis revealed that the treatment resulted in improved subchondral bone regeneration. The defect region exhibited healthy hyaline cartilage formation, as detected by MRI imaging. Moreover, histological examination revealed that the treatment group showed augmented cell proliferation, matrix deposition, secretion of proteoglycans, and the formation of stratified hyaline cartilage over a long-term (6 and 12 months), whereas the control group demonstrated the formation of fibrocartilage. Treatment-induced upregulation of collagen II, aggrecan, and SOX 9 genes (∼10 fold) further provided evidence that the cartilage phenotype was well preserved. Hence, the proposed treatment has significant translational potential for treating adverse OC clinical injuries.

Chronic wounds are a major healthcare burden and may severely affect the social, mental, and economic status of the patients. Any impairment in wound healing stages due to underlying factors leads to a prolonged healing time and subsequently to chronic wounds. Traditional approaches for the treatment of chronic wounds include dressing free local therapy, dressing therapy, and tissue engineering based scaffold therapies. However, traditional therapies need improvisation and have been advanced through breakthrough technologies. The present review spans traditional therapies and further gives an extensive account of advancements in the treatment of chronic wounds. Cutting edge technologies, such as 3D printing, which includes inkjet printing, fused deposition modeling, digital light processing, extrusion-based printing, microneedle array-based therapies, gene therapy, which includes microRNAs (miRNAs) therapy, and smart wound dressings for real time monitoring of wound conditions through assessment of pH, temperature, oxygen, moisture, metabolites, and their use for planning of better treatment strategies have been discussed in detail. The review further gives the future direction of treatments that will aid in lowering the healthcare burden caused due to chronic wounds.

Purpose In chronic hyperglycemia, the advanced glycation end product (AGE) interacts with its receptor (RAGE) and contributes to impaired wound healing by inducing oxidative stress, generating dysfunctional macrophages, and prolonging the inflammatory response. Additionally, uncontrolled levels of proteases, including metallomatrix protease-9 (MMP-9), in the diabetic wound bed degrade the extracellular matrix (ECM) and biological cues that augment healing. A multifunctional antimicrobial hydrogel (Immuno-gel) containing RAGE and MMP-9 inhibitors can regulate the wound microenvironment and promote scar-free healing. Results Immuno-gel was characterized and the wound healing efficacy was determined in vitro cell culture and in vivo diabetic Wistar rat wound model using ELISA, Western blot, and Immunofluorescence staining. The Immuno-gel exhibited a highly porous morphology with excellent in vitro cytocompatibility. AGE-stimulated macrophages treated with the Immuno-gel released higher levels of pro-healing cytokines in vitro. In the hydrogel-wound interface of diabetic Wistar rats, Immuno-gel treatment significantly reduced MMP-9 and NF-κB expression and enhanced pro-healing (M2) macrophage population and pro-healing cytokines. Conclusion Altogether, this study suggests that Immuno-gel simultaneously attenuates macrophage dysfunction through the inhibition of AGE/RAGE signaling and reduces MMP-9 overexpression, both of which favor scar-free healing. The combinatorial treatment with RAGE and MMP-9 inhibitors via Immuno-gel simultaneously modulates the diabetic wound microenvironment, making it a promising novel treatment to accelerate diabetic wound healing.

Diabetes has currently acquired the status of epidemic worldwide, and among its various pathological consequences like retinopathy and nephropathy, bone fragility fractures from diabetic osteopathy occurs in later stages and is equally destructive. Chronic hyperglycemia culminates into deteriorating microvasculature and quality of bone, making it prone to fractures. Among these, hip fractures are most common, especially in older diabetic patients apart from underlying neuropathy. Our study is an attempt to ameliorate hip fragility fracture and nerve trauma with electrical stimulation as an interface in a chronic diabetic rat model. We have fabricated reduced graphene oxide-substituted hydroxyapatite as an electroactive bone substitute and incorporated it into chitosan gelatin cryogels. The in situ reduction of graphene oxide during sintering of hydroxyapatite imparts higher potential to the fabricated composite in dealing with problem at question. The cryogels depicted optimum in vitro biocompatibility and enhanced mineralization after ectopic subcutaneous implantation in rats. The therapeutic potency of composite cryogels was evaluated in a hip fracture model with compression to the sciatic nerve in diabetic rats, mimicking the severe clinical trauma. The presence of cryogels in the femoral neck canal coupled with electrical stimulation and biochemical factors significantly improved bone regeneration in diabetic rats as depicted with microcomputed tomography analysis and histology images. The application of electrical stimulation also ameliorated the nerve trauma observed with 70% improvement in electrophysiological parameters such as the compound muscle action potential with combinatorial therapy. We therefore report the successful implication of a multitarget therapy in a chronic diabetic rat model unraveling the bone-nerve crosstalk with electroactive smart cryogels.