Janus hydrogel with dual antibacterial and angiogenesis functions for enhanced diabetic wound healing

Anti-infection and neovascularization at the wound site are two vital factors that accelerate diabetic wound healing. However, for a wound healing dressing, the two functions need to work at different sites(inner and outer), giving big challenges for dressing design. In this study, we fabricated a novel sodium alginate/chitosan(SA/CS) Janus hydrogel dressing by the assembly of SA hydrogel loaded with silver nanoparticles(Ag NPs) and CS hydrogel impregnated with L-arginine loaded sodium alginate ...     

Hemocompatibility of Ca2+‐Crosslinked Nanocellulose Hydrogels: Toward Efficient Management of Hemostasis

The present work investigates Ca²⁺‐crosslinked nanofibrillated cellulose hydrogels as potential hemostatic wound dressings by studying core interactions between the materials and a central component of wounds and wound healing—the blood. Hydrogels of wood‐derived anionic nanofibrillated cellulose (NFC) and NFC hydrogels that incorporate kaolin or collagen are studied in an in vitro whole blood model and with platelet‐free plasma assays. The evaluation of thrombin and factor XIIa formation, platelet reduction, and the release of activated complement system proteins, shows that the NFC hydrogel efficiently triggered blood coagulation, with a rapid onset of clot formation, while displaying basal complement system activation. By using the NFC hydrogel as a carrier of kaolin, the onset of hemostasis is further boosted, while the NFC hydrogel containing collagen exhibits blood activating properties comparable to the anionic NFC hydrogel. The herein studied NFC hydrogels demonstrate great potential for being part of advanced wound healing dressings that can be tuned to target certain wounds (e.g., strongly hemorrhaging ones) or specific phases of the wound healing process for optimal wound management.     

肝素在生长因子控制释放中的应用*

典型的抗凝血药物肝素作为硫酸化的多糖在体内具有多重生物活性,而这些生物活性是通过与生长因子和细胞因子等蛋白质的相互作用来发挥的。由于它与肝素亲和性生长因子具有特异的糖胺聚糖-蛋白质相互作用,近年来被广泛地应用于生长因子的控制释放中,以达到稳定负载于载体材料特别是水凝胶载体中的生长因子并保持其生物活性、延缓释放的作用。本文介绍了近年来肝素在组织工程用生长因子控制释放系统中应用研究的最新进展。     

Drug‐Loaded Elastin‐Like Polypeptide–Collagen Hydrogels with High Modulus for Bone Tissue Engineering

Emphasizing the role of hydrogel stiffness and cellular differentiation, this study develops collagen and elastin‐like polypeptide (ELP)–based bone regenerative hydrogels loaded with recombinant human bone morphogenetic protein‐2 (rhBMP‐2) and doxycycline with mechanical properties suitable for osteogenesis. The drug‐incorporated collagen–ELP hydrogels has significantly higher modulus of 35 ± 5 kPa compared to collagen‐only hydrogels. Doxycycline shows a bi‐phasic release with an initial burst release followed by a gradual release, while rhBMP‐2 exhibits a nearly linear release profile for all hydrogels. The released doxycycline shows anti‐microbial activity against Pseudomonas aeruginosa, Streptococcus sanguinis, and Escherichia coli. Microscopic observation of the hydrogels reveals their interconnected, macroporous, 3D open architecture with pore diameters between 160 and 400 µm. This architecture supports human adipose–derived stem cell attachment and proliferation from initial days of cell seeding, forming a thick cellular sheath by day 21. Interestingly, in collagen and collagen–ELP hydrogels, cell morphology is elongated with stretched slender lamellipodial formation, while cells assemble as spheroidal aggregates in crosslinked as well as drug‐loaded hydrogels. Osteogenic markers, alkaline phosphatase and osteocalcin, are expressed maximally for drug‐loaded hydrogels compared to those without drugs. The drug‐loaded collagen–ELP hydrogels are thus promising for combating bacterial infection and promoting guided bone regeneration.     

Cytotoxicity and wound healing properties of PVA/ws-chitosan/glycerol hydrogels made by irradiation followed by freeze–thawing

Hydrogels based on poly(vinyl alcohol), water-soluble chitosan and glycerol made by irradiation followed by freeze–thawing were evaluated as wound dressing. MTT assay suggested that the extract of hydrogels was nontoxic towards L929 mouse fibroblasts. Compared to gauze dressing, the hydrogel can accelerate the healing process of full-thickness wounds in a rat model. Wounds treated with hydrogel healed at 11th day postoperatively and histological observation showed that mature epidermal architecture was formed. These indicate that it is a good wound dressing.     

Injectable baicalin/F127 hydrogel with antioxidant activity for enhanced wound healing

Baicalin, extracted from traditional Chinese medicine Scutellaria baicalensis Georg, possesses multiple pharmacological activities and has great potential for chronic skin wound repair. However, the poor solubility and lack of suitable vehicles greatly limit its further application. Herein, we proposed a convenient and robust strategy, employing PBS solution as solvent, to enhance the solubility of baicalin. Furthermore, we constructed injectable baicalin/F127 hydrogels to study their application in skin wound treatment. The composition and temperature sensitivity of baicalin/Pluronic® F-127 hydrogels were confirmed by FTIR and rheological testing, respectively. In vitro release measurement indicated that the first order model was best fitted with the release profile of baicalin from hydrogel matrix. Besides, MTT assay, AO/EO staining assay as well as hemolytic activity test revealed the excellent cytocompatibility of baicalin/F127 hydrogels. Antioxidant activity assay demonstrated the cytoprotective activity of baicalin/F127 hydrogels against reactive oxygen species (ROS). Furthermore, the in vivo experiments exhibited the ability of baicalin/F127 hydrogel to accelerate wound healing. In conclusion, this novel injectable baicalin/F127 hydrogel should have bright application for chronic wound treatment.     

Hyaluronic acid-methacrylic anhydride/polyhexamethylene biguanide hybrid hydrogel with antibacterial and proangiogenic functions for diabetic wound repair

Diabetic wounds lead to a decrease in quality of life and an increase in mortality. Current treatment strategies include preventing bacterial adhesion while improving microcirculation. As a new type of wound dressing that imitates natural skin, hydrogel has gradually emerged with its excellent properties. However, existing hydrogels rarely achieve satisfactory results in promoting wound repair and antibacterial simultaneously. In this case, we prepared methacrylic anhydride chemically modified hyaluronic acid as a hydrogel matrix, added polyhexamethylene biguanide as an antibacterial component, and loaded sodium alginate/salidroside composite microspheres which could sustainably release salidroside and thus promote angiogenesis. Hybrid hydrogel (HAMA/PHMB-Ms) was synthesized via photocrosslinking, and its chemical structure, particle size distribution and microstructure were characterized. The satisfactory antibacterial properties of the HAMA/PHMB(15%)-Ms hydrogel were studied in vitro, and its antibacterial rates against E. coli and S. aureus were 97.85% and 98.56%, respectively. In addition, after demonstrating its good biocompatibility, we verified that the HAMA/PHMB-Ms hydrogel has increased granulation tissue formation, more collagen deposition, more subcutaneous capillary formation, and better wound healing than blank control, HAMA and HAMA/PHMB hydrogel on the back wound model of diabetic mice. The results confirmed that HAMA/PHMB-Ms hydrogel was a promising material for the treatment of the diabetic wounds.     

Biodegradable Sodium Alginate/Carrageenan/Cellulose Composite Hydrogel Wound Dressings Containing Herbal Extracts for Promoting Blood Coagulation and Wound Healing

Accelerating the coagulation process and preventing wound infection are major challenges in the wound care process. Therefore, new multifunctional wound dressings with procoagulant, antibacterial, and antioxidant properties have enormous potential for clinical application. In this work, biodegradable hydrogels containing herbal extracts are prepared for wound dressings. First, the active ingredients are extracted from Amaranthus spinosus (A. spinosus) and Rubia cordifolia (R. cordifolia) and added to the hydrogels prepared from microcrystalline cellulose (MCC), carrageenan, and sodium alginate. Then the composite hydrogels are air-dried to obtain the wound dressings. The wound dressings prepared in this work have good biocompatibility and moisture retention. The mechanical properties of the wound dressings are further improved with the addition of MCC. Besides, the wound dressings have excellent procoagulant, antibacterial, and antioxidant properties due to the presence of R. cordifolia extract. Overall, the most effective group of wound dressings with different ingredient formulations reduces clotting time by 75% and largely inhibits bacterial growth. The wound dressings perform well in the animal wound models to promote wound healing. These results indicate that the hydrogel wound dressings prepared in this work have great potential for medical applications.     

Hyaluronan/Collagen Hydrogels with Sulfated Hyaluronan for Improved Repair of Vascularized Tissue Tune the Binding of Proteins and Promote Endothelial Cell Growth

Innovative biomaterial‐based concepts are required to improve wound healing of damaged vascularized tissues especially in elderly multimorbid patients. To develop functional hydrogels as 3D cellular microenvironments and as carrier or scavenging systems, e.g., for mediator proteins or proinflammatory factors, collagen fibrils are embedded into a network of photo‐crosslinked acrylated hyaluronan (HA), chondroitin sulfate (CS), or sulfated HA (sHA). After lyophilization, the gels show a porous structure and an improved stability against degradation via hyaluronidase. Gels with CS and sHA bind significantly more lysozyme than HA/collagen gels and retard its release. The proliferation and metabolic activity of endothelial cells are significantly increased on sHA gels compared to CS‐ or only HA‐containing hydrogels. These findings highlight the potential of HA/collagen hydrogels with sulfated glycosaminoglycans to tune the protein binding and release behavior and to directly modulate cellular response. This can be easily translated into biomimetic biomaterials with defined properties to stimulate wound healing.     

Stimulation of Microvascular Networks on Sulfonated Polyrotaxane Surfaces with Immobilized Vascular Endothelial Growth Factor

Modulation of material properties and growth factor application are critical in constructing suitable cell culture environments to induce desired cellular functions. Sulfonated polyrotaxane (PRX) surfaces with immobilized vascular endothelial growth factors (VEGFs) are prepared to improve network formation in vascular endothelial cells. Sulfonated PRXs, whereby sulfonated α‐cyclodextrins (α‐CDs) are threaded onto a linear poly(ethylene glycol) chain capped with bulky groups at both terminals, are coated onto surfaces. The molecular mobility of sulfonated PRX surfaces is modulated by tuning the number of threading α‐CDs. VEGF is immobilized onto surfaces with varying mobility. Low mobility and VEGF‐immobilization reinforce cell proliferation, yes‐associated protein activity, and rhoA, pdgf, ang‐1, and pecam‐1 gene expression. Highly mobile surfaces and soluble VEGF weakly affect these cell responses. Network formation is strongly stimulated in vascular endothelial cells only on low‐mobility VEGF‐immobilized surfaces, suggesting that molecular mobility and VEGF immobilization synergistically control cell function.     

Development and evaluation of novel hydrogel for preventing postoperative pancreatic fistula

Pancreatic fistula is a complication that frequently occurs after pancreatic surgery. Although various attempts have been made to prevent pancreatic fistula after pancreatic surgery, no effective methods have been developed thus far. In this study, to prevent the pancreatic fistula, we attempted to prepare the hydrogels consisting of two types of polyvinyl alcohol (PVAs), Poval® and Exceval® by the freezing–thawing (F/T) method. As the concentration and the number of F/T cycles increased, it was revealed that the swelling degree tended to decrease, and tensile strength tended to increase. Especially, Exceval® formed more robust hydrogels than that of Poval® hydrogel prepared by the same conditions. Furthermore, the release behavior of tartrazine from 10% Exceval® hydrogels differed depending on the number of F/T cycles. It was also revealed that the diffusion pattern of the drug in the hydrogel differed along with the release, and the entire amount of tartrazine in the hydrogel was released by 120 min. As nafamostat mesylate was loaded, in vivo study, Pancreatic enzyme values were obtained after 48 h, which allowed comparison of the preventive effects against pancreatic fistula between the untreated group, the Exceval® hydrogel group, and nafamostat mesylate-containing Exceval®-applied group. Furthermore, there was a significant difference between the untreated group and the hydrogel-applied group. Besides, PVA hydrogels prepared by the F/T method could probably absorb pancreatic enzymes. This study found that Exceval® hydrogel prepared by the F/T method was considered a novel hydrogel formulation to prevent pancreatic fistula.     

Strategies Using Gelatin Microparticles for Regenerative Therapy and Drug Screening Applications

Gelatin, a denatured form of collagen, is an attractive biomaterial for biotechnology. In particular, gelatin particles have been noted due to their attractive properties as drug carriers. The drug release from gelatin particles can be easily controlled by the crosslinking degree of gelatin molecule, responding to the purpose of the research. The gelatin particles capable of drug release are effective in wound healing, drug screening models. For example, a sustained release of growth factors for tissue regeneration at the injured sites can heal a wound. In the case of the drug screening model, a tissue-like model composed of cells with high activity by the sustained release of drug or growth factor provides reliable results of drug effects. Gelatin particles are effective in drug delivery and the culture of spheroids or cell sheets because the particles prevent hypoxia-derived cell death. This review introduces recent research on gelatin microparticles-based strategies for regenerative therapy and drug screening models.     

A Shear-Thinning,Self-Healing,Dual-Cross Linked Hydrogel Based on Gelatin/Vanillin/Fe3+/AGP-AgNPs: Synthesis,Antibacterial, and Wound-Healing Assessment

A shear-thinning and self-healing hydrogel based on a gelatin biopolymer is synthesized using vanillin and Fe³⁺ as dual crosslinking agents. Rheological studies indicate the formation of a strong gel found to be injectable and exhibit rapid self-healing (within 10 min). The hydrogels also exhibited a high degree of swelling, suggesting potential as wound dressings since the absorption of large amounts of wound exudate, and optimum moisture levels, lead to accelerated wound healing. Andrographolide, an anti-inflammatory natural product is used to fabricate silver nanoparticles, which are characterized and composited with the fabricated hydrogels to imbue them with anti-microbial activity. The nanoparticle/hydrogel composites exhibit activity against Escherichia coli, Staphylococcus aureus, and Burkholderia pseudomallei, the pathogen that causes melioidosis, a serious but neglected disease affecting southeast Asia and northern Australia. Finally, the nanoparticle/hydrogel composites are shown to enhance wound closure in animal models compared to the hydrogel alone, confirming that these hydrogel composites hold great potential in the biomedical field.     

Enhanced skin wound healing by a sustained release of growth factors contained in platelet-rich plasma

Platelet-rich plasma (PRP) contains growth factors that promote tissue regeneration. Previously, we showed that heparin-conjugated fibrin (HCF) exerts the sustained release of growth factors with affinity for heparin. Here, we hypothesize that treatment of skin wound with a mixture of PRP and HCF exerts sustained release of several growth factors contained in PRP and promotes skin wound healing. The release of fibroblast growth factor 2, platelet-derived growth factor-BB, and vascular endothelial growth factor contained in PRP from HCF was sustained for a longer period than those from PRP, calcium-activated PRP (C-PRP), or a mixture of fibrin and PRP (F-PRP). Treatment of full-thickness skin wounds in mice with HCF-PRP resulted in much faster wound closure as well as dermal and epidermal regeneration at day 12 compared to treatment with either C-PRP or F-PRP. Enhanced skin regeneration observed in HCF-PRP group may have been at least partially due to enhanced angiogenesis in the wound beds. Therefore, this method could be useful for skin wound treatment.     

TGF‐β1‐Modified Hyaluronic Acid/Poly(glycidol) Hydrogels for Chondrogenic Differentiation of Human Mesenchymal Stromal Cells

In cartilage regeneration, the biomimetic functionalization of hydrogels with growth factors is a promising approach to improve the in vivo performance and furthermore the clinical potential of these materials. In order to achieve this without compromising network properties, multifunctional linear poly(glycidol) acrylate (PG‐Acr) is synthesized and utilized as crosslinker for hydrogel formation with thiol‐functionalized hyaluronic acid via Michael‐type addition. As proof‐of‐principle for a bioactivation, transforming growth factor‐beta 1 (TGF‐β1) is covalently bound to PG‐Acr via Traut's reagent which does not compromise the hydrogel gelation and swelling behavior. Human mesenchymal stromal cells (MSCs) embedded within these bioactive hydrogels show a distinct dose‐dependent chondrogenesis. Covalent incorporation of TGF‐β1 significantly enhances the chondrogenic differentiation of MSCs compared to hydrogels with supplemented noncovalently bound TGF‐β1. The observed chondrogenic response is similar to standard cell culture with TGF‐β1 addition with each medium change. In general, multifunctional PG‐Acr offers the opportunity to introduce a range of biomimetic modifications (peptides, growth factors) into hydrogels and, thus, appears as an attractive potential material for various applications in regenerative medicine.     

Orthogonal Enzymatic Reactions to Control Supramolecular Hydrogelations

Enzyme‐responsive hydrogels have great potential in applications of controlled drug release, tissue engineering, etc. In this study, we reported on a supramolecular hydrogel that showed responses to two enzymes, phosphatase which was used to form the hydrogels and esterase which could trigger gel‐sol phase transitions. The gelation process and visco‐elasticity property of the resulting gel, morphology of the nanostructures in hydrogel, and peptide conformation in the self‐assembled nanostructure were characterized by rheology, transmission electron microscope (TEM), and circular dichroism (CD), respectively. Potential application of the enzyme‐responsive hydrogel in drug release was also demonstrated in this study. Though only one potential application of drug release was proved in this study, the responsive hydrogel system in this study might have potentials for the applications in fields of cell culture, controlled‐drug release, etc.     

Development of Antibacterial,Degradable and pH-Responsive Chitosan/Guar Gum/Polyvinyl Alcohol Blended Hydrogels for Wound Dressing

The present research is based on the fabrication preparation of CS/PVA/GG blended hydrogel with nontoxic tetra orthosilicate (TEOS) for sustained paracetamol release. Different TEOS percentages were used because of their nontoxic behavior to study newly designed hydrogels’ crosslinking and physicochemical properties. These hydrogels were characterized using Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and wetting to determine the functional, surface morphology, hydrophilic, or hydrophobic properties. The swelling analysis in different media, degradation in PBS, and drug release kinetics were conducted to observe their response against corresponding media. The FTIR analysis confirmed the components added and crosslinking between them, and surface morphology confirmed different surface and wetting behavior due to different crosslinking. In various solvents, including water, buffer, and electrolyte solutions, the swelling behaviour of hydrogel was investigated and observed that TEOS amount caused less hydrogel swelling. In acidic pH, hydrogels swell the most, while they swell the least at pH 7 or higher. These hydrogels are pH-sensitive and appropriate for controlled drug release. These hydrogels demonstrated that, as the ionic concentration was increased, swelling decreased due to decreased osmotic pressure in various electrolyte solutions. The antimicrobial analysis revealed that these hydrogels are highly antibacterial against Gram-positive (Staphylococcus aureus and Bacillus cereus) and Gram negative (Pseudomonas aeruginosa and Escherichia coli) bacterial strains. The drug release mechanism was 98% in phosphate buffer saline (PBS) media at pH 7.4 in 140 min. To analyze drug release behaviour, the drug release kinetics was assessed against different mathematical models (such as zero and first order, Higuchi, Baker–Lonsdale, Hixson, and Peppas). It was found that hydrogel (CPG2) follows the Peppas model with the highest value of regression (R² = 0.98509). Hence, from the results, these hydrogels could be a potential biomaterial for wound dressing in biomedical applications.     

Dual‐Functional Dextran‐PEG Hydrogel as an Antimicrobial Biomedical Material

Microbial infections continually present a major worldwide public healthcare threat, particularly in instances of impaired wound healing and biomedical implant fouling. The development of new materials with the desired antimicrobial property to avoid and treat wound infection is urgently needed in wound care management. This study reports a novel dual‐functional biodegradable dextran‐poly(ethylene glycol) (PEG) hydrogel covalently conjugated with antibacterial Polymyxin B and Vancomycin (Vanco). The hydrogel is designed as a specialized wound dressing that eradicates existing bacteria and inhibits further bacteria growth, while, ameliorating the side effects of antibiotics and accelerating tissue repair and regeneration. The hydrogel exhibits potent antibacterial activities against both gram‐negative bacteria Escherichia coli (E. coli) and gram‐positive bacteria Staphylococcus aureus (S. aureus) with no observable toxicity to mouse fibroblast cell line NIH 3T3. These results demonstrate the immense potential of dextran‐PEG hydrogel as a wound dressing healthcare material in efficiently controlling bacteria growth in complex biological systems.     

Pullulan hydrogels improve mesenchymal stem cell delivery into high-oxidative-stress wounds

Cell-based therapies for wound repair are limited by inefficient delivery systems that fail to protect cells from the acute inflammatory environment. Here, a biomimetic hydrogel system is described that is based on the polymer pullulan, a carbohydrate glucan known to exhibit potent antioxidant capabilities. It is shown that pullulan hydrogels are an effective cell delivery system and improve mesenchymal stem cell survival and engraftment in high-oxidative-stress environments. The results suggest that glucan hydrogel systems may prove beneficial for progenitor-cell-based approaches to skin regeneration.