A Spray‐Filming Self‐Healing Hydrogel Fabricated from Modified Sodium Alginate and Gelatin as a Bacterial Barrier

Self‐healing hydrogels as wound dressings still face challenges in infection prevention, especially in the dressing of mass wounds, due to their inflexibility and the slow formation of the protective film on the wound. Therefore, designing a spray‐filming (rapid‐forming) hydrogel that can serve as a bacterial barrier is of particular significance in the development of wound dressings. Here, a self‐healing hydrogel based on adipic acid dihydrazide‐modified gelatin (Gel‐ADH) and monoaldehyde‐modified sodium alginate(SA‐mCHO) is prepared. Using dynamic, Schiff base bonds, the hydrogels exhibit excellent self‐healing properties. Moreover, the gelation time of SA‐mCHO/Gel‐ADH (SG) hydrogels is shortened to 2–21 s, resulting in rapid filming by spraying the two precursor solutions. In addition, the rapid spray‐filming ability might offer sufficient flexibility and rapidity for dealing with mass and irregular wounds. Notably, the bacterial barrier experiments show that the SG hydrogel films could form an effective barrier to Staphylococcus aureus and Candida albicans for 12 h. Therefore, SG hydrogels could be used in wound dressings and they show great promise in applications associated with mass and irregular traumas.     

Development of a Dual‐Functional Hydrogel Using RGD and Anti‐VEGF Aptamer

Synthetic molecular libraries hold great potential to advance the biomaterial development. However, little effort is made to integrate molecules with molecular recognition abilities selected from different libraries into a single biomolecular material. The purpose of this work is to incorporate peptides and nucleic acid aptamers into a porous hydrogel to develop a dual‐functional biomaterial. The data show that an anti‐integrin peptide can promote the attachment and growth of endothelial cells in a 3D porous poly(ethylene glycol) hydrogel and an antivascular endothelial growth factor aptamer can sequester and release VEGF of high bioactivity. Importantly, the dual‐functional porous hydrogel enhances the growth and survival of endothelial cells. This work demonstrates that molecules selected from different synthetic libraries can be integrated into one system for the development of novel biomaterials.     

抗菌水凝胶敷料的制备及性能

以乙二醇二缩水甘油醚(GDE)为偶联剂,将胍盐低聚物(PHMG)接枝到淀粉上,形成淀粉接枝物(Starch-g-PHMG)。然后,将一定比例的Starch-g-PHMG与淀粉-丙烯酸接枝共聚物共混,制备了抗菌水凝胶敷料(AHD)。通过红外光谱(FT-IR)、元素分析确定了Starch-g-PHMG的分子结构;通过吸液测试、抗菌测试表征了AHD的理化性能。结果表明:在反应温度为60°C,反应时间为3h,w(NaOH)=0.4%时,Starch-g-PHMG中PHMG的接枝效率最高,可达37.5%;AHD的吸液率随着Starch-g-PHMG含量的增加而减少;当w(PHMG)0.33%时,AHD对金黄色葡萄球菌与大肠杆菌的抑菌率可以达到100%。     

Injectable and self-healing hydrogels with tissue adhesiveness and antibacterial activity as wound dressings for infected wound healing

The design of wound dressings with excellent self-healing ability, adequate adhesion, good biocompatibility, and potential antibacterial ability is of great significance for the healing of infected wounds arising from human activities. Herein, a series of multi-functional hydrogel dressings, poly(ionized isocyanoethyl methacrylate-glutamine)/poly(hexamethylene guanidine) (iG_x/PHMG_y) hydrogels, were obtained through homopolymerization of fully ionized isocyanoethyl methacrylate-glutamine (iIEM-Gln) in the presence of poly(hexamethylene guanidine) (PHMG), in which strong hydrogen bonds were formed among urea groups in the P (iIEM-Gln) chain to form a stable hydrogel network. The prepared iG_x/PHMG_y hydrogels exhibited adequate self-healing ability and tissue adhesion, which could be firmly adhered to the wound surface and remained intact during application. In addition, the presence of PHMG imparted good antibacterial activity to the hydrogels for the effective promotion of the wound healing in S. aureus infected skin wound on mice. Overall, this multi-functional hydrogel provides a facile and effective strategy for the design of infected wound dressings, and may show great potential in clinical applications.     

Fine tuning the assembly and gel behaviors of PEGylated polypeptide conjugates by the copolymerization of l‐alanine and γ‐benzyl‐l‐glutamate N‐carboxyanhydrides

Tuning the secondary structure of polypeptide is an effective strategy to modulate the assembly behaviors of polypeptide‐based copolymers. In this study, ring‐opening polymerization of l ‐alanine (Ala) and γ‐benzyl‐l ‐glutamate (BLG) N‐carboxyanhydrides was adopted using mPEG‐NH₂ as the initiator to prepare mPEG‐poly(l ‐alanine‐co‐γ‐benzyl‐l ‐glutamate) (PEAB) copolymers with various Ala to BLG ratios. ¹H NMR spectra and GPC test confirmed their well‐defined chemical structures. FT‐IR spectra indicated that at the powder state, all copolymers adopted both β‐sheet and α‐helical conformations. With the content of PBLG increased, the crystallization temperature and melting points of PEAB copolymers first rose then fell indicated by DSC curves. The self‐assembly of PEAB copolymers in dilute aqueous solution studied by DLS, TEM and circular dichroism spectra showed that PEAB copolymers self‐assembled into nanostructures with diverse morphologies and sizes due to distinct polypeptide conformations. Rheological analysis indicated that the alteration of the polypeptide composition can effectively modulate the modulus of PEAB assemblies in concentrated solutions. In all, copolymerization of two hydrophobic amino acid N‐carboxyanhydrides into the polypeptide block maybe an effective approach for modulating the assembly properties of PEGylated polypeptide. Besides, nanosilver‐encapsulated PEA or PEAB hydrogel showed promising antibacterial effect against Staphylococcus aureus and Bacillus subtillis. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017 , 55, 1512–1523     

肽自组装水凝胶的制备及在生物医学中的应用

短肽自组装水凝胶作为一种新型的生物材料,具有生物相容性高、免疫原性低、含水量高、降解产物可被机体重吸收利用、结构与天然细胞外基质类似等优点,使其在材料科学、生物医药及临床医学等领域具有广阔的应用前景。在这篇综述中,我们主要介绍了常用的几种制备稳定的肽自组装水凝胶方法,包括酶催化的水凝胶化、化学/物理交联的水凝胶化以及光催化的水凝胶化。进一步,我们介绍一些关于肽自组装水凝胶在药物递送和抗肿瘤治疗、抗菌和伤口愈合以及3D生物打印和组织工程中的应用。我们希望通过本文的论述能引起更多的人对肽自组装水凝胶的关注,以推进其在生物医学领域应用的发展。     

Antibacterial,Adhesive, and Conductive Hydrogel for Diabetic Wound Healing

Diabetic mellitus is one of the leading causes of chronic wounds and remains a challenging issue to be resolved. Herein, a hydrogel with conformal tissue adhesivity, skin-like conductivity, robust mechanical characteristics, as well as active antibacterial function is developed. In this hydrogel, silver nanoparticles decorated polypyrrole nanotubes (AgPPy) and cobalt ions (Co²⁺) are introduced into an in situ polymerized poly(acrylic acid) (PAA) and branched poly(ethylenimine) (PEI) network (PPCA hydrogel). The PPCA hydrogel provides active antibacterial function through synergic effects from protonated PEI and AgPPy nanotubes, with a tissue-like mechanical property (≈16.8 ± 4.5 kPa) and skin-like electrical conductivity (≈0.048 S m⁻¹). The tensile and shear adhesive strength (≈15.88 and ≈12.76 kPa, respectively) of the PPCA hydrogel is about two- to threefold better than that of fibrin glue. In vitro studies show the PPCA hydrogel is highly effective against both gram-positive and gram-negative bacteria. In vivo results demonstrate that the PPCA hydrogel promotes diabetic wounds with accelerated healing, with notable inflammatory reduction and prominent angiogenesis regeneration. These results suggest the PPCA hydrogel provide a promising approach to promote diabetic wound healing.     

O‐Mannosylation Affords a Glycopeptide Hydrogel with Inherent Antibacterial Activities against E. coli via Multivalent Interactions between Lectins and Supramolecular Assemblies

Multivalent carbohydrate–lectin interactions play a crucial role in bacterial infection. Biomimicry of multivalent glycosystems represents a major strategy in the repression of bacterial growth. In this study, a new kind of glycopeptide (Naphthyl‐Phe‐Phe‐Ser‐Tyr, NMY) scaffold with mannose modification is designed and synthesized, which is able to perform supramolecular self‐assembly with the assistance of catalytic enzyme, and present multiple mannose ligands on its self‐assembled structure to target mannose‐binding proteins. Relying on multivalent carbohydrate–lectin interactions, the glycopeptide hydrogel is able to bind Escherichia coli (E. coli) in high specificity, and result in bacterial adhesion, membrane disruption and subsequent cell death. In vivo wound healing assays reveal that this glycopeptide hydrogel exhibits considerable potentials for promoting wound healing and preventing E. coli infection in a full‐thickness skin defect mouse model. Therefore, through a specific mannose–lectin interaction, a biocompatible hydrogel with inherent antibacterial activity against E. coli is achieved without the need to resort to antibiotic or antimicrobial agent treatment, highlighting the potential role of sugar‐coated nanomaterials in wound healing and control of bacterial pathogenesis.     

Gallic Acid-Loaded Sodium Alginate-Based (Polyvinyl Alcohol-Co-Acrylic Acid) Hydrogel Membranes for Cutaneous Wound Healing: Synthesis and Characterization

Traditional wound dressings often cannot treat wounds caused by bacterial infections or other wound types that are insensitive to these wound treatments. Therefore, a biodegradable, bioactive hydrogel wound dressing could be an effective alternative option. The purpose of this study was to develop a hydrogel membrane comprised of sodium alginate, polyvinyl alcohol, acrylic acid, and gallic acid for treating skin wounds. The newly developed membranes were analyzed using Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM), X-ray diffraction analysis (XRD), sol-gel fraction, porosity, mechanical strength, swelling, drug release and data modelling, polymeric network parameters, biodegradation, and antioxidation (DPPH and ABTS) and antimicrobial activity against Gram-positive and negative bacteria. The results revealed that hydrogel membranes were crosslinked successfully and had excellent thermal stability, high drug loading, greater mechanical strength, and exhibited excellent biodegradation. Additionally, the swelling ability and the porosity of the surface facilitated a controlled release of the encapsulated drug (gallic acid), with 70.34% release observed at pH 1.2, 70.10% at pH 5.5 (normal skin pH), and 86.24% at pH 7.4 (wounds pH) in 48 h. The gallic acid-loaded hydrogel membranes showed a greater area of inhibition against Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli bacteria as well as demonstrated excellent antioxidant properties. Based on Franz cell analyses, the permeation flux of the drug from optimized formulations through mice skin was 92 (pH 5.5) and 110 (pH 7.4) μg/cm²·h⁻¹. Moreover, hydrogel membranes retained significant amounts of drug in the skin for 24 h, such as 2371 (pH 5.5) and 3300 µg/cm² (pH 7.4). Acute dermal irritation tests in rats showed that hydrogel membranes were nonirritating. Hydrogel membranes containing gallic acid could be an effective option for improving wound healing and could result in faster wound healing.     

Chitosan-Placental ECM Composite Thermos-Responsive Hydrogel as a Biomimetic Wound Dressing with Angiogenic Property

Attempts are being made to develop an ideal wound dressing with excellent biomechanical and biological properties. Here, a thermos-responsive hydrogel is fabricated using chitosan (CTS) with various concentrations (1%, 2.5%, and 5% w/v) of solubilized placental extracellular matrix (ECM) and 20% β-glycerophosphate to optimize a smart wound dressing hydrogel with improved biological behavior. The thermo-responsive CTS (TCTS) alone or loaded with ECMs (ECM-TCTS) demonstrate uniform morphology using SEM. TCTS and ECM1%-TCTS and ECM2.5%-TCTS show a gelation time of 5 min at 37 °C, while no gel formation is observed at 4 and 25 °C. ECM5%-TCTS forms gel at both 25 and 37 °C. The degradation and swelling ratios increase as the ECM content of the hydrogel increase. All the constructs show excellent biocompatibility in vitro and in vivo, however, the hydrogels with a higher concentration of ECM demonstrate better cell adhesion for fibroblast cells and induce expression of angiogenic factors (VEGF and VEGFR) from HUVEC. Only the ECM5%-TCTS has antibacterial activity against Acinetobacter baumannii ATCC 19606. The data obtained from the current study suggest the ECM2.5%-TCTS as an optimized smart biomimetic wound dressing with improved angiogenic properties now promises to proceed with pre-clinical and clinical investigations.     

Mussel-Inspired Adhesive,Antibacterial, and Stretchable Composite Hydrogel for Wound Dressing

Hydrogels have attracted extensive attention in the field of biomedicine because of their similar structure to extracellular matrix (ECM) and good biocompatibility. However, the adhesiveness, mechanical properties, and antibacterial properties of conventional hydrogels are not satisfactory. In this study, multifunctional chitosan/polydopamine/polyacrylamide (CS/PDA/PAM) hydrogels are prepared through a nature-inspired strategy. The catechol group of polydopamine (PDA) component endows CS/PDA/PAM hydrogels with tissue adhesion and self-healing properties. The introduction of chitosan (CS) not only greatly improves antibacterial ability, but also enhances the mechanical properties of CS/PDA/PAM hydrogels. Skin wound healing experiments show that CS/PDA/PAM hydrogels could accelerate skin tissue regeneration and promote wound healing. Therefore, CS/PDA/PAM hydrogels have great potential in the application of new wound dressings.     

Preparation and Application of Quaternized Chitosan- and AgNPs-Base Synergistic Antibacterial Hydrogel for Burn Wound Healing

Infection is the major reason that people die from burns; however, traditional medical dressings such as gauze cannot restrain bacterial growth and enhance the healing process. Herein, an organic- and inorganic-base hydrogel with antibacterial activities was designed and prepared to treat burn wounds. Oxidized dextran (ODex) and adipic dihydrazide grafted hyaluronic acid (HA-ADH) were prepared, mixed with quaternized chitosan (HACC) and silver nanoparticles to fabricate Ag@ODex/HA-ADH/HACC hydrogel. The hydrogel, composed of nature biomaterials, has a good cytocompatibility and biodegradability. Moreover, the hydrogel has an excellent antibacterial ability and presents fast healing for burn wounds compared with commercial Ag dressings. The Ag@ODex/HA-ADH/HACC hydrogel will be a promising wound dressing to repair burn wounds and will significantly decrease the possibility of bacterial infection.     

Non‐Covalently Stabilized Alginate Hydrogels as Functional Cell Scaffold Material

Biopolymers are an attractive class of compounds for being used in biomedical applications as they are widely available from biomass. Their drawback is the lack of mechanical stability and the ability to tune this properly. Covalent chemical cross‐linking is an often used approach but it limits usability due to legislation as well as the need of advanced and specialized knowledge by end users such as clinicians. Here, increased and tunable mechanical properties are achieved of alginate‐based hydrogels with non‐covalent approaches using linear polyethyleneimine (LPEI) as a polyelectrolyte rather than only multivalent metal ions (Ca²⁺). Gel stiffness increases with increasing LPEI content. Gel morphology changes from a thin fibrous mesh for alginate‐Ca²⁺ to thicker fibrous networks when LPEI is introduced. The gels are able to efficiently release encapsulated small molecular dyes and the gels are able to host cells. For the cell encapsulation human skin fibroblasts (HSkF) and human bone marrow‐derived mesenchymal stem cells (hBM‐MSC) are used. HSkF can be successfully incorporated without diminished viability while the matrix components and gel preparation method are not compatible with hBM‐MSC. The newly developed alginate‐based system is regarded as a potential candidate for wound dressing materials.

     

酸敏感型嵌段共聚物mPEG-acetal-PIB的合成、表征及用于构筑水凝胶敷料

利用点击化学(“Click”)反应, 成功制备了一种通过酸敏感缩醛基团键合的两亲性嵌段共聚物, 聚乙二醇单甲醚-acetal-聚异丁烯(简写为mPEG-acetal-PIB). 通过核磁共振氢谱(¹H NMR)、红外光谱(FT-IR)和凝胶渗透色谱(GPC)对聚合物的结构、分子量及分子量分布进行表征. 利用芘荧光探针法、动态激光光散射(DLS)和透射电子显微镜(TEM), 研究共聚物在水溶液中组装的临界聚集浓度(CAC), 胶束的粒径大小、分布以及形貌. 利用DLS跟踪测试聚合物胶束在酸性条件下的粒径变化, 验证mPEG-acetal-PIB的酸敏感性质. 随后, 在体系中引入α-环糊精(α-CD), 诱导形成超分子水凝胶. 利用X射线衍射(XRD)分析PEG与α-CD的包结络合作用, 流变仪测试水凝胶的凝胶化时间和黏弹性. 通过体外细胞毒性试验(MTT法)证明嵌段共聚物mPEG-acetal-PIB及水凝胶均具有良好的生物相容性. 这种水凝胶能够保持创面湿润, 具有温和的冷却作用, 并且由于其带有酸敏感基团, 能够在偏酸性环境降解, 减少炎症发生率, 在水凝胶创伤敷料中具有潜在的应用.     

Nature‐Inspired Bacterial Cellulose/Methylglyoxal (BC/MGO) Nanocomposite for Broad‐Spectrum Antimicrobial Wound Dressing

Bacterial cellulose (BC) is a natural material produced by Acetobacter xylinum, widely used in wound dressings due to the high water‐holding capacity and great mechanical strength. In this paper, a novel antimicrobial dressing made from BC/methylglyoxal (MGO) composite with a dip‐coating method inspired by naturally antimicrobial Manuka honey is proposed, which to our best knowledge, has not yet to be reported. Characterizations by scanning electron microscope and atomic force microscopy show the interconnected nanostructure of BC and MGO and increase surface roughness of the BC/MGO composite. Thermal analysis indicates high temperature stability of both BC and BC/MGO, while compared with BC, BC/MGO exhibits slightly weaker thermal stability possibly due to reduction of hydrogen bonding and increase of crystallinity. Mechanical test confirms the strong mechanical property of BC and BC/MGO nanocomposite. From the disk diffusion antimicrobial test, the BC/MGO nanocomposite with highest MGO concentration (4%) shows great zone inhibition diameter (around 14.3, 12.3, 17.1, and 15.5 mm against Micrococcus luteus, Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli). Compared with other antimicrobial wound dressing composite materials, the proposed BC/MGO nanocomposite has among the greatest antimicrobial property against broad‐spectrum bacteria, making it a promising antimicrobial dressing in chronic wounds care.     

Hydrogel Dressing Containing Basic Fibroblast Growth Factor Accelerating Chronic Wound Healing in Aged Mouse Model

Due to the decreasing self-repairing ability, elder people are easier to form chronic wounds and suffer from slow and difficult wound healing. It is desirable to develop a novel wound dressing that can accelerate chronic wound healing in elderly subjects to decrease the pain of patients and save medical resources. In this work, Heparin and basic fibroblast growth factor(bFGF) were dissolved in the mixing solution of 4-arm acrylated polyethylene glycol and dithiothreitol to form hydrogel dressing in vitro at room temperature without any catalysts, which is convenient and easy to handle in clinic application. In vitro re-lease test shows the bFGF could be continuously released for at least 7 days, whereas the dressing surface integrity maintained for 3 days degradation in PBS solution. Three groups of treatments including bFGF-Gel, bFGF-Sol and control without any treatment were applied on the full-thickness wound on the 22 months old mice back. The wound closure rate and histological and immunohistochemical staining all illustrated that bFGF-Gel displayed a better wound healing effect than the other two groups. Thus, as-prepared hydrogel dressing seems supe-rior to current clinical treatment and more effective in elderly subjects, which shows promising potential to be applied in the clinic.     

Cotton‐hydrogel composite for improved wound healing: Antimicrobial activity and anti‐inflammatory evaluation—Part 2

Infection is one of the major risk factors for the development of chronic wounds. Antimicrobial wound dressing has been pointed out as a viable option for the prevention and treatment of wound infections. Thus, we developed a composite material based on cotton textile substrates functionalized with cyclodextrin‐hydroxypropyl methyl cellulose‐based hydrogel. The composites' ability to encapsulate and release gallic acid (antimicrobial phenolic acid) was evaluated, as well as their mechanical properties and antimicrobial and anti‐inflammatory capacity. All composites were able to retain gallic acid in their structure, with similar loading profile. The presence of gallic acid on composites was confirmed by FTIR and TGA. Composites storage moduli was reduced by the presence of gallic acid. The results suggest a straight relation between the swelling ability and gallic acid drug delivery profile. The drug delivery mechanism, of the developed composites, was mainly controlled by Fickian diffusion, based on the experimental data fitting to the Peppas‐Sahlin model. Gallic acid antimicrobial and anti‐inflammatory properties were transferred to the composite materials. According to the results, the developed composites can be applied on the prevention or treatment of chronic wounds.     

An Extracellular Matrix‐Mimicking Hydrogel for Full Thickness Wound Healing in Diabetic Mice

An extracellular matrix‐mimicking hydrogel is developed consisting of a hyaluronan‐derived component with anti‐inflammatory activity, and a gelatin‐derived component offering adhesion sites for cell anchorage. The in situ‐forming hyaluronan‐gelatin (HA‐GEL) hydrogel displays a sponge‐like microporous morphology. Also, HA‐GEL shows a rapid swelling pattern reaching maximum weight swelling ratio within 10 min, while at the equilibrium state, fully swollen hydrogels display an exceedingly high water content with ≈2000% of the dry gel weight. Under typical 2D cell culture conditions, murine 3T3 fibroblasts adhere to, and proliferate on top of the HA‐GEL substrates, which demonstrate that HA‐GEL provides a favorable microenvironment for cell survival, adhesion, and proliferation. In vivo healing study further demonstrates HA‐GEL as a viable and effective treatment option to improve the healing outcome of full thickness wounds in diabetic mice by effectively depleting the inflammatory chemokine monocyte chemoattractant protein‐1 in the wound bed.     

pH‐Modulating Poly(ethylene glycol)/Alginate Hydrogel Dressings for the Treatment of Chronic Wounds

The development of chronic wounds has been frequently associated with alkaline pH values. The application of pH‐modulating wound dressings can, therefore, be a promising treatment option to promote normal wound healing. This study reports on the development and characterization of acidic hydrogel dressings based on interpenetrating poly(ethylene glycol) diacrylate/acrylic acid/alginate networks. The incorporation of ionizable carboxylic acid groups results in high liquid uptake up to 500%. The combination of two separate polymer networks significantly improves the tensile and compressive stability. In a 2D cell migration assay, the application of hydrogels (0% to 1.5% acrylic acid) results in complete “wound” closure; hydrogels with 0.25% acrylic acid significantly increase the cell migration velocity to 19.8 ± 1.9 µm h⁻¹. The most promising formulation (hydrogels with 0.25% acrylic acid) is tested on 3D human skin constructs, increasing keratinocyte ingrowth into the wound by 164%.