Electrospun Silk Material Systems for Wound Healing

The functional properties of six distinct electrospun silk material groups were evaluated to assess conformational and biocompatible characteristics related to wound dressings. In a hydrated state, all six silk matrices exhibited absorption, water vapor transmission, oxygen permeation and enzymatic biodegradation suitable for full‐thickness wound sites. Employing constrained drying techniques, silk concentration was a determinate factor influencing material structural properties related to the storage and distribution of such wound dressing systems. Subsequently, three electrospun silk models demonstrated ideal biomaterial properties with potential utility for wound dressings.

     

Bioactive Applications for Electrospun Fibers

Electrospinning is a versatile technique providing highly tunable nanofibrous nonwovens. Many biomedical applications have been developed for nanofibers, among which the production of antimicrobial mats stands out. The production of scaffolds for tissue engineering, fibers for controlled drug release, or active wound dressings are active fields of research exploiting the possibilities offered by electrospun materials. The fabrication of materials for active food packaging or membranes for environmental applications is also reviewed. We attempted to give an overview of the most recent literature related with applications in which nanofibers get in contact with living cells and develop a nano-bio interface.     

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.     

Bioinspired Platelet-Anchored Electrospun Meshes for Tight Inflammation Manipulation and Chronic Diabetic Wound Healing

Tight manipulation of the initial leukocytes infiltration and macrophages plasticity toward the M2 phenotype remain a challenge for diabetic wound healing. Inspired by the platelet function and platelet–macrophage interaction, a platelet-anchored polylactic acid-b-polyethylene glycol-b-polylactic acid (PLA-PEG-PLA) electrospun dressing is developed for inflammatory modulation and diabetic wounds healing acceleration. PLA-PEG-PLA electrospun meshes encapsulated with thymosin β4 (Tβ4) and CaCl₂ is fabricated with electrospinning, followed by immersion of electrospun mesh in platelet-rich plasma to firmly anchor the platelets. It is demonstrated that the anchored platelets on electrospun mesh can enhance the initial macrophage recruitment and control the Tβ4 release from electrospun meshes to facilitate the macrophages polarization to the M2 phenotype. The inflammatory regulation promotes the expression of vascular endothelial growth factor and the migration of vascular endothelial cells for angiogenesis, resulting in accelerated diabetic wounds healing. Therefore, this work paved a new way to design platelet-inspired electrospun meshes for inflammation manipulation and diabetic wound healing.     

Poly(3-hexylthiophene)/Poly(methyl methacrylate) Core-Shell Electrospun Fibers for Sensory Applications

New electrospun (ES) sensory fibers consisted of poly(methyl methacrylate) (PMMA) core and poly(3-hexylthiophene-2,5-diyl) (P3HT) shell were successfully prepared using a two-fluid coaxial electrospinning process. Field-emission scanning electron microscope (FE-SEM) studies showed that the prepared ES fibers had diameters of 500–700 nm and worm-like surface structure of P3HT on the fiber. Red emission fibers were exhibited from the laser confocal microscope. Upon exposed to air under light for two weeks, significant blue-shifting on both absorption and luminescence spectra was found on the prepared ES fibers. It was probably due to the chain scission occurred in the P3HT and led to the reduced conjugated length. The sensitivity of the ES fibers was much better than that of the spin-coated P3HT film from the comparison on the variation of photophysical properties. Besides, the EPR result indicated the formation of the P3HT · O₂ charge transfer complex (CTC), leading to the fiber conductivity of 10⁻⁶ S/cm without an external doping. The present study demonstrates that conjugated polymer based ES core-shell fibers may have potential applications for oxygen-sensing devices.     

Antimicrobial and Wound Treatment Aspects of Micro‐ and Nanoformulations of Carboxymethyl,Dialdehyde, and TEMPO‐Oxidized Derivatives of Cellulose: Recent Advances

The remedy for infected chronic wounds such as diabetic foot ulcers is more complicated particularly in the case of patients with an inefficient immune system. Also, fighting against microbial infections in the wound site by available antibiotics may not be effective because of emerging antibiotic resistance properties among pathogenic bacteria and fungi. Recently, applications of micro‐ and nanoformulations of biomaterials have demonstrated improved therapeutic abilities for wound dressings. In this way, carboxymethyl, dialdehyde, and 2,2,6,6‐tetramethylpiperidine‐1‐oxyl‐oxidized celluloses are common biomaterials having outstanding physicochemical and therapeutic properties compared to unmodified cellulose. Therefore, in this review, recent progress in the field of wound healing and antimicrobial activities of these derivatives are presented and discussed.     

Functional Microneedle Patch for Wound Healing and Biological Diagnosis and Treatment

Wound healing, especially chronic wounds, has been one of the major challenges in the field of biomedicine. Drug therapy alone is not effective, so a variety of functional wound healing dressings have been developed. Microneedles have attracted more and more attentions in the field of wound healing dressings due to their penetration and high drug delivery efficiency. In this review, all the studies on the application of microneedles in wound healing in recent years are summarized, classify different microneedles according to their functions in the process of wound healing, discuss the current challenges in the transformation of microneedle technology toward clinical applications, and finally look forward to the future design and development directions of microneedles in this field.     

Bioactive Electrospun Fibers of Poly(ε-Caprolactone) Incorporating α-Tocopherol for Food Packaging Applications

Antioxidant activity is an important feature for food contact materials such as packaging, aiming to preserve freshness and retard food spoilage. Common bioactive agents are highly susceptible to various forms of degradation; therefore, protection is required to maintain functionality and bioavailability. Poly(ε-caprolactone) (PCL), a biodegradable GRAS labeled polymer, was used in this study for encapsulation of α-tocopherol antioxidant, a major component of vitamin E, in the form of electrospun fibers. Rheological properties of the fiber forming solutions, which determine the electrospinning behavior, were correlated with the properties of electrospun fibers, e.g., morphology and surface properties. Interactions through hydrogen bonds were evidenced between the two components. These have strong effect on structuration of macromolecular chains, especially at low α-tocopherol amounts, decreasing viscosity and elastic modulus. Intra-molecular interactions in PCL strengthen at high α-tocopherol amounts due to decreased solvation, allowing good structural recovery after cease of mechanical stress. Morphologically homogeneous electrospun fibers were obtained, with ~6 μm average diameter. The obtained fibers were highly hydrophobic, with fast release in 95% ethanol as alternative simulant for fatty foods. This induced good in vitro antioxidant activity and significant in vivo reduction of microbial growth on cheese, as determined by respirometry. Therefore, the electrospun fibers from PCL entrapping α-tocopherol as bioactive agent showed potential use in food packaging materials.     

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.     

Characterization of Collagen/Lipid Nanoparticle–Curcumin Cryostructurates for Wound Healing Applications

Curcumin‐loaded collagen cryostructurates have been devised for wound healing applications. Curcumin displays strong antioxidant, antiseptic, and anti‐inflammatory properties, while collagen is acknowledged for promoting cell adhesion, migration and differentiation. However, when curcumin is loaded directly into collagen hydrogels, it forms large molecular aggregates and clogs the matrix pores. A double‐encapsulation strategy is therefore developed by loading curcumin into lipid nanoparticles (LNP), and embedding these particles inside collagen scaffolds. The resulting collagen/LNP cryostructurates have an optimal fibrous structure with ≈100 µm average pore size for sustaining cell migration. Results show that collagen is structurally unaltered and that nanoparticles are homogeneously distributed amidst collagen fibers. Hydrogels soaked in saline buffer release about 20 to 30% of their nanoparticles content within 24 h, while achieved 100% release after 25 days. When exposed to NIH 3T3 fibroblasts, these hydrogels provide a satisfactory scaffold for cell interaction as early as 4 h after seeding, with no cytotoxic counter effect. These positive features make the collagen/lipid cryostructurates a promising material for further use in wound healing.     

Photothermal Hydrogels for Promoting Infected Wound Healing

Photothermal therapies (PTT), with spatiotemporally controllable antibacterial capabilities without inducing resistance, have shown encouraging prospects in the field of infected wound treatments. As an important platform for PTT, photothermal hydrogels exhibit attractive advantages in the field of infected wound treatment due to their excellent biochemical properties and have been intensively explored in recent years. This review summarizes the progress of the photothermal hydrogels for promoting infected wound healing. Three major elements of photothermal hydrogels, i.e., photothermal materials, hydrogel matrix, and construction methods, are introduced. Furthermore, different strategies of photothermal hydrogels in the treatment of infected wounds are summarized. Finally, the challenges and prospects in the clinical treatment of photothermal hydrogels are discussed.     

Bioactives from Bee Products and Accompanying Extracellular Vesicles as Novel Bioactive Components for Wound Healing

In recent years, interest has surged among researchers to determine compounds from bee products such as honey, royal jelly, propolis and bee pollen, which are beneficial to human health. Mass spectrometry techniques have shown that bee products contain a number of proven health-promoting compounds but also revealed rather high diversity in the chemical composition of bee products depending on several factors, such as for example botanical sources and geographical origin. In the present paper, we present recent scientific advances in the field of major bioactive compounds from bee products and corresponding regenerative properties. We also discuss extracellular vesicles from bee products as a potential novel bioactive nutraceutical component. Extracellular vesicles are cell-derived membranous structures that show promising potential in various therapeutic areas. It has been extensively reported that the use of vesicles, which are naturally formed in plant and animal cells, as delivery agents have many advantages. Whether the use of extracellular vesicles from bee products represents a new solution for wound healing remains still to be elucidated. However, promising results in specific applications of the bee products in wound healing and tissue regenerative properties of extracellular vesicles provide a good rationale to further explore this idea.     

Bee Venom in Wound Healing

Bee venom (BV), also known as api-toxin, is widely used in the treatment of different inflammatory diseases such as rheumatoid arthritis or multiple sclerosis. It is also known that BV can improve the wound healing process. BV plays a crucial role in the modulation of the different phases of wound repair. It possesses anti-inflammatory, antioxidant, antifungal, antiviral, antimicrobial and analgesic properties, all of which have a positive impact on the wound healing process. The mentioned process consists of four phases, i.e., hemostasis, inflammation, proliferation and remodeling. The impaired wound healing process constitutes a significant problem especially in diabetic patients, due to hypoxia state. It had been found that BV accelerated the wound healing in diabetic patients as well as in laboratory animals by impairing the caspase-3, caspase-8 and caspase-9 activity. Moreover, the activity of BV in wound healing is associated with regulating the expression of transforming growth factor (TGF-β1), vascular endothelial growth factor and increased collagen type I. BV stimulates the proliferation and migration of human epidermal keratinocytes and fibroblasts. In combination with polyvinyl alcohol and chitosan, BV significantly accelerates the wound healing process, increasing the hydroxyproline and glutathione and lowering the IL-6 level in wound tissues. The effect of BV on the wounds has been proved by numerous studies, which revealed that BV in the wound healing process brings about a curative effect and could be applied as a new potential treatment for wound repair. However, therapy with bee venom may induce allergic reactions, so it is necessary to assess the existence of the patient’s hypersensitivity to apitoxin before treatment.     

Collagen Peptides Derived from Sipunculus nudus Accelerate Wound Healing

Marine collagen peptides have high potential in promoting skin wound healing. This study aimed to investigate wound healing activity of collagen peptides derived from Sipunculus nudus (SNCP). The effects of SNCP on promoting healing were studied through a whole cortex wound model in mice. Results showed that SNCP consisted of peptides with a molecular weight less than 5 kDa accounted for 81.95%, rich in Gly and Arg. SNCP possessed outstanding capacity to induce human umbilical vein endothelial cells (HUVEC), human immortalized keratinocytes (HaCaT) and human skin fibroblasts (HSF) cells proliferation and migration in vitro. In vivo, SNCP could markedly improve the healing rate and shorten the scab removal time, possessing a scar-free healing effect. Compared with the negative control group, the expression level of tumor necrosis factor-α, interleukin-1β and transforming growth factor-β1 (TGF-β1) in the SNCP group was significantly down-regulated at 7 days post-wounding (p < 0.01). Moreover, the mRNA level of mothers against decapentaplegic homolog 7 (Smad7) in SNCP group was up-regulated (p < 0.01); in contrast, type II TGF-β receptors, collagen I and α-smooth muscle actin were significantly down-regulated at 28 days (p < 0.01). These results indicate that SNCP possessed excellent activity of accelerating wound healing and inhibiting scar formation, and its mechanism was closely related to reducing inflammation, improving collagen deposition and recombination and blockade of the TGF-β/Smads signal pathway. Therefore, SNCP may have promising clinical applications in skin wound repair and scar inhibition.     

Peptide‐Based Carbohydrate Receptors

A broad spectrum of physiological processes is mediated by highly specific noncovalent interactions of carbohydrates and proteins. In a recent communication we identified several cyclic hexapeptides in a dynamic combinatorial library that interact selectively with carbohydrates with high binding constants in water. Herein, we report a detailed investigation of the noncovalent interaction of two cyclic hexapeptides (Cys‐His‐Cys (which we call HisHis) and Cys‐Tyr‐Cys (which we call TyrTyr)) with a selection of monosaccharides and disaccharides in aqueous solution. The parallel and antiparallel isomers of HisHis or TyrTyr were synthesized separately, and their interaction with monosaccharides and disaccharides in aqueous solution was studied by isothermal titration calorimetry, NMR spectroscopic titrations, and circular dichroism spectroscopy. From these measurements, we identified particularly stable complexes (K_a>1000 M ^?1) of the parallel isomer of HisHis with N‐acetylneuraminic acid and with methyl‐α‐D ‐galactopyranoside as well as of both isomers of TyrTyr with trehalose. To gain further insight into the structure of the peptide–carbohydrate complexes, structure prediction was performed using quantum chemical methods. The calculations confirm the selectivity observed in the experiments and indicate the formation of multiple intermolecular hydrogen bonds in the most stable complexes.     

Hyaluronic Acid (HA)‐Based Silk Fibroin/Zinc Oxide Core–Shell Electrospun Dressing for Burn Wound Management

Burn injuries represent a major life‐threatening event that impacts the quality of life of patients, and places enormous demands on the global healthcare systems. This study introduces the fabrication and characterization of a novel wound dressing made of core–shell hyaluronic acid–silk fibroin/zinc oxide (ZO) nanofibers for treatment of burn injuries. The core–shell configuration enables loading ZO—an antibacterial agent—in the core of nanofibers, which in return improves the sustained release of the drug and maintains its bioactivity. Successful formation of core–shell nanofibers and loading of zinc oxide are confirmed by transmission electron microscopy, Fourier‐transform infrared spectroscopy, and energy dispersive X‐ray. The antibacterial activity of the dressings are examined against Escherichia coli and Staphylococcus aureus and it is shown that addition of ZO improves the antibacterial property of the dressing in a dose‐dependent fashion. However, in vitro cytotoxicity studies show that high concentration of ZO (>3 wt%) is toxic to the cells. In vivo studies indicate that the wound dressings loaded with ZO (3 wt%) substantially improves the wound healing procedure and significantly reduces the inflammatory response at the wound site. Overall, the dressing introduced herein holds great promise for the management of burn injuries.     

Preparation of Silver Nanoparticles Incorporated Electrospun Polyurethane Nano-fibrous Mat for Wound Dressing

Polyurethane foam is currently used as an exudate absorptive wound dressing material. In this study silver (Ag) nanoparticles were incorporated into electrospun polyurethane (PU) nanofiber to enhance the antibacterial as well as wound healing properties. The electrospinning parameters were optimized for PU with and without silver nanoparticles. Silver nanoparticles were synthesized by aqueous and organic methods. The water absorption, antibacterial and cytocompatibility of the PU-Ag nanofibers were studied and compared to that of conventional PU foam. The results indicated that the PU-Ag nanofibers could be used for wound dressing applications.     

Antimicrobial Properties of Plant Fibers

Healthcare-associated infections (HAI), or nosocomial infections, are a global health and economic problem in developed and developing countries, particularly for immunocompromised patients in their intensive care units (ICUs) and surgical site hospital areas. Recurrent pathogens in HAIs prevail over antibiotic-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa. For this reason, natural antibacterial mechanisms are a viable alternative for HAI treatment. Natural fibers can inhibit bacterial growth, which can be considered a great advantage in these applications. Moreover, these fibers have been reported to be biocompatible and biodegradable, essential features for biomedical materials to avoid complications due to infections and significant immune responses. Consequently, tissue engineering, medical textiles, orthopedics, and dental implants, as well as cosmetics, are fields currently expanding the use of plant fibers. In this review, we will discuss the source of natural fibers with antimicrobial properties, antimicrobial mechanisms, and their biomedical applications.     

Effect of Moringa oleifera Leaf Extract on Excision Wound Infections in Rats: Antioxidant,Antimicrobial, and Gene Expression Analysis

The present study investigated the wound healing activity of Moringa oleifera leaf extract on an infected excision wound model in rats. Infection was induced using methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa. An investigation was also done to study the effect of Moringa extract on the vascular endothelial growth factor (VEGF) and transforming growth factor-beta 1 (TGF-β1) gene expression in vitro using human keratinocytes (HaCaT). The methanol extract of M. oleifera leaves was analyzed for the presence of phytochemicals by LCMS. The antimicrobial activity of the extract was also determined. Wound contraction, days for epithelization, antioxidant enzyme activities, epidermal height, angiogenesis, and collagen deposition were studied. M. oleifera showed an antimicrobial effect and significantly improved wound contraction, reduced epithelization period, increased antioxidant enzymes activity, and reduced capillary density. Effect of the extract was less in wounds infected with P. aeruginosa when compared to MRSA. The VEGF and TGF-β1 gene expression was increased by M. oleifera.