Design of moxifloxacin encapsulated network hydrogel wound dressings: Evaluation of polymer-drug,polymer-blood,and polymer-bio membrane interactions

It is an exploration of the inherent wound-healing tendency of Azadirachta indica gum (AIG) or neem gum polysaccharides to develop the hydrogel wound dressings with enhanced potential during wound management. Herein this research work, antibiotic moxifloxacin encapsulated AIG network copolymeric hydrogels were developed by functionalizing with carbapol and poly(acrylamide) [poly(AAm)] for better wound healing. The polymer-drug, polymer-blood, and polymer-bio membrane interactions were evaluated in biomedical properties. The copolymeric network structure was confirmed by scanning electron micrographs (SEMs), atomic force microscopy (AFM), Fourier transform infrared spectroscopy (FTIR), and ¹³C solid-state nuclear magnetic resonance (NMR) spectroscopy. The results confirmed sustained release of the moxifloxacin with diffusion by non-Fickian process and Korsmeyer–Peppas kinetic model in the phosphate buffer saline (PBS). These interactions inferred the blood-compatible (hemolytic index 3.41 ± 0.70%) and mucoadhesive nature (polymer-biomembrane detachment force 0.09 ± 0.01 mN) of hydrogel dressing. The per gram of hydrogel dressings absorbed 10.22 ± 0.23 g of simulated wound fluid which is very useful to maintain moist wound environment for better wound healing. All these interactions and properties indicated the suitability of the hydrogel material for wound dressing applications for better wound care.     

Chitosan/Alginate Hydrogel Dressing Loaded FGF/VE-Cadherin to Accelerate Full-Thickness Skin Regeneration and More Normal Skin Repairs

The process of full-thickness skin regeneration is complex and has many parameters involved, which makes it difficult to use a single dressing to meet the various requirements of the complete regeneration at the same time. Therefore, developing hydrogel dressings with multifunction, including tunable rheological properties and aperture, hemostatic, antibacterial and super cytocompatibility, is a desirable candidate in wound healing. In this study, a series of complex hydrogels were developed via the hydrogen bond and covalent bond between chitosan (CS) and alginate (SA). These hydrogels exhibited suitable pore size and tunable rheological properties for cell adhesion. Chitosan endowed hemostatic, antibacterial properties and great cytocompatibility and thus solved two primary problems in the early stage of the wound healing process. Moreover, the sustained cytocompatibility of the hydrogels was further investigated after adding FGF and VE-cadherin via the co-culture of L929 and EC for 12 days. The confocal 3D fluorescent images showed that the cells were spherical and tended to form multicellular spheroids, which distributed in about 40–60 μm thick hydrogels. Furthermore, the hydrogel dressings significantly accelerate defected skin turn to normal skin with proper epithelial thickness and new blood vessels and hair follicles through the histological analysis of in vivo wound healing. The findings mentioned above demonstrated that the CS/SA hydrogels with growth factors have great potential as multifunctional hydrogel dressings for full-thickness skin regeneration incorporated with hemostatic, antibacterial, sustained cytocompatibility for 3D cell culture and normal skin repairing.     

Characterization of PVA/glycerin hydrogels made by <Emphasis Type="Italic">γ</Emphasis>-irradiation for advanced wound dressings

The aim of this study was to investigate the enhanced absorption property of PVA/Glycerin (PVA/Gly) hydrogel for advanced wound dressing. A simple crosslinking method was introduced to prepare the PVA/Gly hydrogels with the use of γ-irradiation. An absorption ratio and thermal properties of the PVA/Gly hydrogels can be controlled by varying the irradiation dose and weight ratio of the PVA/Gly. When the PVA/Gly content was 20/5 wt% and the irradiation dose at 25 kGy, the PVA/Gly hydrogels showed excellent absorption properties (>350%). These results imply that the PVA/Gly hydrogel is highly absorbent and converts wound exudates to the hydrogel matrices that create a moist and clean environment in the wound healing process. Therefore, the PVA/Gly hydrogel prepared by this method can be used as an advanced wound dressing.     

Wound dressings: Current advances and future directions

Wound healing is a complicated and continuous process affected by several factors, which needs an appropriate surrounding to achieve accelerated healing. Wound healing process recruits three different phases: inflammation, proliferation, and maturation. Due to the different types of wounds, as well as the advancement in medical technology, various products have been developed to repair different skin lesions. Our objective is to investigate the advancement in wound dressings from traditional to the current methods of treatment. The article presents the characteristics of an ideal wound dressing, the requirements for the appropriate selection of different types of wounds, and a detailed classification of wound dressings. Animal origin, herbal origin, and synthetic dressings are firstly introduced and reviewed. Then, nonmedicated dressings including alginate, hydrogel, and hydrocolloid dressings, as well as medicated dressings are discussed. Finally, the developmental prospectives of the new generations of wound dressings for future researches are presented. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136, 47738.     

Preparation and characterization of PVA/PVP/glycerin/antibacterial agent hydrogels using <Emphasis Type="Italic">γ</Emphasis>-irradiation followed by freeze-thawing

Hydrogels for wound dressings from a mixture of poly(vinyl alcohol) (PVA), poly(N-vinylpyrrolidone) (PVP), glycerin and an antibacterial agent were obtained by a γ-irradiation combined with freeze-thawing. The physical properties such as the gelation and swelling degree of the hydrogels were examined. When the PVP/PVA ratio was 6: 4 (wt%) and prepared by combined irradiation and freeze-thawing, it showed an excellent swelling capacity (>1,200%). The antibacterial effect of the hydrogels containing the antibacterial agents was observed to be effective as the concentration of antibacterial agents increased. The results demonstrated that hydrogel in a proper blending ratio could be used as a wound dressing that can accelerate wound healing with an antibacterial effect.     

Multifunctional gentamicin supplementation of poly(γ‐glutamic acid)‐based hydrogels for wound dressing application

The process of wound healing is composed of coagulation, inflammation, fibroplasia, collagenation, epithelization, and wound contraction. The wound dressing should protect the wound from bacterial infection, maintain a moist healing environment, and promote cell migration to reconstruct damaged tissue, and be easy to apply and remove to improve patient comfort. The purpose of our study was to develop multifunctional hydrogels composed of genipin‐crosslinked biodegradable biomaterials of poly(γ‐glutamic acid) and gelatin, encapsulating gentamicin to accelerate wound healing. The results of swelling ratio measurements clearly indicate that hydrogel composition of poly(γ‐glutamic acid)–gelatin had a higher swelling ratio and lower peel adhesion properties than gelatin hydrogel alone. In an in vitro study, the gentamicin incorporated in prepared hydrogels effectively inhibited target microorganisms and produced a higher expression of Type I collagen in fibroblast cells. Confocal laser scanning microscopy revealed that the fibroblast cells cultured in the hydrogel membranes produced fibroblast cell migration and showed a continuous lined cytoskeletal distributing status. In the in vivo study, it was found that the gentamicin incorporated in genipin‐crosslinked γ‐PGA–gelatin wound dressing demonstrates the potential of such biologically functionalized dressing to accelerate wound closure and, hence, its potential clinical usefulness. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Preparation of physically crosslinked PVA/HLC/SA hydrogel and exploration of its effects on full-thickness skin defects

Abstract

In this study, single factor experiments and orthogonal test were designed to fabricate a novel poly(vinyl alcohol) (PVA), human-like collagen (HLC) and sodium alginate (SA) composite hydrogel as wound dressings. The obtained hydrogel dressing was soft, elastic and breathable with uniform macro pores, and it remains soft after lyophilization which restore to the original appearance after absorbing a large amount of water. In vivo full-thickness skin defects treated with the hydrogel dressings in rabbit revealed that the hydrogel promoted wound healing through accelerating reepithelization and the growth of collagen fibers. All the results demonstrated the great potential of the hydrogel as wound dressing.     

Polyzwitterionic hydrogels as wound dressings with enzymatic debridement functionality for highly exuding wounds

Wound debridement is crucial for proper wound care as it promotes fast and efficient wound healing through removal of necrotic tissue. The latter not only impairs new healthy tissue formation but also increases the odour and the wound exudate, allowing bacteria and other harmful foreign invaders to spread and infect the wound. Hydrogel wound dressings are usually applied for promoting autolytic wound debridement but this is slow and not a very efficient process. On the other hand, enzymatic products for wound debridement are either ointments or gels and they are easily washed out when used for treating highly exuding wounds. This study is an attempt to combine enzymatic debridement functionality with the high swelling ability of polyzwitterionic networks and to produce an innovative dressing with debridement functionality for the healing of highly exuding wounds. For this purpose, two polyzwitterionic hydrogels were synthesized, poly(sulfobetaine methacrylate) and poly(carboxybetaine methacrylate) hydrogels, which were loaded with the protease subtilisin DY for imparting debridement functionality. The swelling ability and mechanical properties of zwitterionic polymer (ZP) hydrogels were shown to depend on their different propensities to physical network formation. Poly(carboxybetaine methacrylate) hydrogels demonstrated better capacity for wound exudate absorption as well as for exerting higher enzymatic debridement activity. Both ZP hydrogels were shown to be non‐cytotoxic which confirms their appropriateness for direct contact with injured tissues. Thus, the newly developed ZP hydrogels demonstrate the potential to be used as new dressing materials with enzymatic debridement functionality for highly exuding wounds. © 2019 The Authors. Polymer International published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.     

Poly(vinyl alcohol)/chitosan/honey/clay responsive nanocomposite hydrogel wound dressing

Many efforts have been made to develop modern wound dressings to overcome limitations of traditional ones. Smart nanocomposite hydrogels are appropriate candidates. In this work, a novel responsive nanocomposite hydrogel based on poly(vinyl alcohol)/chitosan/honey/clay was developed and evaluated as a novel wound dressing. The morphology and properties of synthesized nanocomposite hydrogels loaded with honey as a drug model were investigated. The exfoliated morphology of nanocomposite was confirmed by X‐ray diffractometry. Swelling studies were performed at 20 and 37 °C at various pH. The results showed that swelling increased as a result of temperature rise and maximum swelling occurred at a pH of 2. In vitro release of honey was also studied at the same conditions. Corresponding results indicated faster honey release rate at higher pH values. MTT results exhibited no cytotoxicity in nanocomposite hydrogel system. Investigation of antibacterial activity revealed more than 99% antibacterial activity for proposed system. In vivo results confirmed the wound healing ability of developed system. Generally, appropriate properties of proposed system made it ideal in wound dressing applications. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018 , 135, 46311.     

Theophylline‐loaded pectin‐based hydrogels. I. Effect of medium pH and preparation conditions on drug release profile

In this study, a series of theophylline‐loaded calcium pectin gel films were prepared in three different Ca⁺² concentrations with three different methods for wound dressing applications. Drug release performance of the films were investigated in four different medium pH in order to mimic wound healing pH conditions. Hydrogel films were characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, scanning electron microscopy and atomic force microscopy. Their absorbency (fluid handling), swelling behavior, dehydration rate, dispersion characteristic, dressing pH determination, water vapor permeability, oxygen permeability, surface contact angle, flexibility, Shore A hardness, mean mass per unit area and thickness were determined. The effect of the hydrogels on wound healing was evaluated with an in vitro wound healing assay. After evaluating all data, we suggested that the hydrogel film prepared with swelling method using 7% or 10% crosslinker and dried at 26 °C is more suitable for controlled drug release process. We showed that between pH 3.25 and 7.12 the form of the hydrogel did not change, and drug release was continuous. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2018 , 135, 46731.     

A comprehensive review of the polymer-based hydrogels with electrochemically synthesized silver nanoparticles for wound dressing applications

Modernization and improvement of wound dressing materials is an important topic in biomaterials and biomedicine fields, as the traditional materials are inadequate and susceptible to bacterial infections. In recent times, polymer-based hydrogel materials have presented themselves as excellent candidates for new-generation wound dressings with improved properties, such as high sorption ability, good mechanical properties, and low adhesiveness. Additionally, cross linked hydrogel matrices serve as excellent carriers for controlled release of antibacterial agents, such as silver nanoparticles (AgNPs), which are preferred over conventional antibiotics due to multi-phase mechanism of action and low susceptibility to induce bacterial resistance. Their incorporation inside polymer matrices allows improvement of wound dressing properties and sustained protection against bacterial infection. Electrochemical methods for AgNPs synthesis are facile and green alternatives to chemical routes, allowing the formation of highly stable AgNPs with strong antibacterial effect. In this article, we aim to provide a comprehensive review of the existing research on the topic of electrochemically synthesized silver nanoparticles incorporated in polymer matrices with a special focus on the chitosan-based hydrogels as prospective materials for wound dressing applications.     

Theophylline-loaded pectin-based hydrogels. II. Effect of concentration of initial pectin solution,crosslinker type and cation concentration of external solution on drug release profile

A series of drug-loaded pectin hydrogels were prepared by mixing method in two ion types, Ca⁺² or Zn⁺², for wound dressing applications and their drug release performances were investigated at pH 6.4 in four different calcium ion concentrations of external solution. Pectin hydrogels were synthesized in three different concentrations of initial pectin solution and theophylline was used as a model drug. Fourier transform infrared spectroscopy, scanning electron microscopy, and atomic force microscopy were used for hydrogel characterization. Additionally, fluid handling capacity, swelling behavior, dehydration rate, dispersion characteristic, dressing pH determination, water vapor permeability, oxygen permeability, surface contact angle, flexibility, mass per unit area, and thickness were determined for selected hydrogels. One of the most valuable contributions of our study is that the concentration of initial pectin solution and calcium ion concentration of external solution are very important parameters to obtain an effective drug release. After evaluating all data, we have shown that flexible and transparent pectin-based wound dressings can be synthesized as a controlled drug release system. Zinc-containing hydrogel was antibacterial against Staphylococcus aureus and Escherichia coli but not suitable for cell migration. On the other hand, calcium-based hydrogel was nontoxic on the fibroblast cells and it had no negative effect on cell migration. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136, 48155.     

Ultrasmall silver nanoparticles loaded in alginate–hyaluronic acid hybrid hydrogels for treating infected wounds

Nowadays, silver nanoparticles are in the limelight to control infection during wound healing process, and a vast variety of antimicrobial dressings based on colloidal silver have been marketed to fight wound invasion of pathogen bacteria, which represents one of the main adverse effects limiting the repair process. Here we propose a biofunctional hydrogel based on alginate (ALG) and hyaluronic acid (HA) embedding ultrasmall silver nanoparticles (usSN, <1?nm) as antimicrobial component. The hydrogels were fabricated in different size by a straightforward internal gelation method using CaCO₃ and glucono-δ-lactone. To follow usSN release from the hydrogels in aqueous media, catalytic activity of usSN-loaded hydrogels was evaluated. Results suggested that catalytic activity was low in intact hydrogels and high when hydrogels dissolved, which suggests that usSN firmly interact with polymer chains and are available in the medium depending on the extent of hydrogel degradation. HA-containing hydrogels showed faster dissolution in simulated physiological conditions and higher antibiofouling properties as compared to hydrogels made only of ALG. Free usSN were not toxic toward human mesenchymal stem cells (Ad-MSCs), previously isolated from subcutaneous adipose tissue biopsies, up to 50?µg/mL. At this concentration, viability of Ad-MSCs was unaffected whereas their motility was significantly higher as compared to control (p<0.01) for both free usSN and hydrogel integrating. Antimicrobial activity on clinical isolates of both Gram-positive and Gram-negative bacteria demonstrated that usSN at 50?µg/mL were able to kill all the bacteria tested after 24 and 48?h of contact time. In the case of hydrogels, a matrix effect was found and bacterial killing was significant only at 24?h and dependent on bacterial strain, being Gram-negative bacteria more susceptible. These results clearly indicate that usSN interaction with polymer network and exposure time can strongly affect usSN antimicrobial profile in the hydrogel and, in turn, timing of hydrogel change at injured site in a clinical setting. On the whole, ALG/HA hydrogels integrating usSN can be considered a suitable option to fabricate biofunctional dressings for hospitalized patients and worth of further in vivo investigation.     

Advances in wound dressing based on electrospinning nanofibers

In recent years, there has been a significant focus on bioactive dressings suitable for treating chronic and acute wounds. Electrospinning nanofibers are considered advanced dressing options due to their high porosity and permeability to air and water, effective barrier properties against external pathogens, and excellent resemblance to the extracellular matrix for wound healing and skin regeneration. This article reviews the recent advancements in the application of electrospinning nanofibers for bioactive wound healing. The review begins with an overview of the wound healing process and electrospinning methods. It then explores the advantages and disadvantages of different synthetic and natural polymers used in the preparation of electrospinning wound dressings. The natural polymers discussed in this review include collagen, gelatin, silk fibroin, chitosan, hyaluronic acid, and sodium alginate. Additionally, the review delves into commonly used synthetic polymers like polyvinyl alcohol, polyvinyl chloride, polyethylene lactone, polylactide, and polyurethane for wound dressing applications. Furthermore, the review examines the blending of natural and synthetic polymers to create high-performance wound dressings. It also explores the incorporation of functional additives, such as antimicrobial agents, growth factors, and natural extracts, into electrospinning nanofibers to expedite wound healing and tissue repair. In conclusion, electrospinning is an emerging technology that provides unique opportunities for designing more effective wound dressings and care products.     

类氨基酸基载药水凝胶敷料的制备与性能

为制备一种具有良好生物相容性、可控缓释的物理交联的水凝胶敷料,选用类氨基酸单体N-丙烯酰基甘氨酰胺（NAGA）与生物发酵产物衣康酸（IA）为单体,在紫外光条件下,通过自由基聚合,在不需要外加任何交联剂条件下即可形成水凝胶聚（N-丙烯酰基甘氨酰胺-衣康酸）（P(NAGA-IA)）。所得水凝胶具有溶胶-凝胶转变温度（UCST）、较高的水溶胀率（40倍）及力学性能（压缩模量最高540 kPa）、较优的药物负载性和缓释性,这是因为NAGA单元提供分子间多重氢键作用,进而赋予了水凝胶较优的综合性能;而IA单元赋予了聚合物的pH刺激响应性,从而可诱导药物的释放。因此,所得P (NAGA-IA)水凝胶可作敷料用于创伤治疗。     

Novel collagen‐based hydrogels with injectable,self‐healing,wound‐healing properties via a dynamic crosslinking interaction

Collagen‐based hydrogels have gained significant popularity in biomedical applications; however, traditional collagen hydrogels are easily disabled for lack of self‐healing properties due to their non‐reversible bonds. Here, a self‐healing collagen‐based hydrogel has been developed based on dynamic network chemistry, consisting of dynamic imine linkages between collagen and dialdehyde guar gum, as well as diol‐borate ester bonds between guar gum and borax. In addition, macromolecular interactions amongst macromolecules are involved. The above‐mentioned interactions were validated by Fourier transform infrared spectroscopy, sodium dodecyl sulfate polyacrylamide gel electrophoresis and DSC. The as‐prepared collagen‐based hydrogels showed good injectability and rapid self‐healing capacity (within 3 min) as reflected from injection tests, optical microscope observations, rheological measurements, as well as self‐healing studies. In addition, the collagen‐based hydrogels showed accelerated wound‐healing properties. This study offers a facile strategy to endow self‐healing ability on collagen‐based hydrogels without any external stimulus, which show great application potential as wound dressings. © 2020 Society of Chemical Industry     

Manipulating drug release from tridimensional porous substrates coated by initiated chemical vapor deposition

In the recent years, modern wound dressings have attracted much interest to accelerate wound healing processes with the topical delivery of drugs directly on wounds having a significant effect on wound rehabilitation. The objective of this study was to develop a model dressing that would not only provide wound protection from the environment but might also provide the possibility to keep it moist and deliver a drug for potential speeding the healing process. Poly(ethylene terephthalate), cotton fabrics, and polycaprolactone (PCL) nanofibers were used as different tridimensional porous substrates, loaded with a model drug, clotrimazole. The results show that the chemical structure and surface area to volume ratio of the pristine substrates affect the drug release profile. Coating of such substrates by hydrogels poly(2-hydroxyethyl methacrylate) (p-HEMA) and poly(methacrylic acid) (p-MAA) was successfully achieved by initiated chemical vapor deposition. This method was chosen because it is gentle and solventless and most important it can coat free areas within the three-dimensional structures. Scanning electron microscopy results revealed that p-HEMA and p-MAA conformally coated the fibers of the substrates. Moreover, drug release experiments showed that p-HEMA and p-MAA coatings provide barriers preventing sudden drug release. In conclusion, our results indicated the possibility of fabricating dressings containing a drug with tunable drug release profile depending on several parameters even though a strong porous structure exists. © 2019 The Authors. Journal of Applied Polymer Science published by Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136, 47858.     

Borrowing the Features of Biopolymers for Emerging Wound Healing Dressings: A Review

Wound dressing design is a dynamic and rapidly growing field of the medical wound-care market worldwide. Advances in technology have resulted in the development of a wide range of wound dressings that treat different types of wounds by targeting the four phases of healing. The ideal wound dressing should perform rapid healing; preserve the body’s water content; be oxygen permeable, non-adherent on the wound and hypoallergenic; and provide a barrier against external contaminants—at a reasonable cost and with minimal inconvenience to the patient. Therefore, choosing the best dressing should be based on what the wound needs and what the dressing does to achieve complete regeneration and restoration of the skin’s structure and function. Biopolymers, such as alginate (ALG), chitosan (Cs), collagen (Col), hyaluronic acid (HA) and silk fibroin (SF), are extensively used in wound management due to their biocompatibility, biodegradability and similarity to macromolecules recognized by the human body. However, most of the formulations based on biopolymers still show various issues; thus, strategies to combine them with molecular biology approaches represent the future of wound healing. Therefore, this article provides an overview of biopolymers’ roles in wound physiology as a perspective on the development of a new generation of enhanced, naturally inspired, smart wound dressings based on blood products, stem cells and growth factors.     

Development and Characterization of Highly Stable Silver NanoParticles as Novel Potential Antimicrobial Agents for Wound Healing Hydrogels

Recurrent microbial infections are a major cause of surgical failure and morbidity. Wound healing strategies based on hydrogels have been proposed to provide at once a barrier against pathogen microbial colonization, as well as a favorable environment for tissue repair. Nevertheless, most biocompatible hydrogel materials are more bacteriostatic than antimicrobial materials, and lack specific action against pathogens. Silver-loaded polymeric nanocomposites have efficient and selective activity against pathogenic organisms exploitable for wound healing. However, the loading of metallic nanostructures into hydrogels represents a major challenge due to the low stability of metal colloids in aqueous environments. In this context, the aim of the present study was the development of highly stable silver nanoparticles (AgNPs) as novel potential antimicrobial agents for hyaluronic acids hydrogels. Two candidate stabilizing agents obtained from natural and renewable sources, namely cellulose nanocrystals and ulvan polysaccharide, were exploited to ensure high stability of the silver colloid. Both stabilizing agents possess inherent bioactivity and biocompatibility, as well as the ability to stabilize metal nanostructures thanks to their supramolecular structures. Silver nitrate reduction through sodium borohydride in presence of the selected stabilizing agents was adopted as a model strategy to achieve AgNPs with narrow size distribution. Optimized AgNPs stabilized with the two investigated polysaccharides demonstrated high stability in phosphate buffer saline solution and strong antimicrobial activity. Loading of the developed AgNPs into photocrosslinked methacrylated hyaluronic acid hydrogels was also investigated for the first time as an effective strategy to develop novel antimicrobial wound dressing materials.     

In Situ Electrospinning Wound Healing Films Composed of Zein and Clove Essential Oil

Electrospun fibrous membranes have the potential to be effective wound dressings for promoting wound healing. However, the fabrication and application of the common electrospun fibrous wound dressings are usually complicated and separated. Here, electrospun zein/clove essential oil (CEO) fibrous membranes are fabricated and applied as a potential wound dressing through in situ electrospinning process by a portable electrospinning device. The in situ electrospinning process can directly electrospin zein/CEO membranes onto a wound site to cover the wound well and improve the convenience and comfort in use. The as‐spun zein/CEO membranes show a porous structure and exhibit higher gas permeability at 168.2 ± 43.3 mm s^?1, with superhydrophilicity to absorb the wound exudate and good biocompatibility as well as antibacterial effects to protect from infection. Moreover, the mice wound model study suggests that in situ electrospun zein/CEO promotes the wound healing process.