Microalgae-Based Biohybrid Microrobot for Accelerated Diabetic Wound Healing

A variety of wound healing platforms have been proposed to alleviate the hypoxic condition and/or to modulate the immune responses for the treatment of chronic wounds in diabetes. However, these platforms with the passive diffusion of therapeutic agents through the blood clot result in the relatively low delivery efficiency into the deep wound site. Here, a microalgae-based biohybrid microrobot for accelerated diabetic wound healing is developed. The biohybrid microrobot autonomously moves at velocity of 33.3 µm s⁻¹ and generates oxygen for the alleviation of hypoxic condition. In addition, the microrobot efficiently bound with inflammatory chemokines of interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) for modulating the immune responses. The enhanced penetration of microrobot is corroborated by measuring fibrin clots in biomimetic wound using microfluidic devices and the enhanced retention of microrobot is confirmed in the real wounded mouse skin tissue. After deposition on the chronic wound in diabetic mice without wound dressing, the wounds treated with microrobots are completely healed after 9 days with the significant decrease of inflammatory cytokines below 31% of the control level and the upregulated angiogenesis above 20 times of CD31⁺ cells. These results confirm the feasibility of microrobots as a next-generation platform for diabetic wound healing.     

Silicone-coated non-woven polyester dressing enhances reepithelialisation in a sheep model of dermal wounds

Negative-pressure wound therapy (NPWT) also known as V.A.C.?(Vacuum-assisted closure), is widely used to manage various type of wounds and accelerate healing. NPWT has so far been delivered mainly via open-cell polyurethane (PU) foam or medical gauze. In this study an experimental setup of sheep wound model was used to evaluate, under NPWT conditions, the performance of a silicone-coated non-woven polyester (N-WPE) compared with PU foam and cotton hydrophilic gauze, used as reference materials. Animals were anesthetized with spontaneous breathing to create three 3?×?3?cm skin defects bilaterally; each animal received three different samples on each side (n?=?6 in each experimental group) and was subjected to negative and continuous 125?mmHg pressure up to 16?days. Wound conditions after 1, 8 and 16?days of treatment with the wound dressings were evaluated based on gross and histological appearances. Skin defects treated with the silicone-coated N-WPE showed a significant decrease in wound size, an increase of re-epithelialization, collagen deposition and wound neovascularisation, and a minimal stickiness to the wound tissue, in comparison with gauze and PU foam. Taken all together these findings indicate that the silicone-coated N-WPE dressing enhances wound healing since stimulates higher granulation tissue formation and causes minor tissue trauma during dressing changes.     

Adhesive Hemostatic Conducting Injectable Composite Hydrogels with Sustained Drug Release and Photothermal Antibacterial Activity to Promote Full‐Thickness Skin Regeneration During Wound Healing

Developing injectable nanocomposite conductive hydrogel dressings with multifunctions including adhesiveness, antibacterial, and radical scavenging ability and good mechanical property to enhance full‐thickness skin wound regeneration is highly desirable in clinical application. Herein, a series of adhesive hemostatic antioxidant conductive photothermal antibacterial hydrogels based on hyaluronic acid‐graft‐dopamine and reduced graphene oxide (rGO) using a H₂O₂/HPR (horseradish peroxidase) system are prepared for wound dressing. These hydrogels exhibit high swelling, degradability, tunable rheological property, and similar or superior mechanical properties to human skin. The polydopamine endowed antioxidant activity, tissue adhesiveness and hemostatic ability, self‐healing ability, conductivity, and NIR irradiation enhanced in vivo antibacterial behavior of the hydrogels are investigated. Moreover, drug release and zone of inhibition tests confirm sustained drug release capacity of the hydrogels. Furthermore, the hydrogel dressings significantly enhance vascularization by upregulating growth factor expression of CD31 and improve the granulation tissue thickness and collagen deposition, all of which promote wound closure and contribute to a better therapeutic effect than the commercial Tegaderm films group in a mouse full‐thickness wounds model. In summary, these adhesive hemostatic antioxidative conductive hydrogels with sustained drug release property to promote complete skin regeneration are an excellent wound dressing for full‐thickness skin repair.     

On-Demand Removable Self-Healing and pH-Responsive Europium-Releasing Adhesive Dressing Enables Inflammatory Microenvironment Modulation and Angiogenesis for Diabetic Wound Healing

Current diabetic wound treatments remain unsatisfactory due to the lack of a comprehensive strategy that can integrate strong applicability (tissue adhesiveness, shape adaptability, fast self-healability, and facile dressing change) with the initiation and smooth connection of the cascade wound healing processes. Herein, benefiting from the multifaceted bonding ability of tannic acid to metal ions and various polymers, a family of tannin–europium coordination complex crosslinked citrate-based mussel-inspired bioadhesives (TE-CMBAs) are specially developed for diabetic wound healing. TE-CMBAs can gel instantly (< 60 s), possess favorable shape-adaptability, considerable mechanical strengths, high elasticity, considerable wet tissue adhesiveness (≈40 kPa), favorable photothermal antimicrobial activity, excellent anti-oxidant activity, biocompatibility, and angiogenetic property. The reversible hydrogen bond crosslinking and sensitive metal–phenolic coordination also confers TE-CMBAs with self-healability, pH-responsive europium ion and TA releasing properties and on-demand removability upon mixing with borax solution, enabling convenient painless dressing change and the smooth connection of inflammatory microenvironment modulation, angiogenesis promotion, and effective extracellular matrix production leveraging the acidic pH condition of diabetic wounds. This adhesive dressing provides a comprehensive regenerative strategy for diabetic wound management and can be extended to other complicated tissue healing scenarios.     

A Self‐Pumping Dressing for Draining Excessive Biofluid around Wounds

Excessive biofluid around wounds often causes infection and hinders wound healing. However, the intrinsic hydrophilicity of the conventional dressing inevitably retains excessive biofluid at the interface between the dressing and the wound. Herein, a self‐pumping dressing is reported, by electrospinning a hydrophobic nanofiber array onto a hydrophilic microfiber network, which can unidirectionally drain excessive biofluid away from wounds and finally accelerate the wound healing process. The hydrophilic microfiber network offers a draining force to pump excessive biofluid through the hydrophobic nanofiber array, which can further keep those pumped biofluids from rewetting the wounds. In the proof of concept, the self‐pumping dressing unidirectionally drains the biofluid from murine dorsum wounds, thereby resulting in faster wound healing than conventional dressings. This unique self‐pumping dressing has enormous potential to be a next‐generation dressing for healing wounds clinically.     

Injectable hydrogel wound dressing based on strontium ion cross-linked starch

Severe skin wounds cause great problems and sufferings to patients. In this study, an injectable wound dressing based on strontium ion cross-linked starch hydrogel (SSH) was developed and evaluated. The good inject-ability of SSH made it easy to be delivered onto the wound surface. The good tissue adhesiveness of SSH ensured a firm protection of the wound. Besides, SSH supported the proliferation of NIH/3T3 fibroblasts and facilitated the migration of human umbilical vein endothelial cells (HUVECs). Importantly, SSH exhibited strong antibacterial effects on Staphylococcus aureus (S. aureus), which could prevent wound infection. These results demonstrate that SSH is a promising wound dressing material for promoting wound healing.     

Smart Bandage for Monitoring and Treatment of Chronic Wounds

Chronic wounds are a major health concern and they affect the lives of more than 25 million people in the United States. They are susceptible to infection and are the leading cause of nontraumatic limb amputations worldwide. The wound environment is dynamic, but their healing rate can be enhanced by administration of therapies at the right time. This approach requires real‐time monitoring of the wound environment with on‐demand drug delivery in a closed‐loop manner. In this paper, a smart and automated flexible wound dressing with temperature and pH sensors integrated onto flexible bandages that monitor wound status in real‐time to address this unmet medical need is presented. Moreover, a stimuli‐responsive drug releasing system comprising of a hydrogel loaded with thermo‐responsive drug carriers and an electronically controlled flexible heater is also integrated into the wound dressing to release the drugs on‐demand. The dressing is equipped with a microcontroller to process the data measured by the sensors and to program the drug release protocol for individualized treatment. This flexible smart wound dressing has the potential to significantly impact the treatment of chronic wounds.     

Nanofibers prepared by needleless electrospinning technology as scaffolds for wound healing

Electrospun gelatin and poly-ε-caprolactone (PCL) nanofibers were prepared using needleless technology and their biocompatibility and therapeutic efficacy have been characterized in vitro in cell cultures and in an experimental model of a skin wound. Human dermal fibroblasts, keratinocytes and mesenchymal stem cells seeded on the nanofibers revealed that both nanofibers promoted cell adhesion and proliferation. The effect of nanofibers on wound healing was examined using a full thickness wound model in rats and compared with a standard control treatment with gauze. Significantly faster wound closure was found with gelatin after 5 and 10 days of treatment, but no enhancement with PCL nanofibers was observed. Histological analysis revealed enhanced epithelialisation, increased depth of granulation tissue and increased density of myofibroblasts in the wound area with gelatin nanofibers. The results show that gelatin nanofibers produced by needleless technology accelerate wound healing and may be suitable as a scaffold for cell transfer and skin regeneration.     

Preparation of green cellulose diacetate-based antibacterial wound dressings for wound healing

Managing wounds is a growing universal problem and developing effective wound dressings to staunch bleeding and protect wounds from bacterial infections is an increasingly serious challenge. In this work, a remolding electrospinning nanofiber three-dimensional structure wound dressing (CCP) was prepared with superhydrophilicity, high water absorption and absorbing capacity, excellent hemostatic capacity and antibacterial ability, and biocompatibility to promote wound healing. Polyhexamethylene guanidine hydrochloride (PHMG) was grafted to cellulose diacetate (CDA) wound dressing surface through an amide reaction. A water contact angle analysis demonstrated that CCP wound dressing could be beneficial to promote wound exudate management effectively with rapid absorption of water within 0.2 s. In vitro hemo- and cytocompatibility assay showed that a CCP wound dressing had no significant hemotoxicity or cytoxicity. Specifically, CCP wound dressings could be beneficial to accelerate wound hemostasis and further reduce mortality caused by uncontrolled bleeding. Furthermore, CCP wound dressings have an excellent antibacterial ability, which could be beneficial to inhibit wound inflammatory over-reaction and promote normal wound healing. Combined together, the prepared wound dressing in this research effort is expected to have high-potential in clinical applications.     

Experimental wound dressings of degradable PHA for skin defect repair

The present study reports construction of wound dressing materials from degradable natural polymers such as hydroxy derivatives of carboxylic acids (PHAs) and 3-hydroxybutyrate/4-hydroxybutyrate [P(3HB/4HB)] as copolymer. The developed polymer films and electrospun membranes were evaluated for its wound healing properties with Grafts—elastic nonwoven membranes carrying fibroblast cells derived from adipose tissue multipotent mesenchymal stem cells. The efficacy of nonwoven membranes of P(3HB/4HB) carrying the culture of allogenic fibroblasts was assessed against model skin defects in Wistar rats. The morphological, histological and molecular studies revealed the presence of fibroblasts on dressing materials which facilitated wound healing, vascularization and regeneration. Further it was also observed that cells secreted extracellular matrix proteins which formed a layer on the surface of membranes and promoted the migration of epidermal cells from the neighboring tissues surrounding the wound. The wounds under the P(3HB/4HB) membrane carrying cells healed 1.4 times faster than the wounds under the cell-free membrane and 3.5 times faster than the wounds healing under the eschar (control).The complete wound healing process was achieved at Day 14. Thus the study highlights the importance of nonwoven membranes developed from degradable P(3HB/4HB) polymers in reducing inflammation, enhancing angiogenic properties of skin and facilitating better wound healing process.     

Amniotic membrane extract-loaded double-layered wound dressing: evaluation of gel properties and wound healing

The conservative single-layered wound dressing system is decomposed when mixed in polyvinyl alcohol (PVA) solution, which means it cannot be used with a temperature-sensitive drug. The goal of this investigation was to make an amniotic membrane extract (AME)-loaded double-layered wound dressing with an improved healing result compared to the conservative single-layered wound dressing systems. The double-layered wound dressing was developed with PVA/sodium alginate using a freeze–melting technique; one layer was PVA layer and the other was the drug-loaded sodium alginate layer. Its gel properties were assessed compared to single-layered wound dressings. Moreover, in vivo wound-healing effects and histopathology were calculated compared to commercial products. The double-layered wound dressing gave a similar gel fraction and Young’s module as single-layered wound bandages developed with only PVA, and a similar inflammation ability and WVTR as single-layered wound dressings developed with PVA and sodium alginate. Our data indicate that these double-layered wound bandages were just as swellable, but more elastic and stronger than single-layered wound dressings comprised of the same polymers and quantities, possibly giving an acceptable level of moisture and accumulation of exudates in the wound zone. Compared to the commercial product, the double-layered wound dressing comprising 6.7% PVA, 0.5% sodium alginate and 0.01% AME significantly enhanced the wound-healing effect in the wound-healing test. Histological investigations showed that superior full-thickness wound-healing effects compared to the commercial product. Therefore, the double-layered wound dressing would be an outstanding wound-dressing system with improved wound healing and good gel property.     

Bioactive electrospun silver nanoparticles-containing polyurethane nanofibers as wound dressings

Nanofibrous membrane (NFM) intended as wound dressing was prepared by electrospinning polyurethane (PU) solution containing silver ion, followed by reduction of silver ion to silver nanoparticles. The electrospun PU membrane has high surface area-to-volume ratio, controlled evaporative water transmission rate, good fluid drainage ability, and excellent antimicrobial activity. With an aim to promote wound healing, collagen was grafted to fiber surface by low temperature oxygen plasma treatment, which could improve surface hydrophilicity and facilitate covalent binding of collagen molecules to the plasma-treated PU surface. A NFM with no bead formation was obtained with fiber diameters around 159 nm. The presence of embedded silver nanoparticles and surface-grafted collagen was confirmed qualitatively and quantitatively. After modification, the NFM's antimicrobial activity improved to approximately 100% inhibition of bacterial growth with concomitant increase of membrane water absorption ability, which facilitates its use as a functional wound dressing. From animal studies, the NFM was better than gauze and commercial collagen sponge wound dressing in wound healing rate.     

A superabsorbent polymer-containing wound dressing efficiently sequesters MMPs and inhibits collagenase activity in vitro

Superabsorbent polymer (SAP)-containing wound dressings present a valuable and unique category of wound management products. An in vitro approach was used to assess the effects of a new SAP dressing in treatment of non-healing wounds. It was shown that the SAP dressing possesses a significant binding capacity for MMP-2 and MMP-9 in vitro (P < 0.001). The inclusion of the bound proteases was so strong that no MMP-2 and only marginal amounts of MMP-9 were released from the dressing samples in a subsequent elution step. In addition, the SAP dressing was able to take up collagenase and reduce its activity in vitro. However, collagenase was not completely inactivated upon binding and enzyme-mediated substrate turnover could be observed at the dressings. In conclusion, in vitro data confirm the positive effect of the SAP wound dressing observed in vivo. The findings suggest that it should be specifically useful for highly exuding wounds with an elevated proteolytic activity that needs to be reduced to support healing.     

Assessment of the cutaneous wound healing efficiency of acidic,neutral and alkaline bacterial cellulose membrane in rat

Recent research was conducted to evaluate the healing efficiency of bacterial cellulose (BC) as a wound dressing in different pHs and its possibility of being a smart wound dressing that can indicate pHs. BC was produced by environmentally isolated bacterial strains. After washing the best achieved BC, it was floated in normal saline with different pHs with phenol red used as a pH indicator. Finally the wound healing effects of the acidic, neutral and alkaline BC membranes were evaluated in rat cutaneous wounds. Results showed that one of the isolates which its partial 16srRNA genome had 95% similarity with Gluconacetobacter intermedius, had the thickest layer. The microscopic and macroscopic evaluations showed that the acidic BC had the best healing activity. Although the color of the films remained unchanged during the experiments because they were transparent and thin, these changes could not be easily seen. This suggests the use of thicker films such as the ones which are cross linked with some materials (e.g., sterile gauze). In conclusion the pH can affect the healing ability of natural BC and acidic pH had the best wound healing efficiency. In future it is better to use the acidic BC instead of natural one for different wound healing purposes.     

Evaluation of a collagen-glycosaminoglycan complex as a dressing for gingival wounds

Protection of gingival surgical sites by second-intention healing using a collagen-glycosaminoglycan complex (Glycagen^®) has been reported to be clinically effective. Optical and scanning electron microscopy was used to investigate these reports. Wound healing was observed clinically and histologically, at unprotected sites and at sites protected by the wound dressing, over 90 days in four patients. The results confirm the clinical efficacy of this wound dressing.     

The multifunctional wound dressing with core–shell structured fibers prepared by coaxial electrospinning

The non-woven wound dressing with core–shell structured fibers was prepared by coaxial electrospinning. The polycaprolactone (PCL) was electrospun as the fiber’s core to provide mechanical strength whereas collagen was fabricated into the shell in order to utilize its good biocompatibility. Simultaneously, the silver nanoparticles (Ag-NPs) as anti-bacterial agent were loaded in the shell whereas the vitamin A palmitate (VA) as healing-promoting drug was encapsulated in the core. Resulting from the fiber’s core–shell structure, the VA released from the core and Ag-NPs present in the shell can endow the dressing both heal-promoting and anti-bacteria ability simultaneously, which can greatly enhance the dressing’s clinical therapeutic effect. The dressing can maintain high swelling ratio of 190% for 3 d indicating its potential application as wet dressing. Furthermore, the dressing’s anti-bacteria ability against Staphylococcus aureus was proved by in vitro anti-bacteria test. The in vitro drug release test showed the sustainable release of VA within 72 h, while the cell attachment showed L929 cells can well attach on the dressing indicating its good biocompatibility. In conclusion, the fabricated nanofibrous dressing possesses multiple functions to benefit wound healing and shows promising potential for clinical application.     

Natural Carrier-Free Binary Small Molecule Self-Assembled Hydrogel Synergize Antibacterial Effects and Promote Wound Healing by Inhibiting Virulence Factors and Alleviating the Inflammatory Response

Methicillin-resistant Staphylococcus aureus (MRSA)-infected skin wounds have caused a variety of diseases and seriously endanger global public health. Therefore, multidimensional strategies are urgently to find antibacterial dressings to combat bacterial infections. Antibacterial hydrogels are considered potential wound dressing, while their clinical translation is limited due to the unpredictable risks and high costs of carrier excipients. it is found that the natural star antibacterial and anti-inflammatory phytochemicals baicalin (BA) and sanguinarine (SAN) can directly self-assemble through non-covalent bonds such as electrostatic attraction, π–π stacking, and hydrogen bonding to form carrier-free binary small molecule hydrogel. In addition, BA-SAN gel exhibited a synergistic inhibitory effect on MRSA. And its plasticity and injectability allowed it to be applied as a wound dressing. Due to the matched physicochemical properties and synergistic therapeutic effects, BA-SAN gel can inhibit bacterial virulence factors, alleviate wound inflammation, promote wound healing, and has good biocompatibility. The current study not only provided an antibacterial hydrogel with clinical value but also opened up new prospects that carrier-free hydrogels can be designed and originated from clinically used small-molecule phytochemicals.     

Simvastatin-loaded lyophilized wafers as a potential dressing for chronic wounds

Wafers are an established drug delivery system for application to suppurating wounds. They can absorb wound exudates and are converted into a gel, offering a moist environment that is vital for wound healing. Simvastatin-loaded lyophilized wafers were developed using sodium carboxymethyl cellulose (CMC) and methyl cellulose (MC) and evaluated for their potential in the management of chronic wounds. Simvastatin (SIM) was chosen as the model drug since it is known to accelerate wound healing by promoting angiogenesis and lymphangiogenesis. Pre-formulation studies were carried out with CMC, MC, and a mixture of CMC and MC. Wafers obtained from aqueous gels of 3% CMC and blend of CMC-MC in the % weight ratio of 2:1 and 1.5:1.5 were selected for further analysis. The formulated wafers were characterized by microscopic examination, texture analysis, hydration test, rheological studies, FTIR spectroscopy, water vapor transmission and drug release test. Among the selected formulations, simvastatin-loaded CMC-MC (2:1) wafers exhibited the most desired characteristics for wound dressing application, such as good flexibility, hardness, sponginess, and viscosity. It showed a sustained drug release, which is desirable in wound healing, and was more appropriate for suppurating wounds. In conclusion, simvastatin-loaded CMC-MC (2:1) wafers showing potential for wound dressing applications were successfully developed.     

Fabrication of biopolymer based nanocomposite wound dressing: evaluation of wound healing properties and wound microbial load

The aim of this study is to introduce natural‐based polymers, chitosan and starch, to design a remedial nanocomposite, comprising of cerium oxide nanoparticles and silver nanoparticles, to investigate their effects in accelerating wound healing and in wound microbial load. Cerium oxide nanoparticles synthesized in starch solution added to the colloidal dispersion of synthesized silver nanoparticles in chitosan to make a three‐component nanomaterial. Mice were anaesthetized and two parallel full‐thickness round wounds were excised under aseptic conditions with the help of sterile dermal biopsy punch. Furthermore, effects of silver‐chitosan and silver‐cerium‐chitosan nanocomposite had evaluated on rate of wound closure and collagen density and on microbial load of wound in full‐thickness model. Results showed that both silver chitosan and silver‐cerium‐chitosan had significant impact on acceleration of wound closure and collagen content and on reduction of wound microbial load in comparison with control group, which was, received no treatments. However, the silver‐cerium‐chitosan nanocomposite is more potent than silver‐chitosan group and control group in wound closure. The wound healing effects of silver‐cerium‐chitosan nanocomposite are due to unique features of its three components and this nanocomposite promises impressive remedies for clinical application.Inspec keywords: wounds, nanocomposites, nanomedicine, nanoparticles, proteins, cerium, silver, polymers, colloids, patient treatmentOther keywords: biopolymer‐based nanocomposite wound dressing, wound healing properties, wound microbial load, natural‐based polymers, chitosan, remedial nanocomposite, cerium oxide nanoparticles, nanoceria, silver nanoparticles, starch solution, three‐component nanomaterial, synthesised silver nanoparticles, ketamine intraperitoneal injection, silver‐cerium‐chitosan nanocomposite, wound closure, collagen density, wound healing effects, wound care, aseptic conditions, sterile dermal biopsy punch, Ag‐Ce     

Preparation and evaluation of biocomposites as wound dressing material

Collagen was isolated from the chrome containing leather waste (CCLW) which is a major solid waste in leather industry. Composite films were made using sago starch (SG), soya protein (SY), and collagen (C) and were cross linked with glutaraldehyde (G).The films prepared were characterized for their physico chemical properties like tensile strength, infrared spectra, thermogravimetric analysis, surface morphology, and water absorption studies. Better mechanical properties and surface morphology were observed for SG–SY–G–C films compared to other films prepared using collagen. The composite films prepared were used as wound dressing material on the experimental wounds of rats and healing pattern was evaluated using planimetric, biochemical, and histopathological studies. These studies have revealed better wound healing capacity of SG–SY–G–C film and utilization of CCLW in the preparation of value added product like wound dressing material.