Review polymers Hybrid-Based Wound Dressings: Combination of Synthetic and Biopolymers Blessing Atim Aderibigbe Citation: Aderibigbe, B.A. Hybrid-Based Wound Dressings: Combination of Synthetic and Biopolymers. Polymers 2022, 14, 3806. https://doi.org/10.3390/ check

for updates polym14183806 Academic Editor: Shahin Homaeigohar Received: 3 August 2022 Accepted: 5 September 2022 Published: 12 September 2022 CC Publisher's Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. 4.0/). BY Copyright: © 2022 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ MDPI Department of Chemistry, University of Fort Hare, Alice 5700, Eastern Cape, South Africa; baderibigbe@ufh.ac.za Abstract: Most commercialized wound dressings are polymer-based. Synthetic and natural polymers have been utilized widely for the development of wound dressings. However, the use of natural polymers is limited by their poor mechanical properties, resulting in their combination with synthetic polymers and other materials to enhance their mechanical properties. Natural polymers are mostly affordable, biocompatible, and biodegradable with promising antimicrobial activity. They have been further tailored into unique hybrid wound dressings when combined with synthetic polymers and selected biomaterials. Some important features required in an ideal wound dressing include the capability to prevent bacteria invasion, reduce odor, absorb exudates, be comfortable, facilitate easy application and removal as well as frequent changing, prevent further skin tear and irritation when applied or removed, and provide a moist environment and soothing effect, be permeable to gases, etc. The efficacy of polymers in the design of wound dressings cannot be overemphasized. This review article reports the efficacy of wound dressings prepared from a combination of synthetic and natural polymers. Keywords: hybrid wound dressings; synthetic polymers; skin regeneration; natural polymers; wound healing; wounds; wound dressings; biomaterials 1. Introduction Wounds are challenging to treat, especially when they have been invaded by mi- crobes [1,2]. Wound healing involves complex mechanisms that require using appropriate wound dressings to induce a timely wound healing process [3]. Polymers have played a huge role in the design of potent wound dressings. Synthetic and natural polymers are used to prepare wound dressings. Synthetic polymers are characterized by features such as easy preparation resulting in controlled physicochemical properties and stability, good mechanical stability with interesting mechanical properties, and degradation in a controlled manner [4,5]. However, they can induce the risk of toxicity and are biologically inert. Natural polymers, on the other hand, do not offer interesting mechanical properties, are biocompatible, biodegradable with interesting biological activities, and can undergo enzymatic degradation to produce by-products that do not trigger toxic reactions [6,7]. However, their high rate of degradation rates is usually challenging to control [5]. The combination of synthetic polymers together with natural polymers has been widely employed to overcome shortcomings common with both types of polymers [8,9]. The combination of both polymers in the design of wound dressings results in hybrid-based wound dressings. Hybrid wound dressings display excellent features such as improved mechanical properties, accelerate wound healing, excellent flexibility, biocompatibility, biodegradability, high adsorption capacity, etc. [10,11]. They are also appropriate for treating high exuding, bleeding, and infected wounds. They are also suitable to promote skin regeneration [12,13]. The further incorporation of bioactive agents and biological molecules into hybrid-based wound dressing has resulted in materials that exhibit excellent wound healing and skin regeneration [14,15]. This review reports the in vitro and in vivo outcomes of hybrid-based wound dressings. Polymers 2022, 14, 3806. https://doi.org/10.3390/polym14183806 https://www.mdpi.com/journal/polymers Polymers 2022, 14, 3806 2. Wound Healing Mechanisms The physiological and architectural restoration of the skin after an injury is based on four important phases: hemostasis, inflammation, proliferation, and remodeling (Figure 1) [16,17]. Wound healing is complex and specialized cells are involved, such as macrophages, fibroblasts, platelets, endothelial cells, etc. There is a significant interaction between the cells and the extracellular matrix. Wound healing is also influenced by the action of growth factors, chemokines, cytokines, chemokines, receptors, etc. [18,19]. Red blood cell White blood cell Blood clot U Hemostasis Microbes Growth Macrophages factor DOO Inflammation Figure 1. The phases of wound healing. Neutrophils ROS Fibroblast Proliferation Epithelial cells Matured scar === DO Remodeling 2 of 31 Keratinocytes -Fibroblast Hemostasis This phase occurs immediately after an injury, whereby the damaged blood vessels constrict rapidly with a blood clot formation to prevent excess loss of blood [20,21]. The platelets play a crucial role in blood clot formation [22]. The constriction of the blood vessels together with the formation of a blood clot results in the lack of oxygen, changes in pH, and glycolysis [23]. After the narrowing of the blood vessels, the widening promotes the invasion of the wound matrix by thrombocytes. The widening of the blood vessels known as vasodilation is characterized by oedema and local redness of the wound [23]. The blood clot is composed of cytokines, fibrin molecules, growth factors, vitronectin, thrombospondins, and fibronectin. The blood clot also acts as a shield against bacteria invasion and as a reservoir for cytokines and growth factors for wound repair [24]. After the formation of a blood clot, the coagulation process terminates to prevent excessive thrombosis and platelet aggregation [24]. In this phase, the repair of smooth muscle cells and endothelial cells also occurs due to the release of platelet-derived growth factors [25]. The platelet-derived growth factors recruit neutrophils and monocytes, which together with transforming growth factor ß (TGF-ß) from the vasculature induce the inflammatory response [26]. Fibroblasts are also recruited by platelet-derived growth factors, and they migrate to the wound site followed by the production of collagen, glycosaminoglycans, and proteins which promote cellular migration and set the stage for subsequent healing events [23,24]. Inflammation The inflammation phase overlaps with the hemostasis phase. In this phase, neutrophils and monocyte infiltration in the wound bed prevent the invasion of microbes, foreign debris, and tissue damage [27,28]. The neutrophils promote the process of phagocytosis of debris and microbes to allow decontamination of the wound. The three known mechanisms of neutrophils in the destruction of debris and bacteria are: directly ingesting followed by destroying the foreign debris by a process known as phagocytosis; via the release of toxic substances, e.g., lactoferrin, cathepsin, proteases, etc. to destroy bacteria and the dead host tissue; and by the production of chromatin and protease 'traps' to capture and destroy bacteria in the extracellular space [29,30]. The by-product of the neutrophil activity, oxygen-free radicals, exhibit bacteriocidal properties to sterilize the wound. However, Polymers 2022, 14, 3806 3 of 31 the oxygen-free radicals can exasperate inflammation of the microenvironment, thereby resulting in delayed wound healing [29,31]. After the completion of the neutrophil activity, the neutrophils undergo apoptosis and are phagocytosed by macrophages or can be sloughed from the wound surface [30]. Macrophages are attracted to the wound and are released from platelets and damaged cells. In this phase, they can withstand the acidic wound environment [32]. Macrophages are composed of significant amounts of growth factors, which include TGF-B and epidermal growth factors, which are crucial in regulating the inflammatory response [30,33,34]. The inflammatory phase of wound healing can be prolonged to remove excess bacteria and debris from the wound. Prolonged inflammation can result in significant tissue damage and delayed proliferation, resulting in the formation of a chronic wound [30]. Multiple factors have been reported to affect the immune response such as lipoxins and the products of arachidonic acid metabolism, thereby hindering the next phase of wound healing [35]. Fur- thermore, the type of immune response plays a crucial role in the formation of hypertrophic scarring or keloid formation. The differentiation of T-helper (Th) cells, major immune mediators in the inflammatory phase to Th2 cell types, results in hypertrophic scarring [36]. In chronic non-healing wounds, the presence of an abundance of neutrophils makes them become proteolytic environments composed of host-derived proteases. Excessive tissue damage is caused by elevated inflammatory cytokines and collagenases [37]. Proliferation In this phase, there is a complex simultaneous combination of fibroblast migration, angiogenesis, and epithelialization together with a wound retraction [38]. A sufficient supply of gas, blood, nutrients, and metabolites is required [38]. The release of vascular endothelial growth factor (VEGF) and cytokines induces the endothelial cells to promote angiogenesis, the formation of new blood vessels and the repair of damaged blood vessels in the wound site. The migration of fibroblast results in the production of fibronectin and collagen with a replacement of the clot with granulation tissue made up of different ranges of collagen [29]. The fibroblasts are converted to myofibroblast phenotype, which is useful in wound contraction. The myofibroblasts also induce angiogenesis, and the collagens produced by the fibroblasts are responsible for providing strength to the tissues. However, the formation of a hypertrophic scar can be induced by an overproduction of collagen [39]. Several macrophage-derived molecules, such as IL-1, ß-bb (PDGF-bb), IL-6, etc. promote pro-re-epithelialization molecules in the fibroblasts. In wounds without a macrophage- derived molecule, IL-6, there is a lack of appropriate inflammatory response, resulting in hampered collagen accumulation, angiogenesis, and re-epithelialization [40]. The migration of the epithelial cells from the edges of the wound forms a sheet of cells that covers the wound, and this process is known as epithelialization [41]. Epithelialization takes place within 24 h in primary wounds, but in secondary closed wounds, the contraction of large areas lacking epithelial cells occurs before complete epithelialization [29,30]. Remodeling This last phase is characterized by a transition from granulation tissue to scar formation with slow angiogenesis and a replacement of type III collagen with type I collagen that is stronger [28]. This remodeling phase is significantly promoted by myofibroblasts developed from fibroblasts, which are responsible for wound contraction [42]. Some reports have shown that fat cells obtained from the differentiation of myofibroblasts replenish the subcutaneous adipose tissue, and this is influenced by the neogenic hair follicles, resulting in the activation of adipocyte transcription factors and bone morphogenic protein (BMP) signaling [43]. Chronic Wounds Chronic wounds are classified as non-healing wounds over a prolonged period, and they can be classified as diabetic, vascular, diabetic, and pressure wounds [44]. Other examples of chronic wounds are gangrenes, ischemia, etc. [45]. The most common type Polymers 2022, 14, 3806 of chronic wound is the diabetic wound, and it affects 15% of the world population who suffer from diabetes [46]. Due to the prolonged healing period of these types of wounds, the patients usually require long medical care, amputation, and in some cases, long hospital stay [47]. Factors that contribute to chronic wounds are reduced blood supply and re- epithelialization, inflammatory responses that are not controllable, and bacterial infections. There are complications associated with diabetes such as foot infections, etc. Un- controlled diabetes reduces the tissue oxygen rate, thereby damaging blood vessels and forming non-healing ulcers [48]. Venous ulcers are common in older patients and affect the lower limbs due to a damaged deep venous system. It is also characterized by increased blood pressure in the vessels, causing leakage and an accumulation of fibrin that blocks the vascular pathway, reducing the flow of oxygen to the surrounding tissues [45,48]. Pres- sure ulcers are also common in older and paralyzed patients. It occurs due to continuous pressure on the skin, decreasing the diffusion of oxygen in the tissues [45]. Pathophysiology of Chronic Wounds Chronic wounds remain in the inflammatory stage of wound healing due to the persis- tent recruitment of neutrophils and macrophages in the wound bed, which also prolongs the wound healing process (Figure 2) [45,49]. The high production of inflammatory molecules and Reactive Oxygen Species (ROS) in chronic wounds affect the synthesis of collagen, decreases proliferation, and causes an abnormal differentiation of keratinocytes [49]. The altered pattern of cytokine in the wound also contributes to delayed wound healing in diabetes patients. The abnormal expression of growth factors is observed in diabetic foot ulcers that disrupt the healing process. Elevated levels of matrix metalloproteinases and reduced levels of tissue inhibitors of metalloproteinases in chronic wounds also affect the wound healing process [45,49]. Matrix metalloproteinases are crucial for the remodeling of the matrix microenvironment by inducing healing responses, such as cellular migra- tion, proliferation, and angiogenic induction. The high levels of protease results in the damage of extracellular matrix (ECM) and growth factors degradation together with their receptors [50]. The damaged ECM prohibits the wound healing process from moving to the proliferative phase. The aforementioned factor results in an inflammation cycle where more proteases are produced. The persistent inflammatory and hypoxic state of chronic wounds induce a high production of ROS that also destroys the ECM proteins. Defective re-epithelialization IFN-y IL-10 TGF-B Mast cell degranulation Keratinocytes Th1/Th17/ Th22 MMPS CD8+ T cells TNF-a Decreased angiogenesis Figure 2. The immune environment of chronic wounds [50]. Bacterial infection ROS M1↑ Macrophages IL-6 10 Neutrophils MMP2/9 NOS IL-13 TNF-a 4 of 31 TNF-a IL-8 IL-13 NETS Polymers 2022, 14, 3806 5 of 31 The presence of senescent macrophages, keratinocytes, fibroblasts, and endothelial cells in chronic wounds contributes to oxidative stress that results in the damage of de- oxyribonucleic acid (DNA) cell cycle arrest and a defect in the intracellular biochemical pathways including GSK-3ß/Fyn/Nrf2 pathway, etc. [49,50]. Chronic wound healing is characterized by reduced angiogenesis and tissue epithelialization [50]. The mesenchymal stem cells also play an important role in wound healing and are recruited into circulation when there is an injury. However, they are defective and deficient in chronic wounds. The absence of effective receptors or promigratory matrix substrates inhibits cell migration and proliferation in chronic wounds. The hallmarks of chronic wounds have been reported to be impaired neovascularization and angiogenesis, resulting in an insufficient supply of nutrients and oxygen for the cells in the wound bed, leading to non-healing wounds [49]. To accelerate the wound healing process of chronic wounds, researchers have employed the use of microbial agents to treat persistent microbial infections [51,52], the delivery of healthy donor-derived functional mesenchymal stem cells to deal with their deficiency [53], and the administration of antioxidants to reduce the ROS to normal levels, thereby reversing the chronic state of the wounds [54,55]. In the treatment of chronic wounds, debridement is performed to remove non-viable tissues [56]. Anti-inflammatory agents are also employed to deal with prolonged inflamma- tion [57], and the use of appropriate wound dressings that addresses the moisture imbalance is crucial for treating chronic wounds [58]. To promote the formation of granulation tissue and epithelialization, the use of growth factors has been used [59,60]. 3. Hybrid Wound Dressings in Wound Healing Hybrid-based wound dressings have been developed from the combination of natural and synthetic polymers. Different types of hybrid-based wound dressings have been developed, such as foams, hydrocolloids, hydrogels, nanofibers, films/membranes, etc. Different preparation techniques have been employed. This section reports the preparation techniques used as well as in vitro and in vivo biological outcomes. 3.1. Foams The commonly used foam wound dressings are polyurethane foams used for moist wound healing (Figure 3a,b) [61]. Silicone foams are not commonly used. Foam wound dressings are characterized by a porous structure and a film-backing, and they are produced with varied thicknesses [62]. They can be adhesive or non-adhesive. The permeability of the film backings varies with a significant influence on water evaporation and gas exchange capacity [62]. The contact of the wound with the foam products is crucial to facilitate the absorption of the exudate. Their adhesion to the surrounding skin of the wound bed is useful in keeping the dressing and preventing the leakage of the exudates that can cause skin irritation [63]. They are suitable as primary or secondary wound dressings. Some of their unique features include their ability to maintain moisture at the wound bed, to be easily removed from the wound, to protect the wound from bacterial invasion, to provide mechanical protection, and to conform to the body shape; they are also non-toxic, easy to use, etc. [62]. Foams are effective for the management of acute and chronic with medium to heavy exudate [64]. They have been prepared from a combination of synthetic and natural polymers. Most reported foam wound dressings are prepared from synthetic polymers [65,66]. Some are prepared from natural polymers only with high porosity but are prone to enzy- matic degradation [67,68]. Hybrid-based foams have been prepared from polyurethane in combination with natural polymers, such as chitosan, sodium alginate, and hydroxypropyl methylcellulose, by Namviriyachote et al. The foams were loaded with silver nanoparticles and asiaticoside. Foams prepared from alginate displayed a high release of silver nanopar- ticles and asiaticoside. Using natural polymers for the preparation of the foams influenced the compressive strength and absorption properties. The foams were non-cytotoxic and compatible, and they improved the rate of wound closure with a significant formation of