Extended Reading

2026年07月13日

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Chapter 11　Applications of Biomedical Polymers in Skin Wound Repair

11.1　Overview of Skin Wounds

11.1.1　Production and healing of skin wounds

Skin is the largest organ of the human body，which is in direct contact with the surrounding environment and acts as a protective barrier at the interface between the human body and the surrounding environment.The skin has many important functions，including preventing the loss of body fluids and regulating body surface temperature.Due to certain factors，such as an injury and a surgery，the anatomical structure and physiological functions of normal skin can be destroyed and skin trauma occurs.Skin wounds can be classified into acute or chronic wounds depending on the healing process.Acute wounds originate from superficial abrasions to deep injuries，and they can usually heal within 3 weeks.Acute wounds that fail to heal within 2 months usually develop into chronic wounds，such as certain types of ulcers or diabetic wounds.Wound healing requires multiple processes to occur in a specific order.As shown in Figure 11-1，these processes are generally divided into four major stages，namely hemostasis，inflammation，migration，and remodeling/maturation.

The wound healing process begins with hemostasis，i.e.，blood clots form and the wounds close.At this stage，blood vessels constrict to stop bleeding，and platelets are activated.Platelets play several important roles in wound healing，including regulating hemostasis during the aggregation phase and secondary hemostasis during the coagulation phase.Platelets can also produce biologically vasoactive mediators and chemokines，such as proteases，cytokines，and growth factors.Cytokines send chemotactic signals to inflammatory cells and cell populations.Fibrin is formed during secondary hemostasis.The fibronectin clot acts as a temporary matrix，allowing epithelial cells and fibroblasts to migrate to the wound.A blood clot forms and thrombin is activated.Activation of the fibrinolytic system leads to fibrin degradation.In this process，peptides are released to stimulate chemotaxis and increase capillary permeability.Cytokines can also trigger an inflammatory response and play a role in removing debris，damaged or necrotic tissues，and microorganisms，which is followed by granulation tissue formation，re-epithelization，and connective tissue matrix formation.The granulation tissue is composed of dense macrophages，fibroblasts，capillary networks，fibronectin，hyaluronic acid，and endothelial cells.During the formation of granulation tissue，macrophages，fibroblasts，and endothelial cells are interdependent.

Hypoxia is an important factor that triggers the formation of new blood vessels at early stage of wound healing.Before the basement membrane is formed，the wound will continue to seep fluid.At the same time，fibroblasts gather from the edge of the wound，and circulating fibroblasts and mesenchymal stem cells migrate to the immature connective tissue matrix.Re-epithelialization begins at the edge of the wound，where epithelial cells lose hemidesmosome connections and migrate across the wound through a temporary fibrin—fibronectin matrix until they encounter the same cells.Directional migration and proliferation require an effective，balanced，and enzyme-supported“cut and paste”program.After this process，the epithelial cells on the edge of the wound are in direct contact，which is called primary healing.In addition，secondary healing occurs after the migrating cells connect for a certain period.Due to the delayed epithelial closure and the higher formation rate of granulation tissue，the healing process of open wounds is slower.The final stage of the wound healing process is called the contraction stage and begins with the formation of large amounts of collagen in the granular tissue.In the contraction phase，the distance between the edge of the wound is reduced until the wound is tightly closed.This process occurs due to the differentiation of fibroblasts and the differentiation of progenitor cells into myofibroblasts.Myofibroblasts rich in actin skeletal matrix cause the matrix to contract.After the wound shrinks，it enters the remodeling process，in which the production of the matrix is stopped，and fibroblasts and myofibroblasts undergo apoptosis and degeneration.The final result of wound healing may be completely scarless，or it may leave obvious scars due to fibrosis.

11.1.2　Wound dressings

Wound dressings are materials that wrap wounds to cover sores，wounds，or other damage.Wound dressings include primary dressings that are in direct contact with the wound bed and secondary dressings that play an auxiliary role on top of the covered primary dressings.The primary dressings directly cover the wound surface，to treat and protect the wound surface.The secondary dressings can play a role in consolidating the primary dressing，to more fully meet the needs of wound healing.

Early wound dressing products include gauze，tape，natural or synthetic bandages，and absorbent cotton.The gauze dressings are made of woven and non-woven fiber cotton，rayon，and polyester.Because they are cheap and easy to obtain，they are suitable for drainage of many wounds.While due to their dry nature，they can adhere to the wound and cause pain during removal.The gauze dressings can provide some protection to the wound，but it needs to be changed frequently to prevent the maceration of healthy adjacent tissues，which may increase costs and cause repetitive tissue damage.Therefore，when using gauze as a dressing，it can be impregnated with paraffin，iodine，or petroleum to avoid drying，providing a non-adhesive coverage.In 1971，Dr.Winter firstly proposed the concept of“wet wound healing”.They found that the intact blister healed about 2 times quicker than the broken blister，and pointed out that because the epithelial cells could not migrate through the dry or crusted cell layer，they took time to migrate to the moist bed under the scab，allowing the epithelial cells heal longer.A moist environment could promote epithelial cells crawling and reduced scar formation.This conclusion laid the foundation for modern wet wound healing theory，and at the same time promoted the rapid development of new wet wound healing dressings.Compared with the early traditional dressings（e.g.，gauze，oily gauze），new dressings have a positive effect on the wound，promoting hemostasis and the rapid healing of the wound.New dressings mainly include hydrogel dressings and fiber dressings，and these functional dressings are mainly produced by polymer materials.Therefore，the following sections will focus on the research progress of polymer materials in new wound healing dressings and composite functional dressings.

11.2　Polymer Hydrogel-Based Wound Dressings

11.2.1　Introduction of hydrogel materials

Most organisms are composed of soft and water-containing gels.They can sense external environmental stimuli and generate real-time and fast responses.Among all artificial materials，hydrogels are the most similar materials to biological tissues.They are polymer networks formed by light cross-linking of hydrophilic polymers.Water molecules and some small molecules can move in the polymer network.Hydrogels can provide a microenvironment that mimics extracellular mechanisms and can regulate cell behavior and tissue function.In recent years，hydrogels based on synthetic or natural polymers have received extensive attention in the biomedical field.For example，contact lenses made of poly（hydroxyethyl methacrylate），bioadhesives made of recombinant protein or albumin for surgical bonding，wound dressings made of alginate polysaccharides，and hydrogels made of hyaluronic acid are widely used in clinical practice.Hydrogels have good biocompatibility，easy molding and processing，and controllable shape and size，and have broad application prospects in biomedical engineering fields，including three-dimensional tissue engineering matrices，drug carriers，and biocomposites.

According to their source，hydrogels can be classified into two types：natural polymer hydrogels and synthetic polymer hydrogels.Natural polymer hydrogels are mainly formed by natural polymer materials，including collagen，gelatin，fibrin，chitosan，sodium alginate，hyaluronic acid，chondroitin sulfate，agarose，etc.The compositions and structures of the natural polymer hydrogels are similar to the natural extracellular matrix，and they have the advantages of good biocompatibility and biodegradability.However，its mechanical properties are generally low and cannot meet the mechanical requirements for the repair of load-bearing tissues.Synthetic polymer hydrogels are mainly formed by cross-linking synthetic polymer materials，such as poly（ethylene glycol），poly（vinyl alcohol），poly（hydroxyethyl methacrylate），polyacrylamide，poly（acrylic acid），or their derivatives.Generally，synthetic polymer hydrogels have high mechanical properties，controllable structure and performance，and good repeatability.Yet，the lack of biological functions and poor biocompatibility should be considered for synthetic polymer hydrogels.

According to the cross-linking method of hydrogels，they can be divided into physically crosslinked hydrogels and chemically crosslinked hydrogels.Physically crosslinked hydrogels refer to the formation of polymer chains through physical interactions（e.g.，chain entanglement）or weak supramolecular interactions（e.g.，ionic interactions，hydrogen bonds）.The reaction conditions for the formation of the physically crosslinked hydrogel are mild and no chemical cross-linking agent is required.Since the physical cross-linking is nonpermanent，the hydrogel may dissociate when the external environment（e.g.，pH，temperature，ion concentration）changes.The chemically crosslinked hydrogels are constructed using free radical polymerization，ultraviolet irradiation，and enzymatic crosslinking in which a stable covalent bond between polymer chains is generated to construct a hydrogel network.Compared with physically crosslinked hydrogels，their mechanical properties can be significantly improved，but residual chemical cross-linking agents，organic solvents，initiators，etc.may cause potential cytotoxicity.Therefore，the post-treatment for the materials is particularly important.

11.2.1.1　Bioinspired adhesive hydrogels

Inspired by the fascinating biological structure and functions，bioinspired hydrogels have a broad application prospect in the biomedical field.Among them，taking inspiration from the underwater adhesion of natural mussels，barnacles，and other marine organisms，bioinspired adhesive hydrogels have received more and more attention in recent years.Bioinspired adhesive hydrogels refer to hydrogels with high adhesion and biocompatibility，which can replace traditional surgical suture wound closure devices and have the effect of promoting wound healing.The adhesion mainly comes from the interaction between the active groups in the polymer and the active groups in the biological tissue or the multiple supramolecular interactions with the surface.For example，some hydrogels with aldehyde groups can covalently bond with amino groups in biological tissues，thereby exhibiting high adhesion strength to living tissues.Duan et al.prepared an in-situ injectable viscous hydrogel by Schiff base reaction between the amino group of carboxymethyl chitosan and the aldehyde group of oxydextran.Injecting the hydrogel on the burn wound in rats can promote cell adhesion and make epithelial cells migrate to the wound area to promote skin regeneration.

The adhesive protein secreted by mussels has a fast curing speed，high waterproof adhesion ability，and excellent adhesion diversity in water，making it a biological adhesive with great advantages and potential.The catechol group，which is rich in mussel's adhesive protein，plays key roles in wet adhesion and adhesion diversification.Inspired by the strong underwater adhesion ability of mussels，a variety of mussel-like adhesion hydrogels have been developed.For example，Zhang et al.used polydopamine（PDA），reduced graphene oxide（rGO），branched polyethyleneimine（PEI），and polyacrylamide（PAM）to prepare a highly adhesive hydrogel film.After being attached to the wound，the hydrogel converted solar energy into heat energy and heated the wound locally.An increase of the local temperature at the wound site could reduce inflammation and promoted re-epithelialization，angiogenesis，and collagen deposition，thereby significantly promoting wound healing.Liu et al.synthesized a hyperbranched polymer HB-PBAE by the Michael addition reaction between polydopamine（PDA），poly（ethylene glycol diacrylate）（PEGDA700），and pentaerythritol triacrylate（PETA）.Then，HB-PBAE，poly（1-vinyl imidazole）（PVI），and gelatin solution were mixed，and Fe3+was added to prepare a bioinspired adhesive hydrogel.Fe3+can form coordination bonds with catechol group to stabilize the hydrogel.When the dressing needs to be changed，Zn2+aqueous solution can be sprayed on the dressing and the adhesive ability of the hydrogel is significantly reduced.At the same time，PVI and Zn2+form a stable coordination bond，which further enhances the strength of the hydrogel.It can be easily and non-destructively replaced，and there is no obvious dressing residue on the wound，which promotes wound healing（Figure 11-2）.This kind of dressing change promoted by metal ions may provide a new idea for the design of wound dressings.

11.2.1.2　Injectable hydrogels

Injectable hydrogels refer to hydrogels that were fluid before injection，and after injecting into the subcutaneous tissue or muscle tissue through a syringe，they form gel insitu at the wound sites.The formation mechanism is based on the polymer material's response to external stimuli to change the state or conformation of the polymer under physiological conditions and complete the conversion process from solution to gel.The injectable hydrogels usually respond to external stimuli（e.g.，temperature，pH，enzyme）.Because these hydrogels have excellent biocompatibility and mechanical properties，they can quickly close wounds of any shape，bond with the contour of the wound to provide a physical barrier，also maintain the moist environment of the skin，and quickly stop bleeding and prevent wounds infection.These hydrogels are potentially useful in medical dressing.

Zhang et al.designed and developed a PEG2000-based injectable hydrogel by collagen（COL），chitosan（CS），and dibenzaldehyde through dynamic imine bond.COL/CS hydrogel has good thermal stability，injectability，pH sensitivity，and antibacterial capability.COL/CS hydrogel can adhere well to the tissue surface.After the COL/CS hydrogel acts on the moist wound surface，it can effectively promote wound healing and rapid wound hemostasis.Yin et al.introduced dopamine（DA）to aldehyde-modified alginate（ALG）skeleton to form bifunctional ALG and obtained injectable bioadhesive hydrogel（PGA/ALG-CHO hydrogel）with hydrazide-modified poly（L-glutamic acid）.The injectable bioadhesive hydrogel（PGA/ALG-CHO hydrogel）possessed various interactions（e.g.，hydrogen bond andπ-πstacking between catechol groups and tissues），endowing it with superior hemostatic capability.Liu et al.mimicked the characteristics of the extracellular matrix by using sulfhydryl bovine serum protein，KK polypeptide，and Ag+to build a protein-based injectable hydrogel that can promote the healing of infected wounds.In this protein-based hydrogel，Ag+，as a crosslinking agent，can not only provide a sterile microenvironment and strong antibacterial ability but also introduce K2（SL）6K2（KK）peptides to generate blood vessels.In addition，the results of in vivo experiments also showed that the protein-based hydrogel has considerable collagen deposition and vascularization ability in the early stage of wound healing so that new tissues are rapidly regenerated and new hair follicles appear（Figure 11-3）.

11.2.2　Hemostatic hydrogel dressings

A direct result of skin trauma is the occurrence of bleeding.Excessive blood loss is the main cause of death.The use of appropriate hemostatic equipment for first aid treatment can effectively reduce casualties.Since the application of tourniquets in parts of the human body other than the limbs is often limited，rapid hemostatic materials have always been a hot topic in the field of first aid.Currently，the common types of hemostatic dressings mainly include rubber dressings，foam dressings，electrospun fiber dressings，membrane dressings，hydrogel dressings，etc.Among these dressings，hydrogels are of great importance in the application of hemostatic dressings due to their specific crosslinked network structure，semipermeable，bacterial invasion blockage，wound infection prevention，and allow for the passage of oxygen and water.

Hemostatic hydrogel dressings can be obtained by introducing hemostatic factors（e.g.，hemostatic polypeptides，hemostatic drugs）into the gel or via a strong physical barrier.For example，Paul Slezak et al.used click chemistry to graft thrombin receptor agonist peptide-6（TRAP-6）onto poly（vinyl alcohol）（PVA）to obtain a hemostatic polypeptide modified PVA-TRAP-6 hydrogel.Since TRAP-6 has a significant function ofactivating platelets，the hemostatic hydrogel not only exhibits a good biocompatibility，but also significantly shortens the clotting time，and can be used as a hemostatic dressing for wounds and bleeding in tissues and organs（Figure 11-4）.Ouyang et al.designed a light-responsive adhesive that mimicked the composition of the extracellular matrix（ECM），which could quickly gel and fix after ultraviolet irradiation，and adhered and sealed the bleeding artery and myocardial wall.The adhered hydrogel could withstand blood pressure up to 290 mmHg，which is significantly higher than the blood pressure in most clinical settings.This hydrogel can prevent 4-5 mm porcine carotid artery incisions and 6 mm diameter heart penetration holes in the porcine heart.The treated pigs survived after using this hydrogel for hemostatic treatment，which is well tolerated and has significant clinical advantages as a wound sealant.

In addition，the introduction of inorganic nanoparticles（NPs）（e.g.，silica，clays）with hemostatic function into hydrogels is also an effective manner to obtain hemostatic hydrogel dressings.The negatively charged silicate can effectively condense the coagulation factors in the blood，and the fast water absorption of inorganic nanoparticles can effectively concentrate blood components.Hartgerink et al.prepared a nanocomposite hydrogel and the result showed that through the synergistic effect of silicate and collagen，the nanocomposite hydrogel has multiple functions of efficiently enriching coagulation factors and rapidly concentrating blood components，and can achieve rapid hemostasis.

11.2.3　Antibacterial dressings

During the use of the hydrogel wound dressings，the hydrogel dressings directly contact the surface of the tissue，which can reduce the loss of body fluids，and it is also necessary to prevent secondary infection of the wound.Therefore，hydrogel dressings should have good antibacterial properties，which can inhibit the growth of bacteria on the wound surface during use，and at the same time prevent the infection of microorganisms outside the body.In order to meet this requirement，antibacterial hydrogel dressings have emerged，which can be obtained by loading antibacterial agents or modifying hydrogel with the antibacterial motif.

The antibacterial agents loaded hydrogels refer to the hydrogels that directly load the antibacterial agent into the hydrogels.According to different types of antibacterial agents，hydrogels loaded with antibacterial agents can be roughly divided into three types.They are hydrogels loaded with metal ions or metal NPs（such as Ag+，Fe3+，Ag NPs），antibiotics，and non-antibiotics antibacterial drugs.For example，Chen et al.used ferric ethylenediaminetetraacetate（EDTAFe3+）to crosslink hyaluronic acid（HA）to obtain antibacterial hydrogels.When being applied to wounds，HA can be degraded at the site of infection，and the hydrogels can locally release Fe3+complexes.These Fe3+complexes can be rapidly absorbed by surrounding bacteria and reduced to Fe2+.Fe2+reacts with hydrogen peroxide（H2O2）produced by bacteria and inflammatory cells to form hydroxyl radicals through Fenton reaction to destroy the bacterial structure，thereby achieving sterilization（Figure 11-5）.

Unlike hydrogels loaded with antibacterial agents，inherent antibacterial hydrogels refer to hydrogels with inherent antibacterial properties prepared by introducing components with antibacterial functional groups.Inherent antibacterial hydrogels can be divided into cationic polymer hydrogels and antimicrobial peptide-based hydrogels.The inherent antibacterial hydrogels mainly kill the bacteria by interacting with the negatively charged bacterial cell membrane，and the cell membrane structure is destroyed and the intercellular substance flows out.Lei et al.prepared an antibacterial hydrogel based on monodisperse PDAfunctionalized bioactive glass NPs and antibacterial polypeptide F127-e-poly-L-lysine.The nanocomposite hydrogel exhibited highly effective antibacterial properties against bacteria with multidrug resistance and effectively promoted the formation of collagen tissue and the regeneration of blood vessels.

11.2.4　Thermal stimulation wound dressings

As an ancient yet effective method，the application of local heat around the wound can increase blood flow，stimulate the proliferation of fibroblasts，and reduce inflammation.The local heating method can strengthen the metabolism around the wound and promote wound healing.In recent years，many scientific studies have confirmed that the use of photothermal therapy（PTT）can promote wound tissue regeneration，and this therapy has been widely used clinically as adjuvant therapy.Currently，PTT mostly uses lasers with a small area and high energy as the light source，showing excellent tissue penetration ability and minimal damage to surrounding tissues and has been successfully combined with nano-drugs for the treatment of tumor-related or bacterial wounds.

Combining photothermal materials into hydrogels or other scaffold materials is an important way to achieve thermal stimulation wound dressings.For example，Yang et al.developed a multifunctional scaffold containing nano-hydroxyapatite/graphene oxide（nHA/GO）composite particles.Under the NIR irradiation，the scaffold can effectively kill human osteosarcoma cells and also promote tissue regeneration，providing a promising clinical tool for treating osteosarcoma resection tissue damage.In addition，the use of photothermal antibacterial hydrogels are also an important strategy for the treatment of bacterial wound infections.As shown in Figure 11-6，Wang et al.constructed a composite hydrogel（CS/AM NSs hydrogel）with outstanding antibacterial ability by incorporating antimonene nanosheets（AM NSs）with extraordinary photothermal properties into the network structure of chitosan（CS）.When being cultured with bacteria，CS/AM NSs hydrogel could aggregate on the surface of the bacteria through the interaction of CS and bacterial cell membrane.Subsequently，the inherent bactericidal properties of CS would kill certain bacteria.Under the NIR，AM NSs could effectively convert light energy into heat energy to eliminate residual bacteria.Due to the synergy between the capture effect of CS and the photothermal effect of AM NSs，CS/AM NSs hydrogel showed good antibacterial properties against Escherichia coli（E.coli）and Staphylococcus aureus（S.aureus）.

With the abuse of antibiotics，rapid and effective sterilization of wounds infected by drug-resistant bacteria inevitably becomes a serious challenge in the field of wound healing.Chang et al.prepared a multifunctional composite（PDA/Cu-CS）hydrogel mainly composed of polydopamine（PDA）and copper-doped calcium silicate ceramic（Cu-CS）.The PDA/Cu complex in the composite hydrogel played a key role in enhancing photothermal performance and antibacterial activity.The unique“hot ions effect”produced by heating copper ions through the photothermal effect of the composite hydrogel showed high-efficiency，rapid，and long-term inhibition of methicillin-resistant S.aureus and E.coli.The composite hydrogel showed significant biological activity and could effectively remove existing infections in the wound area，and significantly promoted angiogenesis and collagen deposition during the healing process of infectious skin wounds.In addition，Guo et al.developed an injectable double network hydrogel adhesive with high self-healing efficiency and photothermal antibacterial activity to treat multidrug-resistant bacterial infections（MRSA）in the wound.The hydrogel exhibited good tissue adhesion，degradability，photothermal antibacterial activity.

Usually，laser-based PTT still has limitations.Since the penetration depth of NIR is usually less than 1 cm，long-distance light irradiation cannot be achieved，which will hinder its practical application in wound healing.By using appropriate photothermal materials，solar energy can be effectively converted into heat energy.Therefore，it is expected to use sunlight to locally heat the wound to promote wound healing.Zhang et al.proposed a strategy of using self-adhesive photothermal hydrogel films to accelerate wound healing under sunlight（Figure 11-7）.The polyacrylamide hydrogel contains PDA and rGO，which can adhere to the wound and convert solar energy into heat energy，thereby locally heating the wound.The increase of local temperature reduces inflammation and enhances epithelial regeneration，angiogenesis，and collagen deposition.

11.2.5　Electrical stimulation wound dressings

As known，a transepithelial/endothelial potential exists in the organism.When the tissue is damaged，the potential will change，thereby generating a stable and constant directcurrent（DC）electric field，i.e.，the endogenous electric field.Studies have found that the current at the edge of the wound is significantly greater than that at the center of the wound，and the current changes as the wound heals.The internal electrical signal generated by the electric field plays an important role in the healing process of the skin wound.Therefore，by applying an external electric field locally to the wound，it is possible to modify and enhance endogenous bioelectric signals and guide and regulate the distribution，migration，proliferation，and differentiation of fibroblasts，neuronal cells，and endothelial cells，thereby accelerating the orientation of skin tissue repair.Recently，electrical stimulation（ES）therapy at the wound site has been used as an important clinical strategy in the field of tissue repair by reducing wound edema and inflammation，increasing blood microcirculation，and accelerating wound closure.

Wound repair and tissue regeneration are complex processes involving many physiological signals.Therefore，it is possible to use new types of wound dressings with effective biological activity and physiological signal response to accelerating wound healing.At present，researches about ES hydrogel wound dressings are mainly focused on the preparation of conductive hydrogel electrodes and their applications in wound healing.For example，Lu et al.prepared a rGO-CS/SF hydrogel based on PDA，rGO，chitosan（CS），and silk fibroin（SF）.The obtained hydrogel showed good mechanical strength，electrical activity，and anti-oxidizing capability.The composite hydrogels were used as an ES wound dressing.In vitro studies have shown that the electroactive rGO-CS/SF hydrogel can respond to electrical signals and promote cell behavior，and it can also reduce cell oxidation by removing excess reactive oxygen species（ROS）.Studies in the full-thickness skin defect model in vivo showed that it could effectively promote wound healing.

Similarly，Wang et al.prepared a conductive polyHEMA/polypyrrole（PPY）composite hydrogel（Figure 11-8）.When this polyHEMA/PPY hydrogel was used to electrically stimulate diabetic rats，the wound healing was much faster than that achieved by the ES strategy based on commercially available electrodes.

In addition，antibacterial properties and mechanical properties should also be considered when designing a conductive hydrogel.Yang et al.developed injectable，biocompatible，selfhealing，and conductive hydrogels（PPGS）based on poly（3，4-ethylenedioxythiophene），poly（styrene sulfonate），and guar cement for various wounds.The results showed that PPGS had great potential in the fields of tissue engineering and biomedicine.Lin et al.obtained conductive hydrogels（i.e.，PDA@AgNPs/CPHs）by using PDA-modified silver NPs（PDA@AgNPs），polyaniline，and poly（vinyl alcohol），which exhibited extensive antibacterial activity against gram-negative bacteria and gram-positive bacteria and could monitor the large-scale movement of the human body in real-time.In addition，PDA@AgNPs/CPHs have a significant therapeutic effect on diabetic foot wounds by promoting angiogenesis，accelerating collagen deposition，inhibiting bacterial growth，and controlling wound infections.

In addition，the use of ES therapy in clinical operations is often restricted by bulky equipment，and it is difficult to achieve real-time treatment.There is an urgent need for wearable and point-of-care equipment that can generate an electric field at the wound site for skin wound healing.Therefore，self-powered devices such as enzyme biofuel cells and nanogenerators have also attracted growing attention，which is small in size and can produce ES without the need for a commercial power source.For example，Nishizawa et al.used flexible enzyme electrodes and stretchable hydrogels to prepare a stretchable bio-electric paste with a built-in enzyme biofuel cell，which generated ionic current on the skin surface through an enzyme electrochemical reaction.Animal experiment results showed that the ion current of electrospun fibers can promote wounds to heal faster and smoother.Zhang et al.developed a hybrid skin patch with a self-adhesive hydrogel and piezoelectric nanogenerator（HPSP，Figure 11-9），which consists of a mussel-like adhered hydrogel matrix and oriented PVDF nanofibers as piezoelectric nanogenerators.The HPSP has Young's modulus similar to that of the skin.It can self-adhere to the wound site，and locally generate a voltage caused by motions.As a wearable real-time ES device，the patch greatly accelerates the healing process and shortens the closure time of full-thickness skin defects by about 1/3.

11.2.6　Wound dressings for controlled active ingredients release

The treatment of chronic wounds sometimes requires appropriate supplementation of active ingredients，such as growth factors or certain gas stimulation to facilitate wound healing.Therefore，the development of wound dressings containing the controlled release of active ingredients will play an increasingly important role in the treatment of chronic wounds.The growth factor is a kind of polypeptide substance that regulates cell growth and other cell functions by binding to specific，high-affinity cell membrane receptors.It is used in signal transduction，regulation of cell proliferation and differentiation，and tissue maintenance.Recombinant human epidermal growth factor（rhEGF）is widely used clinically in wound treatment as a biological agent that strongly promotes cell regeneration and tissue repair，but its direct use faces the challenge of requiring long-term low-temperature storage.To this end，Han et al.inserted dopamine into clay nanosheets with partial oxidation and incorporated the nanocomposites into polyacrylamide hydrogels.The hydrogels exhibited repeatable and long-lasting adhesion.In addition，the rhEGF could be loaded into the hydrogels，and the rat full-thickness skin defect experiment showed that the hydrogels can be excellent dressings for accelerating wound healing.

The development of effective yet economical methods to improve wound healing is always highly desirable.Due to the advantages of high treatment efficiency and good biocompatibility，gas therapy by using O2，NO，H2S，and others have been proved to have the potential to promote wound healing.Studies have shown that adequate oxygen supply is a prerequisite for wound tissue growth and remodeling.However，insufficient microcirculation at the wound can lead to hypoxia，which is not beneficial for the healing of skin wounds.Therefore，increasing the oxygen content around the wound is one of the most important strategies to promote wound healing.Current oxygen therapies，including hyperbaric oxygen（HBO）and local gaseous oxygen（TGO），mainly use gaseous oxygen delivery，which is not effective in penetrating the skin.Wu et al.developed an oxygengenerating patch made of living microalgae hydrogel，which could generate dissolved oxygen（Figure 11-10）.The transport performance of the dissolved oxygen generated by the patch is more than 100 times than TGO.The patch could promote cell proliferation and migration，and tube formation in vitro，and improve chronic wound healing and skin graft survival in diabetic mice.

In addition，according to the principle of the Bohr effect，CO2 can be used instead of direct use of O2 for skin wound treatment to promote healing.When CO2 dissolves in the tissue surrounding the wound，the decrease in pH will trigger the hemoglobin to release more O2 locally at the site，thereby effectively promoting the healing of the wound.Compared with the direct use of O2，CO2 has a high solubility in body fluids，thus it is more convenient for controlled delivery.In particular，the strategy of accurately releasing CO2 gas on the wound on demand has attracted more and more attention.

Yeh et al.designed a metal ion-ligand coordination NP and used NIR to trigger CO2 release for wound healing.Zhang et al.developed a photothermal hydrogel for on-demand and local delivery of CO2 by combining thermally responsive block copolymer（BCP）of Pluronic F127 and carbon NP（CNP）with amino groups to accelerate the healing of skin wounds.When the hybrid hydrogel was irradiated with light，CNP can convert light energy into heat energy，triggering the decomposition of bicarbonate and local release CO2 at the wound site，which speeded up wound healing by improving local microcirculation and increasing tissue oxygen concentration.In addition，gas delivery can also be combined with photothermal therapy（Figure 11-11）.

11.3　Functionalized Polymer Fiber Dressings

Polymer fibers are also important dressing materials used in skin wound treatment.Medical fiber materials used in the human body must have good biocompatibility.Therefore，the current research on functionalized polymer fiber dressings has important significance and broad development prospects.

11.3.1　Preparation of polymer fibers

Ideal wound dressings should be non-toxic，non-sensitizing，and they can allow gas exchange，absorb wound exudate to protect the wound，form a microenvironment conducive to wound healing，and inhibit bacterial growth.Commonly used fiber dressings，such as cotton gauze，were used for clinical wound care and treatment by covering the damaged skin.However，gauze is prone to cause adhesion between the wound and the dressing，which causes secondary trauma and bacterial growth.In recent years，the preparation technology of fiber dressings has developed vigorously.The micro-nano structured fiber membrane with high specific surface area and high porosity is a new type of wound dressing.Compared with other dressings，it is lighter，thinner，more breathable，and has various functional directions.There are many technologies for preparing micro-nano structured fiber membranes，such as stretching method，template synthesis，phase separation，selfassembly，and electrospinning technology.

Among the preparative technologies of fiber dressings，electrospinning technology is currently the most widely studied technology.Electrospinning technology is a fiber production method that uses electric force to draw charged threads of polymer solutions or polymer melts up to fiber diameters in the order of some hundred nanometers.The electrospinning process is simple，low cost，with wide selection of materials.

Compared with other forms of fiber materials，electrospun fibers show many advantages in medical dressings.Firstly，they have structural advantages.The diameter of the fibers obtained by electrospinning technology ranged from a few nanometers to a few microns，and it has good mechanical strength.Its multi-level geometric size is similar to the microstructure and biological function of the extracellular matrix（ECM）.At present，the electrospun fiber membrane is often used as a scaffold material for tissue engineering.It provides support and guidance for the proliferation and migration of cells and the transfer of active substances，which is conducive to angiogenesis and tissue remodeling.Secondly，electrospun fiber membrane usually has high permeability and porosity，which can quickly absorb the tissue fluid that appears in the wound，facilitating the ventilation of the wound and preventing bacterial infection.Thirdly，the electrospun fiber membrane can also achieve an excellent hemostatic effect by optimizing the fiber material and the electrospun fiber membrane can be used as a drug loading platform to enhance its drug delivery efficacy.For example，it can be loaded with anti-inflammatory drugs，growth factors，antibiotics，etc.，and the drug delivery speed can be adjusted as needed to promote wound healing.Figure 11-12 shows the commonly used strategies for directly preparing drug-loaded electrospun fiber dressings，including blending，coaxial，and emulsion electrospinning.Blended electrospinning usually produces fibers containing active agents dispersed throughout the fiber，while coaxial electrospinning and emulsion electrospinning synthesize core/shell morphologies well to meet different drug loading requirements.

In addition，post-treatment of electrospun fibers can also improve wound healing properties.Generally，the surface of electrospun fibers may lack the properties required for specific biological applications.The property can be imparted by electrostatic adhesion，dip coating，layer-by-layer assembly，or surface chemical reaction.For example，PVA electrospun membranes can be coated with chitosan by simply immersing the PVA membrane in a chitosan solution，which can provide instant hemostatic activity.Epidermal growth factor（EGF）can also be fixed on the surface of the fibers through a facile grafting strategy.In vivo wound studies have shown that EGF conjugated fibers can increase keratinocytespecific genes.Therefore，the incorporation of growth factors can promote gene expression，thereby accelerating wound healing.

11.3.2　Surface wettability

Some serious skin wounds（e.g.，scalds，ulcers）can cause excessive exudation of wound tissue fluid，forming highly exudative wounds that are difficult to heal.The amount of exudation in 24 h can exceed 10 mL，and the dressing infiltration rate is more than 75％.It is also easy to cause adhesion of the wound and dressing，and will cause great pain and inconvenience to the patients.Therefore，high-exudation wounds have higher requirements for the surface infiltration performance of dressing materials.Dressings for high-exudation wounds need to absorb and drain exudate，while they must also maintain the moistness of the wound to promote healing.The commonly used gauze cannot keep moist，which would delay wound healing.At present，wet dressings（e.g.，alginate gels，hydrophilic fibers，foams，and silver ion dressings）can absorb wound tissue fluid and keep the wound moist，promote granulation growth and resist bacterial infections，and are the first choice for high-exudation wounds.Excessive wound tissue fluid caused excessive wound hydration is a serious problem.Generally，traditional wet hydrophilic dressings can absorb part of the wound tissue fluid，but due to its inherent hydrophilicity，it is inevitably to produce wound tissue fluid at the interface between the wound and the dressing.Residual wound tissue fluid will continue to hydrate the wound and complicate the healing process.The biological interface plays an important role in the interaction between wound tissue fluid and biological materials.The surface wettability of the wound dressings usually affects the wetting behavior of the tissue fluid around the wound.Like most traditional dressings，hydrophilic materials are easily wetted by wound tissue fluid，which can over-hydrate the wound.On the contrary，as a waterproof outer layer of the dressing，hydrophobic materials can prevent accidental contact of external liquid with the wound，but they cannot promote the removal of wound tissue fluid.Recently，several asymmetrically（Janus type）wetting materials have shown unique ability to transfer fluid，such as polyester fabrics with wettability gradients，polyurethane（PU）/poly（vinyl acetate）composite fiber membranes，and single-sided fluorinated cotton fabric membrane（Figure 11-13）.Therefore，manipulation of surface wettability may provide opportunities for designing wound dressings with effective wound tissue fluid capabilities.

Wang et al.prepared electrospun hydrophobic polyurethane（PU）nanofiber membranes onto a hydrophilic ultrafine fiber network and constructed a self-absorbent dressing as a biological fluid pump（Figure 11-14）.The network provided drainage force to pump excess biological fluid through the hydrophobic nanofiber membrane to discharge the fluid unidirectionally from the hydrophobic side to the hydrophilic side，thereby preventing the biological fluid from wetting the wound.In the infected wound model，they showed that this self-pumping dressing can heal wounds faster than conventional dressings.This study provided new clues to manage excess biological fluid around wounds to promote faster wound healing and the self-pumping dressing has great potential as the next generation dressing for clinical wound healing.

11.3.3　Hemostatic fiber dressings

Traditional hemostatic materials and products are mainly hemostatic gauze，bandages，and hemostatic sponges.Clinical applications have found that these products have poor hemostatic effects and do not have the ability to actively stop bleeding.They can only meet the hemostatic needs of general or conventional bleeding wounds，and they are not degradable in the body.It is difficult to be absorbed by the body，therefore their applications are quite limited.In recent years，scientists have discovered that the surface modification of gauze，sponge，etc.，with a layer of porous，soft，and water-absorbing fibers with excellent adhesion and blood coagulation will greatly improve their hemostatic properties.For example，Hammond et al.loaded RADA16-I self-assembled polypeptide nanofibers on the surface of gauze or gelatin sponge through layer-by-layer assembly technology to obtain a fast hemostatic gauze or sponge with active coagulation function.Since RADA16-I self-assembled polypeptide nanofibers can effectively aggregate and cross-linking components in the blood，the hemostatic effect of gauze or sponge is greatly improved.Yu et al.prepared hybrid electrospun poly（vinyl pyrrolidone）fibers with curcumin-loaded mesoporous silica for rapid hemostasis and antibacterial wound dressings.It is found that the nanofiber mat has no obvious toxic effect on cell growth，and can enhance the antibacterial effect on S.aureus in vitro.In addition，the hybrid nanofiber mat could quickly turn into hydrogel when in contact with blood and then activated the coagulation system to prevent bleeding from the wound.

In addition，based on improving the hemostatic effect of the materials，further optimization of the preparation process has also aroused the widespread interest of scientific researchers.Long et al.developed a portable electrospun device（about 150 grams）for outdoor use，which can realize the green synthesis of CuS composite nanofibers.These composite nanofibers can be deposited on the wound in-situ while achieving rapid hemostasis and elimination of super bacteria outdoors without the use of other materials or equipments.The compactness of this in-situ electrospun nanofiber on the rough surface of the wound is better than that of the traditional nanofiber pad pressed on the wound.Therefore，nanofibers can not only accelerate hemostasis（＜6 s），but also shorten the healing time of superbacterial infection wounds（18 days）.These dual-function nanofibers combined with portable electrospun equipment can be used for outdoor rapid hemostasis and simultaneous ablation of super bacteria，which can significantly improve outdoor first aid（Figure 11-15）.

11.3.4　Antibacterial fiber dressings

Bacterial infections seriously threaten the wound healing process，and preventing bacterial infections is essential to complete wound healing.The addition of inorganic，organic，or metal antibacterial agents to electrospun fibers has always been an important strategy for obtaining antibacterial fiber dressings.

At present，in clinical operations，systemic antibiotics are often used to treat wound infections.The long-term use of antibiotics with strong potency and rapid sterilization will bring bacterial resistance.If the release concentration is less than the minimum inhibitory concentration，the adverse consequences of resistance will be aggravated.Therefore，controlling a reasonable antibiotic release concentration has always been an important aspect of antibacterial fiber dressings.He et al.loaded enrofloxacin antibiotics into PVDF electrospun nanofibers.Within 0-12 h，the drug release showed a burst behavior，and the cumulative release reached 60％，which can quickly kill bacteria，and then the residual drug continued to release up to 3 days.The sustainable release of the loaded drugs can effectively inhibit the proliferation of bacteria.

In addition，many studies have shown that loading inorganic antibacterial agents including Ag，Zn，and carbon-based nanomaterials，into fibers can kill bacteria，reduce inflammation，or promote epithelial proliferation and regeneration.Some researchers used PVA as a reducing agent to prepare Ag-NPs loaded PVA electrospun fibers.The fibers showed inhibitory effects on E.coli and S.aureus，and the antibacterial efficiency was much higher than that of wound dressings loaded with silver nitrate.

Chang et al.synthesized zinc-doped hollow mesoporous silica nanospheres（HMZS）by the sol-gel method and loaded them into polycaprolactone（PCL）electrospun fiber to prepare a new type of wound healing dressing.As shown in Figure 11-16，the composite electrospun fiber dressing can promote angiogenesis and skin regeneration by releasing Si ions，and enhance hair follicle regeneration and inhibit bacterial growth by releasing zinc ions.

Besides these inorganic materials，some organic polymers，such as quaternary ammonium salts，guanidine group-containing polymers，or antibacterial peptides，also have excellent antibacterial properties.Loading these motifs into the electrospun fiber membranes can even overcome multidrug resistance（MDR）bacterial infections.Recently，Lei et al.developed an elastic，photoluminescence，and antibacterial hybrid polypeptide-based nanofiber matrix as a multifunctional platform for inhibiting MDR bacteria and enhancing wound healing（Figure 11-17）.The hybrid nanofiber matrix is composed of poly（citrate）-εpolylysine（PCE）and polycaprolactone（PCL）.The PCL-PCE hybrid nanofiber matrix exhibits biomimetic elastic behavior，strong antibacterial activity（including the ability to kill MDR bacteria）and excellent biocompatibility，and can effectively prevent wound infections caused by MDR bacteria and enhance wound healing and skin regeneration.

11.4　Challenges and Perspectives

In this chapter，we have reviewed the recent progress of functionalized polymer dressings in promoting wound healing and hemostasis.By using hydrogels，functionalized polymer fibers，etc.，and tuning their chemical composition，network structure，surface wettability，and other features，they can effectively achieve unique functions such as selfadhesion，antibacterial，and exudate removal，thereby promoting wound healing.In addition，the hydrogels can be used as a carrier to effectively combine the photothermal components，nanogenerators，and functional nanocarriers to achieve external stimulation to the wound and promote wound repair.Compared with traditional dressings，functionalized polymer dressings are aimed at the mechanism of wound repair，possible infections and other issues，by activating autologous factors to promote wound repair and inhibit bacterial infections，so as to achieve the purpose of promoting wound healing，which is of great importance as the next-generation dressings.However，we have also noticed that for some chronic hard-to-heal wounds and wounds with drug-resistant bacteria infection，achieving rapid healing is still an important challenge in this field.Moreover，these functionalized polymer dressings are still in their infancy and are more verified in small animal models.It remains challenging to verify their functions in wound healing in large animals and humans.Especially for some functionalized dressings that use nanoparticles and nanodevices，the biological safety of these materials needs to be further verified to ensure that they will not be greatly affected because of leakage and shedding issues.In addition，the development of more convenient and low-cost preparative methods for these functionalized polymer dressings to come true still requires the in-depth crossover and cooperation of scientists and engineers from materials science，clinical medicine，and related industries.With the integration of different disciplines and the rapid development of materials science，interface science，nanodevices，and other related fields，we believe that in the near future，more functionalized polymer dressings will appear and be used in clinical treatment，and ultimately benefiting the patients.

Questions

1.Describe the advantages and disadvantages of traditional dry and hydrogel-based wound dressings.

2.What are the preparative methods of polymer fiber dressings？

3.What external environmental factors are conducive to wound healing？How to achieve？

4.What are the requirements for using hydrogels as wound dressings？5.How to improve the effect of wound repair？