Smart and versatile biomaterials for cutaneous wound healing

Abstract

The global increase of cutaneous wounds imposes huge health and financial burdens on patients and society. Despite improved wound healing outcomes, conventional wound dressings are far from ideal, owing to the complex healing process. Smart wound dressings, which are sensitive to or interact with changes in wound condition or environment, have been proposed as appealing therapeutic platforms to effectively facilitate wound healing. In this review, the wound healing processes and features of existing biomaterials are firstly introduced, followed by summarizing the mechanisms of smart responsive materials. Afterwards, recent advances and designs in smart and versatile materials of extensive applications for cutaneous wound healing were submarined. Finally, clinical progresses, challenges and future perspectives of the smart wound dressing are discussed. Overall, by mapping the composition and intrinsic structure of smart responsive materials to their individual needs of cutaneous wounds, with particular attention to the responsive mechanisms, this review is promising to advance further progress in designing smart responsive materials for wounds and drive clinical translation.

Keywords: Biomaterials; Smart dressings; Stimuli-responsive; Wound healing.

Scheme 1

Schematic illustration of smart and versatile materials for cutaneous wound healing

Fig. 1

Schematic overview of healing processes. A hemostasis and coagulation. B inflammation. C proliferation. D remodeling. Reprinted with permission from ref [17]. Copyright 2014 AAAS

Fig. 2

Typical applications of LNPs in controlled delivery of nucleic acids. A Schematic outlining the molecular process to create mRNA-based FAPCAR T cells in vitro with CD5-targeted LNPs. Reprinted with permission from ref [36]. Copyright 2022 AAAS. B Schematic representation of the keratinocyte-targeted LNPs (TLNPκ). Reprinted with permission from ref [38]. Copyright 2020 American Chemical Society. C Schematic representation of keratinocytes targeting LNPs (TLNκ) to deliver TLNκ/anti-miR-107. Reprinted with permission from ref [39]. Copyright 2018 Elsevier

Fig. 3

Endogenous and exogenous stimulus having been applied in the management of cutaneous wounds

Fig. 4

Wound dressings with hemostatic function. A Antibacterial, anti-oxidant, and electroactive dressing for wound repair based on quaternized chitosan-g-polyaniline (QCSP) and benzaldehyde group functionalized poly(ethylene glycol)-co-poly(glycerol sebacate) (PEGS-FA). Schematic illustration of this hydrogel’s synthesis. (a-c) Synthesis processes; (d) Photos of solutions and hydrogel (QCSP3/PEGS-FA1.5); (e) Two shapes (bending and pressing) of this hydrogel. Reprinted with permission from ref [77]. Copyright 2017 Elsevier. B Schematic diagram for the interface interactions between tissue and hydrogel, with desired properties such as hemostasis. Reprinted with permission from ref [88]. Copyright 2021 Elsevier. C A visible light-stimulating hemostatic adhesive (HAD). (a) Schematic overview of the visible light–responsive photopolymerization device; (b) Before (top), during (middle), and after visible light illumination, a digital image of the HAD gelling transition was taken (bottom); (c) Diagram depicting the formation of rat tail hemorrhage and a hemostatic model; (d) Schematic presentation of hemostatic processes and hemostatic assay using HAD based on a serious liver wound model. Reprinted with permission from ref [64]. Copyright 2021 AAAS

Fig. 5

Wound dressings with antibacterial function. A PDA-coated gold nanorods (GNRs) were used to create a chemo-photothermal therapy platform. (a) Schematic of material synthesis; (b) Schematic of charge reversal and Ag + ion release as a result of acidity; (c) Schematic of bacterial-specific targeting and chemo-photothermal combo treatment. Reprinted with permission from ref [94]. Copyright 2018 Springer Nature. B Schematic representation of a self-healing hydrogel dressing which was conductive and adhesive using Pluronic F127/carbon nanotubes (PF127/CNT) and N-carboxyethyl chitosan (CEC). Reprinted with permission from ref [102]. Copyright 2020 Elsevier. C The drug reservoir was made by mixing ciprofloxacin (Cip, a strong antibiotic)-loaded PDA NPs and glycol chitosan (GC) to generate an injectable hydrogel (PDA NP-Cip/GC hydrogel, dubbed Gel-Cip). Reprinted with permission from ref [103]. Copyright 2018 Elsevier. D Gold nanoclusters modified zirconium-based porphyrin metal–organic frameworks (Au NCs@PCN) were designed for Infected Diabetic Wound Healing. (a) Diagram of the Au NCs@PCN fabrication method; (b) High-temperature death of multidrug resistance bacteria under NIR radiation by CDT, PDT, and PTT; (c) Bactericidal via altering bacterial membrane structure and encouraging angiogenesis and epithelial cell healing by upregulating the expression of associated factors. Reprinted with permission from ref [65]. Copyright 2022 American Chemical Society

Fig. 6

Wound dressings with anti-inflammation function. A Curcumin was delivered via a thermosensitive hydrogel containing the nanodrug in the form of gelatin microspheres (GMs) (Cur) to improves diabetic wound healing. (a) Solution exchange method for producing pure CNPs. (b) The emulsion process loads CNPs into GMs, resulting in CNPs@GMs. (c) In diabetic mice, CNPs@GMs were combined with a thermos-sensitive hydrogel and applied to the wound. (d) GMs were destroyed by MMPs in the microenvironment of a nonhealing wound, and the medication was precisely released. Reprinted with permission from ref [117]. Copyright 2018 American Chemical Society. B Electroactive and antioxidative scaffold was fabricated for wound healing. (a) PDA’s synthetic approach decreased and functionalized pGO. (b) The pGO-CS/SF scaffold is formed with dual cross-links. (c) The skin wound defect was repaired using the scaffold. During wound healing, the scaffold exhibits antioxidative properties and electrical stimulation of the skin tissue. Reprinted with permission from ref [118]. Copyright 2019 American Chemical Society. C Using an efficient and simple one-step technique, ultrasmall Cu5.4O NPs (Cu5.4O USNPs) were created as nanozymes with numerous enzyme-mimicking and widening ROS scavenging capacity against broad ROS-related illnesses, including acute kidney injury, acute liver injury and diabetic wound healing. Reprinted with permission from ref [66]. Copyright 2019 American Chemical Society

Fig. 7

Wound dressings with pro-vascularization function. A PDA modified collagen sponge scaffold (pDA-CSS) was fabricated to deliver PRP for skin repair. (a) PRP is coupled with pDA-CSS to promote the release of growth factors (GFs). (b) Attributed to pro-vascularization and pro-proliferation, the pDA-CSS delivering PRP achieved one-step to accelerate wound healing. Reprinted with permission from ref [125]. Copyright 2021 Elsevier. B A biodegradable scaffold was fabricated to release DFO for angiogenesis and osteogenesis. (a) DFO and charged carboxymethyl chitosan have similar chemical molecular structures (CCS). (b) Illustration angiogenesis benefiting from scaffold. (c) DFO promoted bone repair in MSCs and vascular endothelia cells (ECs) via a biological mechanism. Reprinted with permission from ref [130]. Copyright 2018 Elsevier. C Cavitation molding with a 3D laser for vascularized tissue models. (a) Schematic of femtosecond laser exposure in situ patterning of collagen hydrogel. (b-c) Designed microchannels in a collagen hydrogel, brightfield and confocal pictures (d) Diagram of the dynamics during laser-induced cavitation and after the bubbles have collapsed and the matrix has relaxed. (e) Endothelial cells are seeded directly into the designed channels, resulting in the development of an artificial blood artery. (f-g) Developed vascularized glioblastoma spheroid model with encapsulated U87 glioblastoma cellular spheroids, with concept sketch and confocal fluorescence photographs. Reprinted with permission from ref [67]. Copyright 2022 Wiley-VCH. (D) Endothelial cell networks, dermal fibroblasts, and multilayered keratinocytes were used to create a schematic depicting the arrangement of skin layers. Reprinted with permission from ref [136]. Copyright 2021 IOP Science

Fig. 8

Wound dressings with wound microenvironment regulation function. A Schematic displaying gelatin (GEL)/polyvinyl alcohol (PVA) electrospun nanofibers (BNFs), which was synthesized using electrostatic spinning to load cefradine as a bionic antibacterial functional material. Reprinted with permission from ref [141]. Copyright 2021 MDPI. B HA, carboxylated chitosan (CCS) and human-like collagen (HLC) were mixed to ECM, and glutamine transaminase (TG) was utilized as a crosslinker in a schematic one-pot production procedure of hydrogel-based burn dressing. Reprinted with permission from ref [68]. Copyright 2020 Elsevier

Fig. 9

Self-healing wound dressings for motional wound. A Tannic acid (TA) was used as a multi-functional H-bond supplier to create a GelMA-based double-network (DN) hydrogel with versatile capabilities. The preparation of a versatile GelMA-TA hydrogel (a) with high stiffness, super-elasticity, deformability (b), and in vivo self-healing and adhesive properties is shown schematically (c). GelMA-TA gel has been used in biomedical applications such as skin wound closure (d), sutureless gastric surgery (e), and as a strain sensor when MWCNTs are present (f). Reprinted with permission from ref [69]. Copyright 2018 Elsevier. B Antibacterial adhesive injectable hydrogels with quick self-healing, extensibility, and compressibility were manufactured as wound dressing for joints skin wound healing by mixing quaternized chitosan (QCS) and benzaldehyde-terminated Pluronic®F127 (PF127-CHO) under physiological conditions. (a) Schematic presentation of the hydrogel and TEM images. Scale bar: 200 nm. (b) Rhodamine B coloured QCS/PF1.0 hydrogels in their natural bending, compression, stretching, twisting, and knotting shapes. Scale bar: 1 cm. Reprinted with permission from ref [146]. Copyright 2018 Elsevier

Fig. 10

Self-removal wound dressings. A A reversible PEG-thiol-Aldehyde Addition Reaction and a Thiol-Hemithioacetal Exchange Reaction are used to make moldable and removable wound dressings, and a Thiol-Hemithioacetal Exchange Reaction is used to dissolve hydrogels. Reprinted with permission from ref [151]. Copyright 2019 American Chemical Society. B An easily removable wound dressing with supramolecular hydrogel. (a) Fabrication of supramolecular hydrogels from supramonomers and their breakdown under memantine irrigation and (b) its utilization as a wound dressing. Reprinted with permission from ref [152]. Copyright 2017 American Chemical Society. C A Michael addition reaction between dopamine, poly(ethylene glycol) diacrylate (PEGDA700), and pentaerythritol triacrylate was used to create an injectable adhesive hydrogel-based bandage (PETA). Spraying zinc ions on the dressing could quickly replace it. Reprinted with permission from ref [70]. Copyright 2020 Royal Society of Chemistry

Fig. 11

Wound dressings with monitoring function. A Temperature-monitoring wound dressing with temperature sensor, power manager circuit, data processing, and Bluetooth circuit that can send temperature changes to a mobile device in real time. Reprinted with permission from ref [158]. Copyright 2020 Elsevier. B Smart bandages with flexible pH sensors and a heater to trigger thermo-responsive medication carriers holding antibiotics for chronic wounds (wirelessly connected to smartphone). Reprinted with permission from ref [161]. Copyright 2018 Wiley-VCH. C Real-time monitoring and on-demand treatment of infected wounds using a smart flexible electronics-integrated wound dressing schematics and functioning principles. (a) Within a Bluetooth chip for wireless transmission, the integrated system contains a polydimethylsiloxane-encapsulated flexible electrical layer and a UV-responsive antibacterial hydrogel. (b) An illustration of the integrated system for monitoring infected wounds and providing on-demand therapy. Reprinted with permission from ref [71]. Copyright 2020 Wiley-VCH

Fig. 12

Wound dressings with scar management function. A Silk fibroin/gelatin (SF/GT) electrospun nanofibrous dressings loaded with astragaloside IV (AS) were created to stimulate wound closure, increase angiogenesis, regulate newly formed kinds of collagen, and improve collagen organization in burn wounds. Reprinted with permission from ref [166]. Copyright 2015 Elsevier. B Scheme of PDT with spear and shear, fully armed, for topical deep hypertrophic scar therapy. (a) Dissolving microneedles (MN) based on HAase penetrated the stratum corneum and delivered medicines into hypertrophic scar lesions; (b) By attacking the ECM, HAase-based MN worked as a spear to carry more ALA into deep lesions, enhancing the efficiency of PDT; (c) For increased PDT, Met was used as a shear to impede the self-survival autophagic process. Reprinted with permission from ref [72]. Copyright 2022 Elsevier

Fig. 13

Versatile biomaterials with smart and/or responsive properties. A With the goal of repairing chronic wounds, four different growth factors (EGF, bFGF, PDGF, and VEGF) were loaded, either directly embedded in HA and collagen nanofibers or encapsulated in gelatin NPs (GNs) and subsequently incorporated into nanofibers. Reprinted with permission from ref [171]. Copyright 2014 Elsevier. B F-PNIPAAm/polyaniline (PANI) hydrogels have a network structure. PEO and PPO are poly(ethylene oxide) and poly(propylene oxide), respectively, in Pluronic F127 (F127DA). Reprinted with permission from ref [173]. Copyright 2018 American Chemical Society. C Schematic overview of structure and application of hydrogel dressings. (a) The structure, pH, and glucose response mechanism of PC hydrogel, as well as its application in diabetic foot ulcers and athletic wound healing, are depicted schematically. (b) Testing of mechanical properties of PC hydrogels. Reprinted with permission from ref [73]. Copyright 2022 American Chemical Society. D Possessing multiple responsive properties (temperature, pH and NIR) to release active drugs (like DOX), A pH-sensitive CNF grafted with terminated amino hyperbranched polyamines (HBP-NH2) as a substrate was used to develop a multi-functional and shape-adaptable liquid wound dressing (with CNF) for irregular tumor postoperative infected wounds, with ICG and PNIPAM loaded as NIR and temperature on/off buttons, respectively. Reprinted with permission from ref [174]. Copyright 2021 American Chemical Society