Mussel-inspired, antibacterial, conductive, antioxidant, injectable composite hydrogel wound dressing to promote the regeneration of infected skin
Graphical abstract
Introduction
It is well-known that infection is a major obstacle to wound healing [1], and it has become a continuously growing cause of death among patients with serious illnesses. In addition, the treatment of infection places a substantial burden on the medical system and even society overall. Currently, antibiotics are still the main strategy used in the clinical treatment of infection. Therefore, developing proper antibacterial drug delivery systems that can not only effectively and accurately deliver antibiotics to the wound site but also control the release behaviors for active wound healing are highly desirable [2]. Thus, many types of modern wound dressings including semipermeable films, semipermeable foams, hydrocolloids and hydrogels with sustained drug release properties have been developed in an attempt to not only avoid the infection of defect wounds but also to promote the wound repair process [3], [4], [5], [6]. Among these dressings, due to their hydrophilic nature, hydrogels can reduce the risk of wound infection by absorbing wound exudate and maintaining a moist environment, characteristics which present good potential for improving the repair of damaged tissue.
As a protein derivative, gelatin (GT) is considered beneficial for wound healing due to its non-immunogenicity, cell adhesion behavior and blood coagulation characteristics. GT has been used in combination with a large number of synthetic or natural macromolecules to fabricate wound dressings. For example, the addition of chitosan (CS) can overcome the shortcomings (weak mechanical strength and fast degradation rate) of gelatin-based hydrogels. In addition, CS itself can also trigger hemostasis and accelerate tissue regeneration due to the migration of inflammatory cells and the activation of fibroblasts that produce various cytokines [7]. Moreover, previous works on polyelectrolyte GT-CS scaffolds/films [8], [9] have demonstrated their excellent potential for use in skin tissue engineering applications. On the other hand, excessive reactive oxygen species (ROS) during the wound repair process often affect the repair by changing or degrading extracellular matrix (ECM) proteins, damaging dermal fibroblasts and reducing the function of keratinocytes [10]. Therefore, controlling the levels of ROS has been demonstrated to be an effective way to promote wound healing [11]. However, hydrogels based on GT/CS have no antioxidant capacity. Fortunately, the structure of catechol has been proven to be widely present in a variety of natural antioxidants and plays an important role in scavenging ROS [12]. Thus, grafting dopamine to GT (gelatin-grafted-dopamine (GT-DA)) will endow GT with good antioxidant properties [13], [14]. Moreover, the addition of catechol groups to GT will also enhance the adhesiveness of GT-DA/CS-based hydrogels due to the physical bonding and chemical crosslinking between the catechol or polydopamine group and the wounded tissue [15]. Additionally, the good adhesion properties also allow the hydrogel to seal the wound, achieving a good hemostatic effect [16]. Therefore, grafting dopamine onto GT will give the GT-DA/CS hydrogel good adhesiveness and hemostatic and antioxidant properties, making it an excellent candidate for use in wound dressings.
In addition, researchers have found that the human body has endogenous bioelectric systems. The surface of intact human skin carries a more negative charge than do the deeper skin layers [17]. However, when a defect or wound occurs in the skin, the deeper cells of the epidermis and the cells of the wound are positively charged. The combination of a positively charged wound and negatively charged surrounding intact skin creates what is called a skin battery [18]. This bioelectric current facilitates wound healing best when the wound tissue is moistened. The roles of conductive materials in promoting wound healing have also been demonstrated in previous studies [19], [20], [21], [22], [23], [24], [25]. Due to their excellent mechanical, thermal and electronic properties, carbon nanotubes (CNTs) have led the boom in nanotechnology research in the past decades [26], [27], [28]. Meanwhile, CNTs-embedded scaffolds [29], [30] have been demonstrated to enhance electrical properties and facilitate signal propagation, consequently improving cell-cell coupling [31]. However, the strong hydrophobic interaction between individual CNTs makes it difficult for the original CNTs to disperse in water [32]. Surface coating has been demonstrated to be an efficient way to improve the CNTs dispersion and to reduce their cytotoxicity [33], [34]. Dopamine coating is an easy and effective way to modify the surface of CNTs [35], as dopamine will self-polymerize in alkaline solution and form a layer of polydopamine (PDA) coating on the surfaces of CNTs [31], which avoids the disadvantages of conventional oxidation modification strategies. Additionally, CNTs can strongly absorb near‐infrared (NIR) energy and efficiently convert it into thermal energy, and they also exhibit good photothermal antibacterial effects, which will benefit the healing of infected wounds [36], [37]. Thus, developing CNT-PDA and GT-DA/CS-based antibacterial adhesive antioxidative conductive hydrogels is highly desirable to heal infected wounds.
Here, chitosan, gelatin-grafted-dopamine and polydopamine-coated CNTs were used as building blocks to engineer antibacterial adhesive conductive GT-DA/CS/CNT composite hydrogels by the self-polymerization of dopamine using a H2O2/HRP catalytic system, and their good therapeutic effect in the treatment of infected full-thickness defect wounds was also demonstrated. Chitosan was added into the system to improve the hydrogels’ mechanical properties and compensate for the disadvantage of rapid degradation. The use of the H2O2/HRP catalytic system not only reduced the biological safety problems observed in the traditional oxidative methods but also produced similar or comparatively better mechanical properties than the traditional chemical methods. The swelling ratio, degradation behaviors, morphology and rheology properties of the engineered GT-DA/CS/CNT hydrogels were characterized. The properties of tissue adhesiveness, hemostatic and antioxidant activities, conductivity, photothermal effects and sustained drug release were also studied. Additionally, to endow antibacterial ability to the composite hydrogels, doxycycline was loaded into the polymeric network, and the antimicrobial properties of the GT-DA/CS/CNT/Doxy hydrogels were evaluated against Gram-(+) Staphylococcus aureus (S. aureus) and Gram-(−) Escherichia coli (E. coli). Furthermore, in vitro cytocompatibility and blood compatibility testing of the GT-DA/CS/CNT hydrogels was also conducted. Last, an infected mouse full-thickness skin defect wound model was used to evaluate the therapeutic effects of these hydrogels. These GT-DA/CS/CNT hydrogels’ multifunctional properties, including antibacterial activity, adhesiveness and conductivity, make them excellent candidates for the treatment of infected skin wounds.
Section snippets
Materials
Gelatin (Type A, gel strength ∼ 300 g Bloom, Sigma-Aldrich), dopamine hydrochloride (DA, Sigma-Aldrich, 98%), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, J&K Chemical, >98.5%), N-Hydroxysuccinimide (NHS, Sigma-Aldrich, 98%), carbon nanotube (CNTs, XFNANO, Materials Tech CO. Ltd.), 2,2-Diphenyl-1-(2, 4,6-trinitrophenyl)-hydrazyl (DPPH, J&K Chemical, 97%), horseradish peroxidase (HRP, J&K Chemical, 98%), and doxycycline hydrochloride (J&K Chemical, 98%) were used as received.
Preparation of GT-DA/CS/CNT hydrogel
Herein, we present antimicrobial, adhesive, antioxidative and conductive hydrogels to treat infected skin defect wounds. These designed hydrogels were based on gelatin-grafted-dopamine and polydopamine-coated CNTs. Gelatin, a highly regarded polymer that provides structural integrity and mimics the native composition of the ECM to modulate cell function in human skin, is suitable for skin regeneration applications. Because of its good tissue adhesion characteristics, dopamine was chosen and
Conclusions
We present a series of antibacterial adhesive antioxidant and conductive GT-DA/CS/CNT composite hydrogels produced through the oxidative coupling of catechol groups between gelatin-grafted-dopamine and polydopamine-coated CNTs. The addition of the antibiotic doxycycline endowed the hydrogel with antimicrobial activity, and these multifunctional hydrogels showed great potential for promoting the repair of infected wounds [78], [79]. The porosity, rheology, mechanical properties, conductivity,
Declaration of Competing Interest
The authors declare no competing financial interest.
Acknowledgement
This work was jointly supported by the National Natural Science Foundation of China (grant number: 51673155), the State Key Laboratory for Mechanical Behavior of Materials, the Fundamental Research Funds for the Central Universities, the World-Class Universities (Disciplines), the Characteristic Development Guidance Funds for the Central Universities, the Natural Science Foundation of Shaanxi Province (Nos. 2018JM5026, and 2019TD-020), and the Opening Project of Key Laboratory of Shaanxi
References (82)
- et al.
Evaluation effects of chitosan for the extracellular matrix production by fibroblasts and the growth factors production by macrophages
Biomaterials
(2001) - et al.
In vitro characterization of chitosan–gelatin scaffolds for tissue engineering
Biomaterials
(2005) - et al.
Preparation and characterization of chitosan/gelatin/PVA hydrogel for wound dressings
Carbohyd. Polym.
(2016) - et al.
Surface functionalization of titanium implants with chitosan-catechol conjugate for suppression of ROS-induced cells damage and improvement of osteogenesis
Biomaterials
(2017) - et al.
Bio-inspired adhesive catechol-conjugated chitosan for biomedical applications: a mini review
Acta Biomater.
(2015) - et al.
Biodegradable and electrically conducting polymers for biomedical applications
Prog. Polym. Sci.
(2013) - et al.
Conducting Polymers for Tissue Engineering
Biomacromolecules
(2018) - et al.
Micropatterned, electroactive, and biodegradable poly(glycerol sebacate)-aniline trimer elastomer for cardiac tissue engineering
Chem. Eng. J.
(2019) - et al.
Electroactive biodegradable polyurethane significantly enhanced Schwann cells myelin gene expression and neurotrophin secretion for peripheral nerve tissue engineering
Biomaterials
(2016) - et al.
Fibrin-targeting peptide CREKA-conjugated multi-walled carbon nanotubes for self-amplified photothermal therapy of tumor
Biomaterials
(2016)
Mechanical properties of carbon nanotubes based polymer composites
Compos. Part B-Eng.
Tough and flexible CNT–polymeric hybrid scaffolds for engineering cardiac constructs
Biomaterials
Surface modification of carbon nanotubes by combination of mussel inspired chemistry and SET-LRP
Polym. Chem.
Mechanical properties and electrical conductivity of carbon-nanotube filled polyamide-6 and its blends with acrylonitrile/butadiene/styrene
Polymer
Antibacterial anti-oxidant electroactive injectable hydrogel as self-healing wound dressing with hemostasis and adhesiveness for cutaneous wound healing
Biomaterials
pH-responsive self-healing injectable hydrogel based on N-carboxyethyl chitosan for hepatocellular carcinoma therapy
Acta Biomater.
pH-responsive injectable hydrogels with mucosal adhesiveness based on chitosan-grafted-dihydrocaffeic acid and oxidized pullulan for localized drug delivery
J. Colloid Interf. sci.
Antibacterial adhesive injectable hydrogels with rapid self-healing, extensibility and compressibility as wound dressing for joints skin wound healing
Biomaterials
Injectable antibacterial conductive hydrogels with dual response to an electric field and pH for localized “smart” drug release
Acta Biomater.
Layered double hydroxide as novel antibacterial drug delivery system
J. Phys. Chem. Solids
Antibacterial and conductive injectable hydrogels based on quaternized chitosan-graft-polyaniline/oxidized dextran for tissue engineering
Acta Biomater.
Degradable conductive injectable hydrogels as novel antibacterial, anti-oxidant wound dressings for wound healing
Chem. Eng. J.
Degradable conductive self-healing hydrogels based on dextran-graft-tetraaniline and N-carboxyethyl chitosan as injectable carriers for myoblast cell therapy and muscle regeneration
Acta Biomater.
Electrospun conductive nanofibrous scaffolds for engineering cardiac tissue and 3D bioactuators
Acta Biomater.
Dermal wound healing processes with curcumin incorporated collagen films
Biomaterials
Electroactive anti-oxidant polyurethane elastomers with shape memory property as non-adherent wound dressing to enhance wound healing
Chem. Eng. J.
Anti-inflammatory and pro-inflammatory roles of TGF-β, IL-10, and IL-22 in immunity and autoimmunity
Curr. Opin. Pharmacol.
Dynamic covalent constructed self-healing hydrogel for sequential delivery of antibacterial agent and growth factor in wound healing
Chem. Eng. J.
Chitosan-doxycycline hydrogel: an MMP inhibitor/sclerosing embolizing agent as a new approach to endoleak prevention and treatment after endovascular aneurysm repair
Acta Biomater.
Bacteria-responsive intelligent wound dressing: simultaneous In situ detection and inhibition of bacterial infection for accelerated wound healing
Biomaterials
Cobalt-mediated multi-functional dressings promote bacteria-infected wound healing
Acta Biomater.
Chronic wound healing: a review of current management and treatments
Adv. Ther.
A functional chitosan-based hydrogel as a wound dressing and drug delivery system in the treatment of wound healing
RSC Adv.
Antimicrobial peptides and wound healing: biological and therapeutic considerations
Exp. Dermatol.
Wound dressings–a review
BioMedicine
Assembly of bifunctional aptamer-fibrinogen macromer for VEGF delivery and skin wound healing
Chem. Mater.
Injectable alginate microsphere/PLGA–PEG–PLGA composite hydrogels for sustained drug release
RSC Adv.
Extracellular matrix metabolites as potential biomarkers of disease activity in wound fluid: lessons learned from other inflammatory diseases?
Brit. J. Dermatol.
Reactive oxygen species (ROS) and wound healing: the functional role of ROS and emerging ROS-modulating technologies for augmentation of the healing process
Int. Wound J.
Nanostructured polymeric coatings based on chitosan and dopamine-modified hyaluronic acid for biomedical applications
Small
Hyaluronic acid catechol: a biopolymer exhibiting a pH-dependent adhesive or cohesive property for human neural stem cell engineering
Adv. Funct. Mater.
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