A physically crosslinked polydopamine/nanocellulose hydrogel as potential versatile vehicles for drug delivery and wound healing
Graphical abstract
Introduction
A wound could be identified as a defect or a break in the skin, mainly resulting from thermal or physical injuries. The wound healing process includes five stages, i.e. haemostasis, inflammation, migration, proliferation and maturation (Boateng, Matthews, Stevens, & Eccleston, 2008). Traditional wound dressing mainly contained natural or synthetic bandages, gauzes, and cotton wool. The main functions of these dressings were to keep the wound dry. However, a warm moist wound environment was beneficial for wound healing (Korting, Schöllmann, & White, 2011). Hydrogel dressings are superior to other dressing materials with the merits of the ability of providing the moist environment and absorbing wound exudates, and they can avoid the secondary damage when dressing changed (Chang & Zhang, 2011; Deligkaris, Tadele, Olthuis, & Berg, 2010).
Most recently, use of hydrogels loaded with antibiotic drugs for treatment of infection after tissue damages (such as surgery, burn, or ulcers) has attracted considerable attentions (Venugopal, Low, Choon, & Ramakrishna, 2008). Tetracycline hydrochloride (TH) is a well-known broad-spectrum antibiotic with low toxicity and it has an ability to promote attachment of fibroblasts. Controlled release of TH was performed with various drug release delivery such as supramolecular hydrogels based on amphiphilic 3,4,5-trihydroxybenzoic derivatives (Chen et al., 2009), semi-IPN hydrogels based on polyvinyl alcohol and poly (acrylamide-co-styrene) (Bajpai, Bajpai, & Shukla, 2003), sodium acrylate/acrylamide modified hydrogels (Bardajee, Pourjavadi, & Soleyman, 2011), and polyacrylamide-based hydrogels (Singh, Chauhan, Sharma, & Chauhan, 2007). However, most of them were prepared by chemical approaches (Konieczynska, & Grinstaff, 2017). In contrast, physically crosslinked hydrogels are formed by molecular entanglements and molecular self-assembly through ionic or hydrogen bonds. These hydrogels have many advantages such as nonuse of toxic crosslinking agents and easy degradation (Peppas, Bures, Leobandung, & Ichikawa, 2000).
Recently, cellulose nanofibrils (CNFs) based hydrogels fabricated by physical approach were investigated in the applications for wound healing. CNFs can be easier to form hydrogels with higher porosity and higher water capacity, particularly for the CNFs with special functional groups (e.g. carboxyl, amino groups). Basu et al. confirmed that the TOCNFs (prepared by 2, 2, 6, 6-tetramethylpiperidine-1-oxyl (TEMPO)-mediated oxidation) hydrogels could be used as the potential materials for wound healing (Basu, Lindh, Alander, Strømme, & Ferraz, 2017), but they did not investigate the drug release properties of the TOCNFs hydrogels.
Also, stimuli-responsive hydrogels can give a timely response to external stimuli depending on the environment changes, including temperature, pH, light, and magnetic or electrical field (Prabaharan & Mano, 2006). Among these stimuli-responsive hydrogels, near-infrared responsive (NIR) hydrogels have been reported to be suitable for biological applications (Prabaharan & Mano, 2006). It was reported that polydopamine (PDA) has potential to be used as a photothermal agent with biocompatibility and biodegradability compared with other photo-absorbing agents, such as carbon nanotubes, graphene oxide nanosheets, and gold nanoparticles (Liu et al., 2014). In addition, PDA possesses many function groups, like amine, imine and catechol groups. These function groups could serve as the anchors for the loading of drugs as well as the bonding with TOCNFs though hydrogen bonding, π-π stacking, or van der Waals interactions. Hence, PDA is expected to be a suitable component to make a new composite hydrogel with TOCNFs. Also, the strength of the composite hydrogel is expected to be improved and the composite hydrogel could have multi-responses (like NIR and pH responses) with increased drug loading and controlled drug release.
Therefore, the objectives of this study include: (1) prepare a novel physically crosslinked composite TOCNFs hydrogels enhanced by PDA; (2) characterize the microstructure, mechanical property, NIR responsiveness, drug release and antibacterial abilities of the resulting composite hydrogel, and (3) investigate the performance of the in vivo wound healing of prepared PDA/TOCNFs composite hydrogel. We believe that this is the first study to fabricate the PDA/TOCNFs composite hydrogels via physical crosslinking method for the applications in drug release and wound healing. The results obtained will be of great importance for the potential application of the composite hydrogel based on TOCNFs and PDA in drug delivery system and wound healing.
Section snippets
Materials
Dopamine hydrochloride (98%) and tetracycline hydrochloride (TH, 98%) were obtained from Macklin Reagents (Shanghai). Ethanol (AR, >99.7%), ammonia (28–30%), pentobarbital (98%) and sodium bromide (99%) were received from Sinopharm Chemicals Reagents Co., Ltd. (China). Sodium hypochlorite (active chlorine 14%) and 2, 2, 6, 6-tetramethylpiperidine-1-oxyl (TEMPO, 98%) were purchased from Aladdin Reagents (Shanghai, China). The bleached softwood kraft pulp (BSKP) was obtained from Mudanjiang
Characterization of the PDA/TOCNFs hydrogel
The PDA/TOCNFs hydrogels were prepared by simply mixing PDA and TOCNFs together in the calcium chloride solution. The carboxylate groups formed in TOCNFs are demonstrated by FTIR spectra and the peak at 1612 cm−1 is the characteristic absorption of sodium carboxylate groups (−COONa) in TOCNFs (Fig. 1). The weak shoulder peak at 1725 cm−1 was mainly assigned to the free carboxyl groups (-COOH) (Cheng et al., 2017). The carboxylate content of TOCNFs was 1.2 mmoL/g, which was apparently higher
Conclusion
A novel multi-responsive composite hydrogel with drug release and wound healing ability was prepared using physical Ca2+ cross-linking of PDA and TOCNFs. The PDA acted as highly effective photothermal and reinforcing agents as well as drug carriers, while TOCNFs provided a 3D framework structure. Results showed that, the PDA/TOCNFs hydrogels had excellent pH/NIR responsive ability and could control the drug delivery in an on-demand manner under lower pH value or NIR irradiation. The drug was
Disclosures
The authors declare no competing financial interest.
Author contributions
The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.
Ethical approval
The animal experiments were proceeded in accordance with the protocols adopted by the local ethical committee (Ethical Committee of Qingdao University) and laboratory animal administrations rules of China.
Acknowledgements
The financial support of this research was from the National Natural Science Foundation of China (Nos. 31470609, 31700509, and 21476091), the National Key Research and Development Program of China (No. 2017YFB0307900), as well as the Primary Research and Development Plan of Shandong Province (No. 2016CYJS07A02).
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