Preparation of antibacterial hydrogel from poly(aspartic hydrazide) and quaternized N-[3-(dimethylamino) propyl] methylacrylamide copolymer with antioxidant and hemostatic effects for wound repairing

Skin tissue is the largest, most exposed and also most vulnerable tissue outside the human body [1], [2]. Once the damage occurs to the skin, the repairing process appears to be very complex, which includes four interactive and successive steps: hemostasis, inflammation, proliferation, and remodeling/maturation [3], [4], [5]. In many situations, different types of wound dressings including gauze, sponge, hydrogel are applied to promote the wound healing efficiency [6], [7], [8]. The ideal dressings with a combination of enhanced hemostatic activity and antimicrobial properties are highly desirable in clinic [9], [10]. Among which, the hydrogels had received great attention due to its good biocompatibility based on extracellular matrix (ECM) mimicking microporous structures [9], [11], [12], [13] and sustained drug release properties [14], [15]. Moreover, the injectable hydrogels can form in situ to fill the irregular wound cavity for hemostasis, integrate multiple functions such as anti-oxidation, enhance cell migration and proliferation to promote wound healing in multiple processes [16], [17], [18], [19].

When used as wound dressing, biodegradable hydrogels fabricated from polysaccharide [20], [21], [22], [23], protein are preferred along with other biocompatible polymers [24], [25], [26]. Furthermore, the hemostatic performance of the hydrogels can be further enhanced by loading hemostatic drugs like tranexamic acid (TXA) [27], [28], [29], [30]. At the same time, the bacteria infection during the wound repairing process can cause inflammatory response to slow down the angiogenesis and wound repairing process [31], [32]. Therefore, designing biocompatible hydrogel wound dressing with antibacterial activity should be a promising strategy for effective infection prevention to promote the wound repairing process [33]. Since conventional inorganic antibacterial components always exhibit dose-dependent cytotoxicity [34], [35], [36], the hydrogels with intrinsic antimicrobial activity like quaternary ammonium are increasingly desired [37], [38], [39], [40]. Based on above concept, cellulose [41] and chitosan based antibacterial hydrogels were fabricated [42] and showed expected antibacterial performance.

In this work, copolymer of diacetone acrylamide (DAA) and N-[3-(dimethylamino) propyl] methyl acrylamide (DMAPMA) with light emitting tetraphenylethylene (TPE) terminal group [TPE-P(DAA-co-DMAPMA)] (TPDD) was synthesized and reacted with bromohexane to synthesize quaternary ammonium bearing quaternized TPDD (QTPDD). At the same time, the poly(aspartic hydrazide) (PAH) as multihydrazide cross-linker was synthesized to fabricate quaternary ammonium bearing hydrogels through Schiff-base reaction [43], [44], [45]. The quaternary ammonium moiety endowed the hydrogel with excellent antibacterial performance to both E. coli and S. aureus [33]. At the same time, the protocatechualdehyde (PCA) was grafted to the hydrogel through dynamic acylhydrazone bond to endow the hydrogel with reactive oxygen species (ROS) scavenging property [46], [47], [48], [49], [50], [51]. Moreover, TXA as a hemostatic drug was loaded to enhance the hemostatic performance of the hydrogel [52]. The liver injury and tail amputation hemostasis models confirmed the strong hemostatic effect of TXA loaded hydrogels. Moreover, the hydrogel promoted wound repairing rate by preventing infection, reducing oxidative stress and supplying a mild bioenvironment. As a result, the antibacterial hydrogel with dynamic bond grafted catechol moiety could find application as a TXA loading platform for hemostasis and wound healing applications.

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