A biocompatible and easy-to-make polyelectrolyte dressing with tunable drug delivery properties for wound care

Abstract

Chitosan (CS) is a biodegradable and biocompatible polysaccharide which displays immune-stimulatory effects and anti-bacterial properties to facilitate wound closure. Over the years, different CS-based dressings have been developed; however, most of them are not fully biodegradable due to the involvement of synthetic polymers during dressing fabrication. In addition, preparation of many of these dressings is laborious, and may impose damaging effects on fragile therapeutic molecules. The objective of this study is to address these problems by developing a tunable, biocompatible, and biodegradable CS-based dressing for wound treatment. The dressing is fabricated via electrostatic interactions between CS and carmellose (CM). Its swelling properties, erosion behavior, loading efficiency and drug release sustainability can be tuned by simply changing the CS/CM mass-to-mass ratio. Upon loaded with minocycline hydrochloride, the dressing effectively protects the wound in mice from infection and enhances wound closure. Regarding its high tunability and promising in vivo performance, our dressing warrants further development as a user-friendly dressing for use in wound care.

Introduction

Chitosan (CS) displays good biocompatibility and immune-stimulatory effects (De Souza et al., 2009). It also facilitates tissue repair and wound closure (Jayakumar et al., 2011), and shows anti-microbial activity against diverse pathogens (including bacteria (Escarcega-Galaz et al., 2018), filamentous fungi (Roller & Covill, 1999), and yeasts (Pena et al., 2013)). In particular, CS effectively acts against gram-positive and gram-negative bacteria (Perinelli et al., 2018), with low toxicity shown in mammalian cells. These properties render CS favorable to be exploited as a dressing for offering a moist environment for wound healing while protecting the wound from bacterial infection. Over the years, different CS-based dressings have been developed (Augustine et al., 2019, Hashemi Doulabi et al., 2018, Li et al., 2018, Tamer et al., 2018). For instance, a hydrogel fabricated from CS and poly(vinyl alcohol) (PVA) has previously been adopted to generate a minocycline-loaded dressing. The dressing has been found to suppress bacterial proliferation, to maintain a moist environment over the wound bed, and to enhance collagen proliferation in the wound area (Zhang et al., 2015). More recently, temperature-responsive polyelectrolyte complexes have been generated from poly(N-isopropyl acrylamide) and thiolated CS for sustained release of ciprofloxacin. These complexes have been found to suppress bacterial proliferation (Mishra et al., 2017). All these have corroborated the practical potential of CS-based dressings in wound management.

Many of the reported CS-based dressings in the literature, however, involve the use of synthetic polymers (e.g., PVA and poly(N-isopropyl acrylamide)), which are poorly biodegradable, during dressing fabrication. In addition, generation of most of those dressings relies on crosslinking induced by chemical triggering, radiation grafting, or freeze–thaw processing. Many of these processes are not only laborious and time-consuming, but may also damage fragile therapeutic molecules if drug loading is performed at the time of dressing fabrication. All these have complicated the preparation and use of these dressings in the clinical context. Development of an easy-to-make, fully biocompatible polyelectrolyte dressing, which on one hand can retain the bioactivity of the loaded drug and on the other hand can sustain drug release, is in dire need. The objective of this study is to meet this need by reporting a tunable CS/carmellose (CM) polyelectrolyte dressing as a sustained drug delivery system for wound healing applications (Fig. 1). CM is selected to complex with CS because it is widely used as a food additive. Along with the track record of biomedical use of CM in the literature (Ogushi et al., 2007, Pal et al., 2006, Spera et al., 2017, Vinklarkova et al., 2017, Wang et al., 2019), the biocompatibility and safety of CM are guaranteed. Compared with solutions of other anionic polysaccharides such as xanthan gum and alginate, the CM solution has been reported to be more effective in preventing the sedimentation of mixed agents (Molla et al., 2007). This enables the formation of a more homogenous dressing in which drug molecules are distributed more evenly. In this study, formation of the dressing is mediated simply by electrostatic interactions between amine groups of CS and carboxyl groups of CM. This allows the dressing to be made merely by having the two polymer solutions to be mixed right before application. Fabrication of the dressing, therefore, is simple and convenient. Finally, the swelling properties and erosion behavior, and hence the drug release sustainability, of the dressing can be easily tuned by moderating the CS/CM mass-to-mass ratio. This allows the drug release profile given by the dressing to be tailored to meet the needs of different situations.