Therapy of infected wounds: overcoming clinical challenges by advanced drug delivery systems

Abstract

In recent years, the incidence of infected wounds is steadily increasing, and so is the clinical as well as economic interest in effective therapies. These combine reduction of pathogen load in the wound with general wound management to facilitate the healing process. The success of current therapies is challenged by harsh conditions in the wound microenvironment, chronicity, and biofilm formation, thus impeding adequate concentrations of active antimicrobials at the site of infection. Inadequate dosing accuracy of systemically and topically applied antibiotics is prone to promote development of antibiotic resistance, while in the case of antiseptics, cytotoxicity is a major problem. Advanced drug delivery systems have the potential to enable the tailor-made application of antimicrobials to the side of action, resulting in an effective treatment with negligible side effects. This review provides a comprehensive overview of the current state of treatment options for the therapy of infected wounds. In this context, a special focus is set on delivery systems for antimicrobials ranging from semi-solid and liquid formulations over wound dressings to more advanced carriers such as nano-sized particulate systems, vesicular systems, electrospun fibers, and microneedles, which are discussed regarding their potential for effective therapy of wound infections. Further, established and novel models and analytical techniques for preclinical testing are introduced and a future perspective is provided.

Keywords: Antimicrobial resistance; Bacterial biofilm; Drug delivery systems; In vitro wound models; Wound dressings; Wound infection.

Fig. 1

a Schematic illustration of the wound infection continuum consisting of 5 stages, from the stage of local infection bacteria organize themselves in biofilms. b Biofilms show a prevalence of 75% in chronic wounds. c Risk factors promoting wound infection

Fig. 2

Drug incorporation strategies for particulate and vesicular carriers. a Particulate carriers consisting of different materials such as metals or polymers can be modified and loaded with drugs in different ways. b Liposomes can incorporate drugs either in the lipophilic membrane or the hydrophilic core

Fig. 3

Drug incorporation strategies into fibers. a Blend electrospinning, a mixture of drugs, polymers and solvents is directly spun. b Co-axial electrospinning, where two solutions are separately spun through a nozzle with two concentric openings. c Emulsion electrospinning, where drug solutions are emulsified. d Attachment of drugs to the surface by physical or chemical immobilization post-electrospinning. e SEM image of electrospun fibers

Fig. 4

Drug incorporation strategies into microneedles. a Coated microneedles. b Hydrogel-forming microneedles, the drug diffuses from the patch through the microneedles. c Dissolving microneedles, in which the drug is encapsulated. d LM image of dye-loaded microneedles

Fig. 5

Schematic overview of models of infected human skin wounds: planktonic bacteria can be used to either infect in vivo, in vitro, or ex vivo wound models directly or to develop in vitro static or dynamic biofilm models; precultured bacterial biofilms can also infect wound models

Fig. 6

Noninvasive measurement of a wound model, resulting in a three-dimensional visualization of the wound with optical topography and different Raman spectra for the epidermis and dermis, as well as a false-color Raman image of a virtual section of the wound