Elsevier

Acta Biomaterialia

Volume 103, February 2020, Pages 52-67
Acta Biomaterialia

Review article
Topical antimicrobial peptide formulations for wound healing: Current developments and future prospects

https://doi.org/10.1016/j.actbio.2019.12.025Get rights and content

Abstract

Antimicrobial peptides (AMPs) are the natural antibiotics recognized for their potent antibacterial and wound healing properties. Bare AMPs have limited activity following topical application attributable to their susceptibility to environment (hydrolysis, oxidation, photolysis), and wound (alkaline pH, proteolysis) related factors as well as minimal residence time. Therefore, the formulation of AMPs is essential to enhance stability, prolong delivery, and optimize effectiveness at the wound site. Different topical formulations of AMPs have been developed so far including nanoparticles, hydrogels, creams, ointments, and wafers to aid in controlling bacterial infection and enhance wound healing process in vivo. Herein, an overview is provided of the AMPs and current understanding of their formulations for topical wound healing applications along with suitable examples. Furthermore, future prospects for the development of effective combination AMP formulations are discussed.

Statement of Significance

Chronic wound infection and subsequent development of antibiotic resistance are serious clinical problems affecting millions of people worldwide. Antimicrobial peptides (AMPs) possess great potential in effectively killing the bacteria with minimal risk of resistance development. However, AMPs susceptibility to degradation following topical application limits their antimicrobial and wound healing effects. Therefore, development of an optimized topical formulation with high peptide stability and sustained AMP delivery is necessary to maximize the antimicrobial and wound healing effects. The present review provides an overview of the state-of-art in the field of topical AMP formulations for wound healing. Current developments in the field of topical AMP formulations are reviewed and future prospects for the development of effective combination AMP formulations are discussed.

Introduction

Skin is comprised of protective layers of cells (epidermis and dermis) and their secretions, required for establishing a semi-permeable environmental barrier that acts as a first line of defense against continuous assault by a diverse range of microbes [1]. Following surgery, burns, accidental injury, skin diseases, microbial infection or metabolic dysfunction; the barrier function is breached giving rise to the development of a wound [2]. Wound healing is a complex biological process essential for the repair and restoration of the tissue functions following injury [3].

Classically cutaneous wound healing involves the initial inflammation phase, followed by a period of tissue regeneration including epithelialization, angiogenesis, and collagen deposition and extracellular matrix remodeling [4,5]. Failure of the mechanisms underlying the recovery of damaged tissues results in the formation of chronic non-healing wounds [6,7]. The most common medical conditions aggravating the wound healing process to develop chronic wounds include diabetes, venous or arterial disease, and microbial infections [8]. Opportunistic pathogens, such as the gram-positive bacterium Staphylococcus aureus or the gram-negative bacterium Pseudomonas aeruginosa, have the ability to colonize the wound and form biofilms characterized as an aggregation of immobilized bacterial cells in an adhesive extracellular matrix [9,10]. Microbial biofilms are poorly penetrated by the antibiotics or host clearance mechanisms (e.g., antibodies and phagocytes) making it extremely difficult to eradicate the bacteria [11], [12], [13]. Additionally, toxins produced by bacteria contribute to immune cell recruitment leading to chronic inflammatory response [7,14]. Chronic wound infections are an alarming cause of death in severely ill hospitalized patients and pose a significant clinical and economic burden on the healthcare system [15].

Multicellular organisms have successfully developed an arsenal of host-defense molecules, including gene-encoded antimicrobial peptides (AMPs,) aimed at controlling microbial proliferation and signaling host cells to alter their behavior in response to injury [16,17]. In this review, we describe the AMPs and their role as antimicrobial and wound healing peptides, topical formulations of AMPs, and future prospects on the development of effective topical formulations.

Section snippets

Antimicrobial peptides (AMPs)

AMPs are produced by plants, animals, fungi, protozoa, and bacteria [18]. When humans are exposed to potentially harmful pathogens e.g., through contact, inhalation, and ingestion, we have different strategies to cope with these assaults, one of them being the production of AMPs [19], [20], [21]. Unlike innate mechanisms of immunity during pathogenic invasion followed by T and B cells activation against specific antigens [22,23]; the endogenous peptides (either expressed or induced) provide a

Factors to be considered for the development of topical AMP formulations

The previous sections have explained the potential of AMPs to elicit both antimicrobial and wound healing (granulation tissue formation, angiogenesis, re-epithelialization, and collagen synthesis) effects. However, the activity of an AMP is dependent on different factors including their size (number of amino acids), conformation (e.g. α-helix, β-sheet), net charge (usually AMPs are positively charged so that they can interact with negatively charged bacterial membrane), charge distribution

Formulations types for topical AMP applications

A careful consideration of different parameters affecting the AMP stability and potency needs to be considered during their formulation. In the past few decades, a plethora of studies have been performed to develop different AMP formulations which include but are not limited to nanoparticles, hydrogels, nanoparticles+hydrogels, creams, ointments, and wafers. Detailed information on these topical formulations used for wound healing are described below:

Conclusions and future prospects

Incorporation of AMPs into nanoparticles enhances the stability and overall activity of the peptides by protecting them against degradation and controlling their release for longer periods of time. In some instances, nanoparticles can even improve the peptide solubility and provide targeted delivery. However, the major concern with the nanoparticle formulations is their residence time at the site of application. The limited bioadhesivity and suspension form of the nanoparticles makes them

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

The study was supported by the program Bedre-Helse from the Research Council of Norway, project nr 273646.

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