Atopic dermatitis (AD) is a complex, chronic, and recurrent inflammatory itchy skin disorder. It usually begins in early childhood and can last throughout adulthood in the majority of cases. Over the previous decade, the prevalence of AD has climbed by more than 20% in some countries and this continues to rise, affecting not only developed but also developing low-income countries, particularly among infants and children [1, 2]. Infancy or childhood account for about 80% of disease cases, with the remaining 20% appearing in adulthood. The point prevalence for adults ranges from 2.1 to 4.9%, while that for children varies from 2.7 to 20.1% among nations [3]. An international, cross-sectional, web-based survey of children and adolescent (6–18 years old) was conducted and the study reported that the overall paediatric prevalence of diagnosed AD was 9.8 and 15.1% in the United States (US) and Canada, respectively. In Europe, Germany had the lowest prevalence (8.4%), and the Southern European countries of Spain and Italy had the highest prevalence, 18.6% and 17.6%, respectively. However, the prevalence in the United Kingdom (UK) was also only marginally lower at 15.3%. Interestingly, the rates in east asia were similar in Japan (10.7%) and Taiwan (11.3%) [2]. According to the International Study of Asthma and Allergies in Childhood (ISAAC), the 12-month prevalence of AD among Malaysian children has increased from 9.5% in ISAAC-1 (1994–1995) to 12.6% in ISAAC-3v (2002–2003), with an average increase of 0.49% annually [4]. In developing nations (Malaysia, Indonesia, and the Philippines), the direct medical expenses for a child with AD have been estimated to cost between USD199 to 743 per child [5]. It was found that families for children with a high severity of AD were over six times more likely to have a low quality of life and parents of children with AD are known to be associated with depression and stress [6]. Therefore, having an effective and safe therapy for long haul AD is crucial.
Atopic dermatitis is characterized by sensitive and dry skin with- localized or disseminated eczematous lesions usually accompanied by a severe itching sensation. The heterogeneous clinical phenotype varies by age, severity and ethnic background [7]. During the development of AD, the water permeability of the skin is enhanced owing to the impairment of the skin function and resulted in an increased transepidermal water loss (TEWL); thus, the skin becomes extremely dry. When the skin is dry, the protective barrier function of the cutaneous horny layer is compromised, and the skin readily develops dermatitis in response to various external stimuli, such as dry air, sweat and skin microorganisms. This phenomenon results in various skin lesions such as pruritic, erythema, edema, excoriation, and thickening of the skin, and in severe cases, it leads to a significant impairment in the patient’s life [1, 8].
The AD is caused by complex interactions of genetic predispositions, environmental triggers and immune dysregulation leading to the epidermal barrier defect [9–12]. Genetics play a significant role in the proper functioning of the skin barrier. Filaggrin is a major epidermal protein and its mutation has been shown to be a key player in the pathogenesis of AD. Filaggrin is a large (37-kD), histidine-rich protein named after its ability to aggregate keratin intermediate filaments (filament aggregating protein) in the skin [13, 14]. Filaggrin is specifically deaminated by peptidyl deiminase, then broken down into smaller peptides and free amino acids, creating natural moisturizing factors (NMF) such as carboxylic acid or urocanic acid. NMF helps to avoid gaps between corneocytes thus improving the integrity of the stratum corneum (SC) [2]. Structural proteins such as filaggrin are needed for the proper functioning skin. It was shown that AD patients with filaggrin mutations are more frequently affected by reduced health-related quality of life when compared with AD patients with wild-type filaggrin [14, 15].
Besides genetic determination, the epidermal barrier function also depends on the immune dysregulation. Type 2 immune cytokines, e.g., IL-4 and IL-13, have demonstrated to play important roles in the chemokine production, skin barrier dysfunction, suppression of antimicrobial peptides (AMP), and allergic inflammation [16]. Disrupted epidermal barrier and environmental triggers also stimulate keratinocytes to release IL-1β, IL-25, IL-33 and macrophage-derived chemokines, which activate dendritic cells and Langerhans cells. Activated dendritic cells stimulate Th2 cells to produce IL-4, IL-5, IL-13, IL-31, and IL-33, which leads to barrier dysfunction, decreased AMP production, impaired keratinocyte differentiation, and itchy symptoms. IL-4, IL-13, IL-3 and IL-33 downregulate the production of epidermal barrier proteins, including filaggrin, keratins, loricrin, involucrin, and cell adhesion molecules [17–20]. Furthermore, a damaged epidermal barrier not only leads to the development of AD, but also raises sensitization to allergens, thereby increasing the likelihood of developing food allergy and respiratory airway hyperreactivity.
It was shown that AD frequently leads to skin colonization with Staphylococcus aureus, which is able to produce virulence factors that perpetuate inflammation, even in normal-appearing skin [21]. Normally, the weakly acidic condition of healthy skin prevents colonization by S. aureus. However, the skin pH among the patients with AD shifts toward neutrality, allowing S. aureus to grow and exacerbate the AD symptoms [22]. However, it is important to note that in regard to the skin immunity, the characteristics of AD-derived S. aureus strains differ from those of the standard S. aureus strains. A comparison of laboratory strains of S. aureus (standard strain) and clinical isolates from AD skin (AD strain) revealed that the AD strain alters the T cell responses via Langerhans cells, resulting in Th2-shifted immune responses. This in turn upregulates proinflammatory cytokines, such as TSLP, IL-4, IL-12, and IL-22; and stimulates mast cell degranulation, which results in skin inflammation [23, 24]. The impact of antimicrobial treatment on S. aureus colonisation and the intensity of AD inflammation has been studied, with varying degrees of success. Topical and systemic antimicrobials were able to lower the colonisation density and resulted in a partial improvement of skin lesions in various open or double-blind placebo-controlled trials [25, 26]. Therefore, the inclusion of substances imparting antimicrobial activity, in textiles or in emollients that are in direct contact with the skin surface can be extremely helpful to these patients.
Skin hydration and controlling the inflammation remain the mainstay for the management of skin dermatitis. In mild AD, unmedicated moisturisers or emollients have been shown to improve the epidermal barrier function and dryness leading to reduction in itchiness. In the case of moderate and severe AD, pharmacological interventions are warranted, including topical corticosteroid and calcineurin inhibitors. The treatment choice in AD depends on the age of the patient, the site of skin lesions, chronicity of skin lesions, severity of skin inflammation. However, these drugs tend to give rise to adverse reactions of itching, burning or stinging sensation when used for more than 3–4 weeks. Therefore, many formulation strategies, including the use of micro- and nanoparticulate systems, biopolymer composites, textile fabrication are being extensively researched with an aim to produce a safe and effective delivery system for the topical delivery of the drug compounds with minimal side effects.
Biopolymers are receiving increasing attention as alternatives to synthetic polymers in several technological processes ranging from environmental to food and health applications. Among them, chitosan is one of the most promising biopolymers, being produced usually from heterogeneous alkaline de-N-acetylation of chitin. Several beneficial therapeutic properties of chitosan,have been ascribed to namely hemostatic, coagulant, immunostimulant and antimicrobial properties [27]. Over the decades, chitosan has become the focus of lead biomaterials in bioactive delivery systems design. The amazing features of chitosan allow the use of chitosan as carriers of drugs, small RNAs and biologics to treat various inflammatory diseases, especially brain diseases, tumors as well as skin diseases such as AD[28–31]. This review outlines the recent development of various forms of chitosan-based drug delivery systems for the treatment of AD from research articles published from years 2012 to 2022. These delivery systems include hydrogels, films, micro- and nanoparticulate systems as well as chitosan textile. The patent trends and future perspective on chitosan based formulations for the atopic dermatitis are also discussed.