Status and Future Scope of Soft Nanoparticles-Based Hydrogel in Wound Healing

Abstract

Wounds are alterations in skin integrity resulting from any type of trauma. The healing process is complex, involving inflammation and reactive oxygen species formation. Therapeutic approaches for the wound healing process are diverse, associating dressings and topical pharmacological agents with antiseptics, anti-inflammatory, and antibacterial actions. Effective treatment must maintain occlusion and moisture in the wound site, suitable capacity for the absorption of exudates, gas exchange, and the release of bioactives, thus stimulating healing. However, conventional treatments have some limitations regarding the technological properties of formulations, such as sensory characteristics, ease of application, residence time, and low active penetration in the skin. Particularly, the available treatments may have low efficacy, unsatisfactory hemostatic performance, prolonged duration, and adverse effects. In this sense, there is significant growth in research focusing on improving the treatment of wounds. Thus, soft nanoparticles-based hydrogels emerge as promising alternatives to accelerate the healing process due to their improved rheological characteristics, increased occlusion and bioadhesiveness, greater skin permeation, controlled drug release, and a more pleasant sensory aspect in comparison to conventional forms. Soft nanoparticles are based on organic material from a natural or synthetic source and include liposomes, micelles, nanoemulsions, and polymeric nanoparticles. This scoping review describes and discusses the main advantages of soft nanoparticle-based hydrogels in the wound healing process. Herein, a state-of-the-art is presented by addressing general aspects of the healing process, current status and limitations of non-encapsulated drug-based hydrogels, and hydrogels formed by different polymers containing soft nanostructures for wound healing. Collectively, the presence of soft nanoparticles improved the performance of natural and synthetic bioactive compounds in hydrogels employed for wound healing, demonstrating the scientific advances obtained so far.

Keywords: cutaneous lesions; gel; nanostructures; natural products; polymers.

Figure 1

Flowchart of major wound healing outcomes. The wound healing process undergoes four stages: (A) Immediately after skin injury, the hemostasis initiates to stop bleeding; (B) Inflammation is mainly characterized by the presence of inflammatory cells in scar tissue and infection prevention; (C) The shift from the inflammatory phase to the proliferative phase occurs after fibroblasts’ migration to the wound, the accumulation of collagen and the formation of new endothelial structures inside the wound; (D) The last stage is the remodeling that consists of wound closure, organized collagen deposition, re-epithelialization, and scar tissue formation; (E) Acute injuries, such as surgical incisions, usually heal within days or weeks, and their extremities move closer together, thus decreasing the risk of infection; (F) Chronic wounds are defined as any interruption in the continuity of body tissue that hinders healing process and long-last permanence; (G,H) Infections can be hazardous to tissue, delaying the tissue restoration and increasing expenses, the duration of treatments, and the risk of complications. The healing process is influenced by various factors, including pressure, a dry environment, trauma, infection, and necrosis.

Figure 2

Nano-based hydrogels containing soft-particle-loaded active substances may improve the healing process. The major functions of wound dressings are to remove wound exudates, prevent the entry of harmful bacteria from the wound, and promote the establishment of the best milieu for natural healing. The association of nanocarriers can enhance the bioadhesiveness of the hydrogel and the permeation and penetration of actives at the wounded site, accelerating the healing process. The image was created using Mind the Graph platform (www.mindthegraph.com, accessed on 8 January 2022), Publicdomainvectors.org site (https://publicdomainvectors.org/, accessed on 8 January 2022), and Microsoft^® PowerPoint^® (Washington, DC, USA).

Figure 3

The healing effect was observed by % contraction of wound area over the treatments. (A) Representative images of wound healing in Wistar rats; (B) Percentage wound area contraction over the treatment. Groups identification: Group I received no treatment; Group II was treated with silver sulfadiazine semisolid formulation; Group III was treated with the hydrogel containing non-encapsulated curcumin (CUR-gel); Group IV was treated with a nano-based hydrogel of curcumin-loaded NE (CUR-NEG). Data are available at 10.3390/gels7040213 [85].

Figure 4

Effect of hydrogel containing Astragaloside IV-loaded SLN in wound healing and anti-scar potential after skin application. (A) Wound closure percentage (* p < 0.05, blank control; # p < 0.05, astragaloside IV solution; & p < 0.05, blank SLN-hydrogel). (B) Masson’s trichrome staining of normal skin. (C) Masson’s trichrome staining at 1-, 3-, and 7-weeks post-wounding: (I) blank control; (II) blank SLN-hydrogel; (III) astragaloside IV solution; and (IV) astragaloside IV SLN-hydrogel. (D) CD31 immunohistological staining at 3 weeks post-wounding: (I) blank control; (II) blank SLN-hydrogel; (III) astragaloside IV solution; (IV) astragaloside IV SLN-hydrogel; and (V) normal skin (red arrows indicate newly formed blood vessels). Figure reproduced with permission from Chen and co-workers [64].

Figure 5

Effect of the treatments in the wound healing process. (A) Representative images of the wound healing process taken on day 0, day 3, day 7, and day 11 over the treatment; (B) Comparison of the percent wound contraction over the treatment. Data are available at 10.3390/antiox10050725 [82].

Figure 6

Lumina images for mouse punch biopsy wounds inoculated with luminescent Staphylococcus aureus followed by treatment with different groups: blank co-gels: hydrogel without Vancomycin; Van-loaded co-gels: hydrogel with non-encapsulated Vancomycin; Van-Lipo loaded co-gels: hydrogel with Vancomycin-loaded liposomes; CMP-Van-Lipo: hydrogel of collagen mimetic peptide conjugated vancomycin-loaded liposomes. Figure reproduced with permission from Thapa and co-workers [78].

Figure 7

Mechanisms of controlled and sustained drug release from polymeric nanoparticles: (A) drug diffusion through the matrix, (B) polymer degradation, and (C) polymer swelling and erosion. The image was created using Mind the Graph platform (www.mindthegraph.com, accessed on 8 January 2022), Publicdomainvectors.org site (https://publicdomainvectors.org/, accessed on 8 January 2022), and Microsoft^® PowerPoint^® (USA).

Figure 8

Cells-scratch wound healing in vitro assay. (A) Effects of TP@H (Hydrogel containing green tea polyphenol non-encapsulated) and TPN@H (Hydrogel containing green tea polyphenol-loaded nanospheres) on the migration of fibroblasts HFF-1 cells - Scale bar: 500 μm. (B) Quantitative analysis of the migration rates in (A). The blue fluorescence showed the nucleus, stained with DAPI The asterisks denote statistic differences with p-value p < 0.01 (**) or p < 0.001 (***). Figure reproduced with permission from Chen and co-workers [79].