Advanced Hydrogels as Wound Dressings

Abstract

Skin is the largest organ of the human body, protecting it against the external environment. Despite high self-regeneration potential, severe skin defects will not heal spontaneously and need to be covered by skin substitutes. Tremendous progress has been made in the field of skin tissue engineering, in recent years, to develop new skin substitutes. Among them, hydrogels are one of the candidates with most potential to mimic the native skin microenvironment, due to their porous and hydrated molecular structure. They can be applied as a permanent or temporary dressing for different wounds to support the regeneration and healing of the injured epidermis, dermis, or both. Based on the material used for their fabrication, hydrogels can be subdivided into two main groups-natural and synthetic. Moreover, hydrogels can be reinforced by incorporating nanoparticles to obtain "in situ" hybrid hydrogels, showing superior properties and tailored functionality. In addition, different sensors can be embedded in hydrogel wound dressings to provide real-time information about the wound environment. This review focuses on the most recent developments in the field of hydrogel-based skin substitutes for skin replacement. In particular, we discuss the synthesis, fabrication, and biomedical application of novel "smart" hydrogels.

Keywords: regenerative medicine; skin substitutes; sprayable “smart” hydrogels; tissue engineering; wound dressings with integrated sensors; “in situ” forming hydrogels.

Figure 1

The structure of human skin consisting of three primary layers—the epidermis, the dermis, and the hypodermis. The two inserts (right site) show their detailed cellular structure at higher magnification. The epidermis consists mainly of keratinocytes, melanocytes, and Langerhans cells. The dermis contains fibroblasts, neutrophils, mast cells, and dermal dendritic cells embedded within the dermal matrix rich in collagen and elastin. Beneath the dermis lies the subcutaneous adipose tissue (hypodermis) containing mesenchymal stem cells.

Figure 2

A schematic depicting the process of wound healing, including four continuous phases—homeostasis, inflammation, proliferation, and remodeling. In these four overlapping stages. First, blood platelets are activated to form a blood clot and have also a role in leukocyte recruitment. Next, neutrophils and macrophages clean the wound site from dead cells, bacteria, and other pathogens or debris. Then, fibroblasts migrate, proliferate, and activate the angiogenesis process. Finally, granulation tissue is formed, the extracellular matrix proteins are deposited to reconstitute the dermal tissue, and the epidermis is regenerated. Eventually, many of the formed capillaries and fibroblasts disappear.

Figure 3

(a) Spraying of the MeTro/GelMA composite hydrogel on a porcine skin and the crosslinking process of the MeTro/GelMA under visible light exposure; (b) MeTro/GelMA monomers and their bonds under light exposure [65].

Figure 4

(a) Rheological evaluation of KaMA hydrogel with low and high MA degree; as shear rate increases, the viscosity drops; (b) spraying ability of the KaMA hydrogel with high MA [60].

Figure 5

(a) Comparison of blood clot formation time in vitro between the control surface (surface without hydrogel) and the treated surface, containing the nanocomposite hydrogel with ZnO/PD and L-glutamic acid; (b) differences in wound size between control (untreated) wounds and wounds covered with the nanocomposite hydrogel containing ZnO/PD and L-glutamic acid in vivo; (c) histological analyses comparing the appearance of control wounds versus wounds treated with the nanocomposite hydrogel with ZnO/PD and L-glutamic acid in vivo [52].

Figure 6

(a) Schematic illustrating the application of a pH sensor-based hydrogel containing pH-sensitive beads on skin and the color changes in basic and acidic environment; (b) macroscopic pictures of hydrogel fiber-based patches with pH-sensitive beads under acidic and basic conditions; (c) images representing color changes of pH-sensitive dressings placed on pig skin when sprayed with solutions of different pH values [115].

Figure 7

(a) Schematic of the interaction between modified chitosan hydrogel and an enzyme; (b) images of modified hydrogel before and after enzymatic degradation [118].

Figure 8

Schematic of a flexible “smart” wound dressing. The dressing is comprised of a pH sensor and a flexible heater to trigger thermo-responsive carriers containing drugs. Drug carriers are embedded in a sheet of alginate hydrogel, casted around the pH sensors and on the heater. Finally, the sensors and the heater are connected to an electronic module that is able to record the data from sensors and power the heater. The electronic module can also communicate with computers and smartphones wirelessly [120].