Hydrogel Dressings Accelerating Diabetic Wound Healing
Compromised vessel networks and persistent inflammation in diabetic wounds prevent transport to and from wound sites, disrupting wound healing.
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The World Health Organization estimates that over 420 million people are living with diabetes worldwide. A common complication of diabetes is diabetic foot ulcer, and globally, there is a lower extremity amputation every 20 seconds.
The global diabetic foot ulcer treatment market was valued at USD 8.2 billion in 2022 and is expected to reach USD 14.4 billion by 2032. The majority of diabetic wound care products are passive dressings, which merely provide a protective barrier against the external environment and do not actively promote wound healing. Here, we will describe three recent hydrogel technologies with novel concepts to promote diabetic wound healing.
What is a hydrogel?
Hydrogels are three-dimensional networks of crosslinked polymers that can absorb a large amount of water and swell while maintaining their structure. Hydrogels have uses in a variety of biomedical applications thanks to their superabsorbancy, biodegradability, biocompatibility, hydrophilicity and viscoelasticity.
Hydrogel with antibiofilm and antioxidant properties
In a recent study, Pranantyo et al. described a synthetic hydrogel, named PPN, fabricated from crosslinked polyethylene glycol (PEG) hydrogel tethered with an antibacterial cationic polymer, polyimidazolium (PIM), and the antioxidant N-acetylcysteine (NAC).
The authors found that their hydrogels were able to swell up to 10 times their initial water volume, and the swollen form was stable and exhibited constant mass after incubation for seven days in bacterial extracts and infected wound fluids. This suggests that PPN can soak up wound exudates and resist degradation by infected wound fluids, enabling the hydrogel to be ultralow-leachable and leave minimal residue at wound sites after dressing removal. This is crucial to prevent material-related inflammation.
Using a 3D de-epidermised dermis human skin equivalent (DED-HSE) model, a living ex vivo tissue construct in which decellularized dermal scaffolds from human donors are repopulated with allogeneic donor keratinocytes, the authors showed that by day seven, their hydrogel was able to heal 40–50% of the initial wound size and promote proliferation of keratinocytes.
Next, using an infected diabetic mice model, the team found that wounds treated with their hydrogel had more than 99.9% reduction in the colonization of all bacterial strains, including methicillin-resistant Staphylococcus aureus (MRSA), surpassing commercial silver-based antimicrobial dressings. This advantage also allowed their hydrogel-treated wound to be resolved of inflammation as indicated by a lower number of inflammatory monocytes in the wound tissues.
Impressively, the antioxidants in the hydrogel also led to an increase in the concentrations of growth factors including vascular endothelial growth factors (VEGF) that promoted blood vessel formation and thicker granulation tissue associated with improved proliferation of fibroblasts and keratinocytes.
Hydrogel loaded with exosomes
Adipose-derived stem cell (ADSC)-derived exosomes are therapeutic agents in tissue regeneration as they contain bioactive proteins, nucleic acids and lipids. These molecules can contribute to wound healing by promoting anti-inflammation, inhibiting apoptosis and facilitating cell migration and proliferation.
In a study published in Nature Communications, Han and colleagues describe the development of a hydrogel loaded with ADSC-derived exosomes and bovine serum albumin (BSA)-based oxygen nanobubbles to form a multifunctional wound dressing to boost oxygen levels in wound tissues and promote tissue regeneration.
Using human dermal fibroblasts in vitro, the authors showed that the oxygen nanobubbles relieved cells of hypoxia. Previous studies have found that hypoxic conditions lead to lower exosome delivery efficiency.
Finally, using a rat model of full-thickness wounds, hydrogel-treated animals showed flatter wound surfaces with continuous epidermis, demonstrating minimal keloid formation and scarless wound healing. Furthermore, the treated animals had a higher density of newly formed blood vessels and less inflammation.
There were also lower numbers of pro-inflammatory M1-like macrophages and higher numbers of anti-inflammatory M2-like macrophages. While this hydrogel was not used in a diabetic wound setting in the paper, the authors concluded that the technology has the potential to be applied to diabetic wounds, particularly because of its oxygen-supplying advantage.
Mechanotherapy with hydrogel
One medical device that is used for diabetic wound treatment is topical negative-pressure wound treatment (NPWT), which provides mechanical suction to remove wound fluids and is correlated with improved wound closure.
The best effects were seen with three days of stimulation, an hour a day, while continual stimulation beyond day three led to a reduction in cell proliferation. Interestingly, the team found that fibroblasts were mechanically responsive while keratinocytes were not. Mechanical stimulation primarily activated fibroblasts to produce more extracellular matrix proteins and secretome, which activated keratinocytes, causing them to secrete more VEGF via the Ras/MEK/ERK pathway.
Wanting to maximize the therapeutic impact of mechanical stimulation, the team also analyzed public databases of single-cell RNA sequencing and identified an exceptionally mechano-sensitive subpopulation of fibroblasts. They further verified this by showing that this subtype of fibroblasts proliferated faster and produced more collagen under mechanical stimulation.
Using an in vivo diabetic mouse model, the team further showed that combining cell mechanotherapy led to a 200% faster wound healing rate with 200% better vascularization. As PEGDA is a non-biodegradable material and the hydrogel was applied to the wound surface rather than implanted, there was also no material-associated inflammation as assessed by counting the macrophage population and quantifying inflammation genes.
Wound dressings play an important role in wound management. Although most commercial products are merely serving as a protective barrier, hydrogel can be endowed with additional properties to make it antibacterial or bioactive, which can accelerate wound healing. The use of multifunctional hydrogels as active wound dressings can help speed up wound healing, thus reducing the overall time for patients to restore their lifestyles and decreasing overall healthcare costs.
