Hydrogel with built-in antibiofilm and antioxidative functions promotes faster healing of infected chronic wounds

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Diabetic wounds are often chronically infected and notoriously difficult to treat. Two primary reasons for this include bacterial biofilm formation and high levels of oxidative stress. A novel hydrogel dressing was recently developed to combat both of these undesirable properties and tested for its effect on diabetic-infected wound healing. published in the report Nature communication.

Study: Hydrogel dressings with intrinsic antibiofilm and antioxidant dual functionality accelerate healing of infected diabetic wounds.  Image credit: New Africa/Shutterstock.com
Study: Hydrogel dressings with intrinsic antibiofilm and antioxidant dual functionality accelerate healing of infected diabetic wounds.. Image credit: New Africa/Shutterstock.com

Background

Wound healing is recognized in four stages, namely, coagulation, inflammation, proliferation and maturation. When this does not happen, chronic scarring occurs. Most are caused by chronic inflammation triggered by competing pro- and anti-inflammatory signals leading to loss of redox homeostasis.

Chronic inflammation attracts leukocytes that release reactive oxygen species (ROS), a defense against microbial invasion. However, these ROS antagonize wound healing by damaging living tissues and cells at various levels and promoting breakdown and further inflammation.

In the worst case, excessively high ROS levels cause cells to die in and around the wound by apoptosis and other mechanisms of programmed cell death. Neighboring cells react to this and eventually die themselves, causing severe necrosis or tissue death, typical of such lesions. This means that tissue debridement or even counting, at times, becomes necessary to treat these lesions.

Biofilm formation by microbes is another complication leading to chronic wounds, which prevents topical antioxidants from acting on the wound surface. Biofilms consume nutrients from the wound bed and secrete extracellular polymeric substances (EPS) that form a protective barrier against immune cells, antibiotics, and other antimicrobials. Furthermore, they remain stable on the wound surface until clinically removed.

Biofilm microbes are, in fact, the primary species found in chronic wounds and in many cases are resistant to treatment. Generally, they are methicillin-resistant Staphylococcus aureus (MRSA) or carbapenem-resistant Pseudomonas aeruginosa (CRPA).

Chronic wounds cost the economy more than $50 billion in the United States alone, in just one year. And this is only expected to increase as the population around the world grows. Diabetic wounds are among the most common types of chronic wounds and, unfortunately, have about a 31% risk of death, like cancer.

Simple wound dressings are less effective in chronic wounds. Dressings designed for chronic wounds have not yet been developed as stand-alone treatments. Currently, specialized chronic wound dressings require additional use of photothermal radiation or release and leave significant amounts of antibiotics or metal ions in the wound.

The present study was motivated by the need for improved chronic wound dressings that would be self-sufficient, would not contaminate the wound, and would not produce unwanted discharge and moist wound material.

The researchers used a hydrogel, PPN, composed of crosslinked polyethylene glycol (pEG) hydrogels are highly potent antibacterial cationic polymers, polyimidazolium (pIM), and antioxidants N-acetylcysteine ​​(NAC). Cationic hydrogels kill bacteria by absorbing them into their pore spaces and then contacting the pore walls.

PPN was designed to have dual functionality, antagonizing both biofilm formation and oxidative stress in the wound bed. Both properties will work together to promote healing of infected diabetic wounds.

Very little of this hydrogel penetrates the wound, and it does not contain antibiotics or metal compounds, ensuring that the wound is not contaminated by any of these after the dressing is removed.

What does the study show?

PPN showed high antibacterial activity in vitro. Hydrogel formulations swell, absorbing 10-12 times their original weight of water within an hour. Within two days, when tested on infected wounds in a murine model, the hydrogels turned dirty yellow, likely due to absorption of fluid and dead bacteria into the wound. They were structurally stable, however, indicating that they did not break in the presence of infected wounds.

The researchers tested these hydrogels on a human skin model that was grown into a 3D structure. It demonstrated enhanced keratinocyte differentiation in the presence of NAC. In addition, it accelerates re-epithelialization and, thus, wound closure. Notably, silver dressings have been shown to inhibit keratinocyte proliferation in chronic wounds.

Next, they applied the dual-functionality hydrogel to infected wounds in diabetic mice, which closely resembled human diabetic wounds. Wounds were coated with a biofilm containing either MRSA or CRPA.

Hydrogels have shown excellent biocompatibility compared to currently used silver dressings. Infected wounds treated with hydrogel showed faster healing than control animals. Bacterial counts drop rapidly and steeply in the first three days and remain low for the next two weeks.

In contrast, bacterial reduction was lower for both silver dressings and control dressings. Lesions were smaller and minimal in PPN-treated wounds compared with silver or control dressings or no treatment. Indeed, untreated wounds show biofilm formation and pus discharge with sloughing wounds with evidence of reinfection.

Wound healing factors were found at higher levels in PPN-treated wounds than in untreated or control-treated wounds. More mature collagen was found in the PPN-treated wound, indicating better regeneration of skin structure. Both components of PPN have been found to contribute to improved outcomes compared to either alone.

Hydrogels can be formulated in a variety of ways for application in superficial or deep wound healing. Its advantages include the absence of wound contamination and it does not require photothermal irradiation or other healing methods.

What are the effects?

PPN first removes bacteria from the wound site, allowing the number of inflammatory cells to decrease. ROS levels are reduced by the NAC component, which allows them to diffuse into the hydrogel, enhancing immunity while alleviating oxidative stress. Also, it stimulates the release of wound-healing factors.

Finally, NAC stimulates keratinocyte differentiation and restoration of a normal epithelial covering over the wound. All of these promote wound healing.

This PPN dressing is more potent antibacterial than silver dressing with activity against MRSA and CRPA. It does not cause further inflammation and accelerates wound healing. The potential of multiple formats to meet different needs and its possible extension to other biomedical needs make this hydrogel a promising option for the treatment of chronic infected diabetic wounds.



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