A new bioinspired adhesive made from a temperature-responsive hydrogel appears to speed up wound healing and so could find use in a wide range of application areas, including regenerative medicine and soft robotics. The material, which works like embryonic skin in that it draws wound edges together by contracting, has already been tested on the skin of mice with promising results.
Most treatments for skin wounds – be they cuts, blisters or burns – involve placing a barrier (such as cotton wool or gauze) over them to retain moisture and reduce exposure to infection by delivering, in some cases, antimicrobial agents.
Although researchers have developed more advanced dressings in recent years, containing, for example biologically active agents such as growth factors, these can be difficult to fabricate and are expensive. Growth factors can also have unwanted side effects.
Mimicking embryonic skin
A team led by David Mooney of the Wyss Institute for Biologically Inspired Engineering at Harvard University has now developed an active adhesive dressing (AAD) inspired by developing embryos, whose skin heals completely without producing scar tissue. It does this by producing cables made of the protein actin. These cables form at the edge of skin cells surrounding a wound and then contract, creating a mechanical force that draws the wound edges together like a purse string.
To mimic this mechanism, Mooney and colleagues have invented new wound dressings using a thermo-responsive hydrophobic polymer PNIPAm alginate hydrogel. Similar hydrogels developed recently are tough and have high adhesive energies of up to 1000 J/m2 on various tissues, including skin.
The hybrid hydrogel begins to contract at temperatures greater than 32°C. When placed on skin (which is between 35°C and 37°C), it transmits the force of contraction to the underlying tissue. The researchers also made it antimicrobial by adding silver nanoparticles (AgNPs) to it. AgNPs are already widely employed in wound care products, including commercially available alginate hydrogels and antimicrobial gauzes.
To test the antimicrobial function of their new alginate hydrogel, they analysed bacterial growth on agar plates in the presence of the material with and without AgNPs. They found that hydrogels containing AgNPs effectively inhibited bacterial growth. No AgNPs leaked from the hydrogel either, which proves that its antimicrobial function comes from the release of silver ions, not nanoparticles, from the gels.
Forming strong covalent bonds with skin
To form strong covalent bonds between skin tissue and the functional groups in the hydrogel matrix, the researchers primed the hydrogel surface with chitosan and carbodiimide coupling agents. The chitosan penetrates the skin and the hydrogel, while EDC [1-ethyl-3-(3- dimethylaminopropyl)carbodiimide] and NHS (N-hydroxysuccinimide) facilitate the formation of amide bonds between tissue proteins, chitosan, and alginate within the matrix, explains study co-first author Jianyu Li, who is currently assistant professor at McGill University in Canada.
They tested their AAD on pig skin and found that it bonded 10 times more strongly than Band-Aid©. On patches of mouse skin, it closed wounds and reduced the size of the wound area by as much as 45% (compared to an untreated sample).
The gel also closed wounds faster than other types of hydrogels as measured by the wound half-life – that is time required to reduce the wound area by half after application. The researchers found that the rate of wound closure with AAD compared well with that of photo-cross-linked chitosan hydrogels and microporous gel scaffolds. What is more, they say that the AAD appears to be safe for biological tissue since it does not cause inflammation or allergic reactions.
Finally, to simulate how the AAD mechanically interacts with wounded skin and to help optimize the closure process, the team also developed finite element models using the commercial software ABAQUS. “We are continuing this research with studies to learn more about how AAD performs across a range of different temperatures, as body temperature can vary at different locations,” explains team member Benjamin Freedman.
Chronic wounds could benefit
As well as skin wounds, the AAD could also be employed on chronic wounds, such as diabetic ulcers and pressure sores, and wounds in other epithelial tissues such as the intestine, lung and liver, adds Mooney. It may even be used in drug delivery and as a component of soft robotics-based therapies.
This work opens new avenues for developing wound dressings based on adhesive and stimuli-responsive hydrogels, he says. Unlike many other such materials, the AAD requires no additional reagents or sophisticated apparatus (such as UV light, for example) to work since it takes advantage of the natural temperature change when the dressing is placed on the body.
Reporting their work in Science Advances, the researchers told Physics World that they are now moving from the product development and preliminary in vivo study stages to preclinical animal trials.
Future experiments will also look at how the expression of genes known to be important in wound healing and collagen organization impact skin tissue healing over time. “It will be important to find out how the mechanical cues exerted by AAD affect the biological process of wound healing – and in particular how they affect the phenotype, migration, and activity of relevant cells such as fibroblasts,” they say.