The skin is the body’s largest and most important organ. Subject to a number of injuries from scrapes and grazes to infections and ulcers, it makes sense that wound care is undoubtedly an important caveat of patient healthcare. This is even more important if you consider the skin’s ability to heal declines and becomes frailer as we age, and the increase in ageing population.
With a greater demand for wound care than ever, skin wounds require more effective wound products than the traditional treatment. Traditional wound healing – your typical gauzes and bandages – despite their ability to absorb exudate and protect the wound, aren’t always the best choice when the constant replacement to prevent maceration and adhesion to the wound can be painful for the patient. Modern wound dressings, however, are a bit more complicated in comparison, as they are designed around wound healing and changes that can happen in the healing process and selected for use based on a number of factors, such as size, volume of exudate and infection. Hydrogels are one such modern dressing material that is increasingly receiving attention for their high water content and biocompatibility, and subsequent wound-healing abilities.
Hydrogels offer a number of advantages for wound healing and are subject to much research and development. “When applied over a lesion, these special gels can promote healing by absorbing discharged fluids (exudate) and keeping the wound protected, well-hydrated, and oxygenated,” explains Ryota Teshima, Department of Chemistry, Graduate School of Science, Tokyo University of Science. Known as ‘moist wound healing’, he explains, hydrogels can either be natural or synthetic, whereas synthetic materials can offer highly modified physical attributes and adhesive characteristics where natural hydrogels exhibit enhanced biocompatibility and biodegradability in comparison.
“There’s some disadvantages with natural drug materials in that we don’t understand their chemistry and structure,” adds Kris Killian, associate professor, School of Materials Science & Engineering and School of Chemistry, University of New South Wales. “This makes it difficult to discern what’s going to happen when we use them, because they’re just too complex.” Killian points to its immunogenicity when derived from animals as an example, where they can elicit an unwanted immune response. Synthetic materials offer a number of advantages as you can control the chemistry and properties, so it’s easier to manufacture with a reduced negative response. “The negative is that we’re not as good as Mother Nature,” he admits “So most of the time when we make a synthetic material to mimic a natural material, it just doesn’t work as well.”
Faster and wider wound healing
This is something Killian’s lab has set out to solve: “Hydrogels are being used in bandages for wound healing and in clinical settings at the hospital,” he explains, “But it’s going to be a type that’s derived from a natural material that has all these negatives, or a synthetic one that doesn’t mimic biology.” His lab, therefore, has been searching for new materials that mimic biology, and thanks to his students they used computational tools to design something unique. The interesting thing about this model, Killian explains, is that it is made from natural materials, a short peptide made of 10 amino acids that looked to form a gel naturally that hadn’t previously been reported.
While they predicted the peptide would assemble into a gel in the computer model, what they hadn’t anticipated was its antimicrobial properties that could kill bacteria while supporting human cells. “Bacterial cells will die when they get into contact with it, but the cells in our skin, in our body, love this stuff. They recognise it as being related to a natural material,” says Killian. “Now we have something that we can make synthetically in the lab, which will make it much more useful for manufacturing and for application.” The hydrogel has some interesting attributes, he continues, that are better than nature. For instance, it is self-healing on a short timescale and becomes a liquid when applied to the site before forming a rigid gel to protect the wound.
While Killian’s hydrogel has yet to be fully tested, he’s hopeful for its potential applications in wound care. For instance, he points to recent animal testing as an example where other materials have helped form new tissue and help rebuild the wound. That is what he and his lab are hoping for, and with the hydrogel’s antimicrobial properties this could also help tackle the increase of antibiotic-resistant bacteria that is a huge problem in medical care at the moment. “The fact that it has these really interesting mechanical properties suggests that it could be used in innovative ways that currently aren’t possible,” he adds. “So, we’re really hopeful that it will allow wound healing to happen faster and over a larger volume.”
Teshima, on the other hand, lead author of ‘Low-adhesion and low-swelling hydrogel based on alginate and carbonated water to prevent temporary dilation of wound sites’ in the International Journal of Biological Macromolecules, has been developing his natural hydrogel since high school. Seeing its potential in wound healing, he followed this through to his research to form his hydrogel. “This hydrogel is composed of a network of biopolymers called alginates. Alginate is a natural polysaccharide polymer extracted from brown algae and is a sticky seaweed,” he explains. This polymer has an interesting reaction whereby the carboxy groups in the polymer react with calcium ions (Ca2+) to form a hydrogel. “This reaction is fascinating because a biopolymer with high biocompatibility can be easily made into a hydrogel with Ca2+, which is a familiar ion in our bodies.” Alginate also has the added bonus that it can be extracted from washed up seaweed and can contribute to the UN’s Sustainable Development Goals, he adds.
As Teshima continues, many developed hydrogels for wound care have adhesive properties to skin tissue so they follow its movement, stretch and can expand the wound once it swells up after absorbing exudates. “This not only could cause pain to the user but also may put them at higher risk of bacterial infection due to the wound area expansion,” he adds. It’s necessary then to experiment with hydrogels to effectively treat wounds without interfering with the wound healing process. Alginate is not adhesive to cells or skin, he stresses, so its application as a non-adhesive wound dressing just made sense. Conventional gelation methods used to prepare hydrogels usually include an acidic agent to induce a gelation reaction of alginate by generating Ca2+ from CaCO3. However, this risks acidification of the gel and damaging tissues and cells. So, Teshima developed a novel gelation method that uses carbonated water.
“By using carbonated water as a substitute for the conventional acidic agent, I have demonstrated that the acidic substance (such as carbon dioxide) in the hydrogel is released to the atmosphere after gelation, thereby preventing acidification of the gel,” he explains. This is the same as carbon dioxide released from Coca-Cola and soda. After evaluating the biocompatibility and cell adhesion of the prepared hydrogels on NHDF cells (human dermal fibroblasts), the viability of the NHDF cells co-cultured with hydrogels was almost 100% with indications of low cell adhesion on the prepared hydrogel surface. “These results demonstrate that the prepared alginate hydrogel has sufficiently high biocompatibility and low cell adhesion as a wound dressing material.”
When compared with a wound dressing in clinical use, VIEW GEL, Teshima’s hydrogel demonstrated lower adhesion and swelling, and in a study using mice the low adhesion and low swelling of his hydrogel compared with VIEW GEL were shown to inhibit wound site expansion due to the gel swelling, which is the opposite of conventional wound-healing gels. “The greatest benefit of this hydrogel is that it suppresses the wound expansion,” he explains. While the detrimental effects of this expansion have yet to be demonstrated, Teshima imagines it would be painful for the patient. “I believe that this hydrogel is an attractive hydrogel that can promote wound healing without unnecessary physical stress to the wound site.” The only drawback Teshima indicates in the development of his hydrogel is the cost, however, as it has yet to be produced at a lower cost compared to other clinical formulations.
Understanding what doctors want
Both Teshima and Killian are hopeful for the road ahead, but it is not without challenges. For Teshima, there is still more research to be done to anticipate whether the developed hydrogel can help skin tissue build up nicely. “In the published paper, we determined wound closure from visual and image-calculated areas,” he explained. “We intend to continue our research on how to quickly and cleanly heal wounds while suppressing unnecessary expansion of the wound site.”
For Killian, the hardest part is getting the format right and understanding what doctors need. While he may think it’s perfect, he explains, doctors are the ones who use it and may have different needs than anticipated. “I think a lot of challenges are just getting the composition right and formulation, and convincing doctors that it’s something they need.” Not to mention the added caveat of manufacturing and the right logistics. “I’m pretty confident,” he stresses, “but we have to do due diligence and this is what the animal trial will help us do.”
Hydrogels are clearly an excellent medical material for wound healing and Killian is confident that his hydrogel is one such material, with the potential for a range of procedures and even for patients to use at home as an antimicrobial cream. For Teshima’s hydrogel, already tested in clinical applications elsewhere, he is similarly confident that future medical professionals will use this gel to its full potential for tailor-made medical care. The possibilities of these two hydrogels in wound healing are clear, only time will tell if they reach their potential.
