Researchers at the Wyss Institute for Biologically Inspired Engineering at Harvard University, Harvard’s John A. Paulson School for Engineering and Applied Sciences (SEAS), and McGill University  developed Active Adhesive Dressings (AADs), which accelerates wound healing through multiple mechanisms including contracting in response to exposure to the skin temperature.  This new, scalable approach to speeding up wound healing based on these body heat-responsive hydrogels proved to provide these characteristics;

• Mechanically dynamic
• Tough and stretchy
• Highly bonding adhesive
• Antimicrobial without the need for any additional apparatus or stimuli.

Whereas, conventional dressings, such as adhesive gauze bandages;

• Passively aid healing by maintaining moisture at wound sites
• Limits bleeding
• Reduces some exposure to infectious pathogens

Recent developments in these conventional dressings have focused on drug and cell delivery to promote the healing process.  But these approaches are often complicated by;

• Inadequate amounts of drug delivered to be effective
• Drug side effects
• Complex finished product development and manufacturing
• Additional hurdles in the regulatory approval process, and
• Overall higher costs

Skin cuts, scrapes, blisters, burns, splinters, gashes, and punctures are ways skin can be traumatized.  In these instances, most conventional treatments involve merely placing a barrier over it (usually an adhesive gauze bandage) to keep the wound site moist, limit bleeding, and reduce infections, as mentioned.  But they do not actively assist in the healing process. The new thermoresponsive bioinspired adhesive developed by the Wyss Institute researchers adheres strongly to the skin and actively contracts wound openings in response to exposure to the skin temperature. In vitro and in vivo studies demonstrate their efficacy in promoting and accelerating skin wound healing, which is reported and detailed in their published paper, Science Advances.

In self-wound healing, contraction of skin surrounding the wound contributes to the healing response.  It reduces the size of the tissue defect and decreases the amount of damaged tissue that requires repair. This natural response involves myofibroblasts, which are located in existing fibers and surrounds borderss of the wound. These myofibroblasts work to pull newly formed collagen fibers in damaged tissues toward the center of the defect, thus reducing the size of the tissue defect. This contraction is accomplished by the two proteins, actin and myosin, that make up myofibroblasts. Actin and myosin interact with the newly formed collagen fibers in the extracellular matrix, forming a web-like adhesive base for wound gap contraction.

The AADs take their inspiration from this natural process of skin’s ability to heal itself without forming scar tissue.

To mimic this process and restore this wound contraction function, and avoid wound infection, the researchers designed their AAD with temperature-triggered contraction and antibacterial function.  Its thermoresponsive function of the AAD included poly(N-isopropyl acrylamide) (PNIPAm), a commonly used thermoresponsive polymer, which repels water and shrinks at around 32°C (18, 19).

To transmit the stress to the skin, strong tissue adhesion was achieved via bonding of the adhesive hydrogel to the underlying tissue with chitosan and carbodiimide mediated reactions.

To provide antimicrobial capabilities, silver nanoparticles (AgNPs) were incorporated in the chitosan hydrogel matrix. AgNPs have been widely used in wound care products, including commercially available alginate hydrogels (e.g., ALGICELL) and antimicrobial gauze).

To date, this AAD is known to be the first design of a mechanically active wound dressing for wound management that is therapeutic (wound healing), mechanically dynamic, antibacterial, and biological-free.

“This technology has the potential to be used not only for skin injuries, but also for chronic wounds like diabetic ulcers and pressure sores, for drug delivery, and as components of soft robotics-based therapies,” said the study’s co-author David Mooney, Ph.D., a Founding Core Faculty member of the Wyss Institute and Robert P. Pinkas, Professor of Bioengineering at SEAS.

“The AAD bonded to pig skin, with over ten times the adhesive force of a Band-Aid^®, and prevented bacteria growth.  So this technology is already significantly better than most commonly used wound protection products, even before considering its wound-closing properties,” said Benjamin Freedman, Ph.D., a Postdoctoral Fellow in the Mooney lab who led the project.

To test how well their AAD closed wounds, the researchers tested it on patches of mouse skin and found that it reduced the size of the wound area by about 45% compared to virtually no change in the untreated control group.  It also sealed wounds faster than other treatments and did not illicit inflammation or immune responses.

In addition, the AAD was tunable as demonstrated by researchers who were able to manipulate the magnitude of the wound closure function of the AAD by adjusting various amounts of acrylamide monomers during the formulation and/or manufacturing process. “This property could be useful when applying the adhesive to wounds on a joint like the elbow, which moves around a lot and would probably benefit from a looser bond, compared to a more static area of the body like the shin,” said co-first author Jianyu Li, Ph.D., a former Postdoctoral Fellow at the Wyss Institute and SEAS, who is now an Assistant Professor at McGill University.

The research team also created a computer simulation of AAD-assisted wound closure, which predicted that AAD could result in human skin wound openings to contract at a rate comparable to that of mouse skin. “We are continuing this research with studies to learn more about how the mechanical cues exerted by AAD impact the biological process of wound healing, and how AAD performs across a range of different temperatures, as body temperature can vary at different locations,” said Benjamin Freedman. He also said, “We hope to pursue additional preclinical studies to demonstrate AAD’s potential as a medical product, and then work toward commercialization.”

“This is another wonderful example of a mechanotherapy in which new insights into the key role that physical forces play in biological control can be harnessed to develop a new and simpler therapeutic approach that may be even more effective than drugs or complex medical devices,” said Wyss Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School (HMS) and the Vascular Biology Program at Boston Children’s Hospital, and Professor of Bioengineering at SEAS.

This invention may open new avenues for developing wound dressings based on adhesive and stimuli-responsive hydrogels. The in vitro and in vivo studies demonstrated that the AAD actively contracted wounds and accelerated wound healing.

The active wound contraction of AAD takes advantage of the intrinsic temperature change during placement of a dressing onto the body and requires no additional reagent or apparatus for external stimuli [e.g., acid, vacuum, and ultraviolet (UV) light].

The AAD was compared to commercially available wound care products, including a skin graft, i.e., ALGICELL (Derma Sciences), Band-Aid , DERMABOND (Johnson&Johnson), Tegaderm (3M), COSEAL, TISSEEL (Baxter).  They were compared by calculating the wound half-life (i.e., the time required to achieve 50% wound areal contraction) of each product. Whereas the results showed that the rate of wound closure with AAD was comparable to that of other photos–cross-linked chitosan hydrogels and microporous gel scaffolds.

The researchers developed a novel design of mechanotherapeutic dressings that may create a new paradigm for wound management.  Inspired by embryonic wound contraction and exploiting recent advances in hydrogels and adhesives, this work led to AAD with an unprecedented combination of mechanical, biological, and antibacterial properties. The AAD forms strong adhesion to skin and generates sufficient contractile strains, in response to exposure to skin temperature to enhance healing.  A finite element model suggests avenues to further program the performance of AAD and the feasibility of using AAD on human skin.

These new mechanobiological materials may open new avenues for wound management and find broad utility in the field of regenerative medicine, as they may be similarly useful in treatment of wounds in other epithelial tissues such as intestine, lung, and liver. They may also be useful in drug delivery and as components of soft robotics based therapies.

Additional authors of the paper include co-first author Serena Blacklow, Blacklow, a former member of the Mooney lab who is now a graduate student at the University of California, San Francisco; Mahdi Zeidi, a graduate student at University of Toronto, and Chao Chen, a former graduate student in SEAS who is now a postdoc at Umass Amherst.

This research was supported by the National Institutes of Health, the Wyss Institute for Biologically Inspired Engineering at Harvard University, the National Sciences and Engineering Research Council of Canada, the Canada Foundation for Innovation, and the Harvard University Materials Research Science and Engineering Center.

The original article was by Lindsay Brownell, and first published here: https://wyss.harvard.edu/news/time-heals-all-wounds-but-this-adhesive-can-help/

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