Melanin pigment imparts color to our skin, eyes, and hair. It also acts as a free radical scavenger to aid skin wound healing, where excessive release of reactive oxygen species (ROS) hinder the process. Dermatologist and skin biologist Kurt Lu and nanomaterials scientist Nathan Gianneschi, both at Northwestern University, decided to exploit this property of melanin to facilitate the removal of ROS to accelerate tissue repair after skin injury.
While extracting melanin from nature is possible, researchers can’t use the product for therapeutic purposes. “It's not a pure thing,” said Lu. “It comes attached with a lot of other. . . contaminants.” Instead, Lu and Gianneschi engineered synthetic melanin particles.
“It’s an amino acid-based material that we produce in the lab, and so we’re able to control its properties,” said Gianneschi. He and his team increased melanin’s baseline activity as an ROS scavenger by using a range of different methods. The team recently showed that applying their optimized synthetic version of melanin to skin injured by chemical or UV exposure accelerated healing in mice (1). Topical application of this super melanin on chemically injured human skin patches obtained from discarded tissue after plastic surgeries also promoted tissue repair. Lu and Gianneschi hope to use their synthetic melanin to treat everything from everyday burns to skin damage from chemotherapy.
How did you become interested in melanin?
Gianneschi: Our team’s interest in melanin emerged around 2014. Its ubiquitous and enigmatic nature fascinated us. It’s everywhere. It’s found in all forms of life, and it’s used in all kinds of different ways. It’s present in deep sea fish with clear skin and in those that are completely black. In a totally different environment, at the ocean surface, limpets use melanin to protect their nucleic acids from UV damage. We wanted to understand it.
How did the collaboration for this project begin?
Lu: Our department of Dermatology at Northwestern holds a monthly meeting that has a segment called “bench to bedside,” where we invite researchers beyond our fields of expertise to talk about their work. We were very lucky to have Nathan give an amazing talk about his work on melanin in March of 2020.
Gianneschi: At the time, my colleagues and I thought about melanin as a sunscreen because it absorbs a certain amount of UV light. At the meeting, I talked about the idea of using it to protect skin from UV damage. Our team had developed a method for engineering melanin (2). We were already collaborating with other dermatology researchers at Northwestern University to investigate how these synthetic melanin particles interact with the skin.
Following the meeting, Kurt and I started collaborating on a project based on a crucial insight he provided: Melanin’s mechanism of action lies not only in light absorption, but also in neutralizing harmful radicals that are produced in the skin during and after damage. We hypothesized that topically applying melanin would facilitate skin healing after injury.
What challenges did you encounter while engineering melanin?
Gianneschi: Unlike proteins and nucleic acids, melanin’s structure is not entirely defined by its sequence. It also lacks the information content of polysaccharides where the precursor molecules dictate the outcome.
We relied on advanced characterization tools for understanding the nature of melanin. It was a laborious multiyear effort, but we needed to know what we were making to make it correctly.
What is the mechanism of action of these synthetic melanin particles?
Lu: There are several mechanisms at play. As we initially hypothesized, one key property of synthetic melanin is its potential as a radical scavenger. As the project progressed, we realized that it does that in a specific way.
In the realm of skin burns, whether caused by radiation, chemical, or UV exposure, we aim to provide an alternative beyond the standard of care, which is mostly supportive care right now.
- Kurt Lu, Northwestern University
Melanin binds to ROS, but it also allows the skin’s own antioxidant system to be rescued. For instance, it increases superoxide dismutase (SOD) activity, which is part of the defense mechanism against harmful ROS. However, sometimes this defense system gets overwhelmed. By absorbing ROS, melanin allows the organism’s own SOD levels to recover.
By rescuing SOD, a cascade of downstream effects takes place. One of them is a decrease in the expression of matrix metallopeptidase 9 (Mmp9), which is an enzyme that degrades skin components. Lower levels of Mmp9 result in shallower injuries, leading to faster healing. Additionally, immune cells in skin treated with synthetic melanin exhibit a proresolution phenotype, contrasting with the more proinflammatory profiles of immune cells in untreated damaged skin.
We found that the treatment helps orchestrate the immune system to repair the skin. That was a big surprise.
What are the next steps in translating this to humans?
Lu: Before initiating human trials, the FDA demands specific requirements for assessing the compound’s safety. That is our focus now. We expect to gather that data soon, but we have good reasons to believe that these synthetic melanin particles are safe. First, because of their biomimetic nature, they’re almost a replica of melanin. Second, we designed these particles so that they temporarily stick to the surface of the skin, preventing further absorption. We have tested several over-the-counter vehicles to deliver them, such as creams, lotions, and ointments. We are currently exploring the lowest effective concentration.
Meeting regulatory criteria involves testing the compound in a larger animal model. Pigs are the standard in this case because their skin thickness, lipids, and immunology resemble that of humans.
We have active protocols addressing these requirements and may wrap them up soon to present our proposal to the FDA. We’re very excited!
For which patients is this treatment intended?
Lu: In the realm of skin burns, whether caused by radiation, chemical, or UV exposure, we aim to provide an alternative beyond the standard of care, which is mostly supportive care right now.
One group of patients we’re interested in is those undergoing chemotherapy. As clinicians, we apply nitrogen mustard onto the skin to treat certain kinds of skin lymphoma. It has important benefits, but it also has side effects, including skin damage. This is why we tested our synthetic melanin on mouse skin and human skin patches damaged by nitrogen mustard. We hope that our optimized melanin aids these patients in healing and prevents premature cancer treatment stops.
Our broader vision includes potentially integrating synthetic melanin particles into first aid kits suitable for different scenarios, since accidental burns occur frequently at home or in the restaurant industry.
Our hearts are in trying to bring this new technology platform forward, so we’re really looking at many possible ways to apply it.
This interview has been edited for length and clarity.
References
- Biyashev, D. et al. Topical application of synthetic melanin promotes tissue repair. NPJ Regen Med 8, 61 (2023).
- Siwicka, Z.E. et al. Synthetic Porous Melanin. J Am Chem Soc 143, 3094-3103 (2021).
