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Researcher’s Collaborations Produce Versatile Nanoceria Platform for Treating Diabetic Wounds, Lung Injury and Heart Attack

October/November 2024

By Kathleen Snoeblen

Ironically, as a kid, Dr. Sudipta Seal vowed: “I knew that one thing I will NOT be is a professor. I grew up in a professorial house in a very small town on the outskirts of Calcutta where my late dad was a university professor of chemistry.” Seal’s reason for not following his father’s footsteps? “Thirty, forty years back, teaching as a profession had a lot of prestige in India at the time, but there was zero money.”

Dr. Sudipta Seal in his UCF lab

Even more surprising, Seal said that he “definitely” was not going to be a science person. “And what do I do now?” he laughed. “I do chemistry!”

Luckily for UCF, Seal didn’t follow his childhood plans. “I chose the engineering pathway, and I briefly worked for one of the top steel companies in India,” he said, but he eventually decided to look for an academic position. Reflecting on his work and research with the university, Seal said, “I’ve had a good twenty-seven-year ride. I was just a naïve grad student doing post-doc work when I came to UCF in 1997.”

Since joining the UCF Knights campus, the Pegasus Professor is still going strong. Seal has 88 UCF inventions to his credit, plus more than 450 journal papers. A pioneer in nanoceria research for the biomedical sector, his work focuses on the nanoscience of advanced materials processing and materials science and engineering. Technology Transfer caught up with UCF’s busy Chair of the Department of Materials Science and Engineering to learn more about four of those inventions, which use the nanoceria platform that he developed.

Nanoceria and Biomedical Applications

Like a lot of ongoing research, Seal’s nanoceria research builds on previous projects and findings. In this case, it’s his research journey with cerium oxide. It began when he was introduced to the rare-earth metal oxide back in 1989 while developing his undergraduate thesis at the Indian Institute of Technology (IIT), India. Then, as a Ph.D. student at the University of Wisconsin, his Ph.D. thesis centered on oxidative stress in cells and how materials play a role. Oxidative stress can generate free radicals that damage proteins, lipids, and DNA and can eventually kill cells.

“My PhD thesis was all on oxidative stress in cells, said Seal. “What is oxidative stress when the cells age? It creates a lot of nasty, harmful radicals like the OH dot, [hydroxyl radical, OH•] or O2 dot [superoxide radical (O2•−).”

With his background in cerium oxide, Seal also worked with a Wisconsin research team on nanotechnology and cerium oxide. “So I knew the material [cerium oxide] from my undergraduate work. I didn’t know how to make them in nanoscale, but I knew how to make them the normal way,” he said. So, he took the opportunity to design and create cerium oxide nanoparticles (CNPs), also called nanoceria.

Discovering the Benefits of Nanoceria: Non-Toxic and Versatile

When Seal came to UCF in 2004, nanoceria was being used for microelectronic processing, but not yet in the biomedical sector. “We at UCF are the first ones to show that this has wonderful properties,” he said, “We filed a patent and were the very first to show nano cerium cell survivability,” referring to U.S. Patent 7,534,453, Cerium Oxide Nanoparticles and Use in Enhancing Cell Survivability. “Then of course, after that, the field has really blossomed,” he added. “There is a wide range of applications in biomedical sciences—from cancer research to bone regeneration, tissue regeneration, and radiation protection,” he says. “All from this almost accidental discovery made at UCF.”

Since then, Seal and his research team have found that nanoceria are “non-toxic, great carriers for delivering therapeutic agents, and have regenerative oxidative properties because of their unique defect structure.” The team even developed a way to produce highly stable nanoceria structures as a platform for various applications.

Seal noted that the nanoceria structure is tweaked, depending on the application. “I’d say, in technical terms, we call it defects,” he said. “But in layman’s terms, I would say I create openings in that crystal structure that I can tinker with to do multiple aspects. This is where the functional materials come in.

“I can take one opening and use it to send something, maybe I can load a drug on it. I can take another opening and keep it open to destroy nasty radicals produced by cells that are not needed,” he said. “It can be DNA, micro-RNA, drugs, all kinds of things.”

He said that nanoceria’s versatility enables companies to encapsulate them in polymers like capsules and orally administer them or put them in injectables. “The sky’s the limit,” said Seal. “There’s also recent data that when combined with drugs, the nanoceria material actually protects the good cells, while the drug kills cancer cells even more potently,” he added.

Most recently, Seal’s cerium oxide/nanoceria journey has led to four technologies that he co-developed with Dr. Kenneth Liechty, who at the time, was with the University of Colorado Anschutz Medical Campus. (Dr. Liechty is now with the University of Arizona).

Nanoceria-miRNA for Diabetic Wound Healing

With UCF’s nanoceria platform and Colorado’s experience in micro-ribonucleic acid (microRNA or miRNA), Seal, Liechty, and their research teams engineered cerium oxide nanoparticles (CNPs) conjugated with a specific type of miRNA called miRNA-146a (or miR-146). Found in all human cells, miRNA plays important roles in many biological processes. For example, miRNA controls functions like cell proliferation, differentiation (development of specific cell functions/characteristics), and cell death.

Sterile, single use, elastic plastic applied on diabetic foot ulcer. Image source: iStock.

Many of us believe that inflammation is bad and prevents wounds from healing properly. However, Seal pointed out that inflammation is a key component of normal wound healing. Unfortunately, people with diabetes tend to have weaker immune systems that cause slower wound healing. As a result, that impaired healing process can actually increase inflammation to a point where the wound grows larger. With that kind of inflammatory response, the body can produce a build-up of excess reactive oxygen species (ROS) molecules, which then leads to increased oxidative stress inside cells.

The UCF-UC invention helps combat inflammation and speeds wound healing with its novel cerium oxide nanoparticle combination (CNPs with miR-146a, also called conjugated CNPs). When separate, the nanoceria and micro-RNA have different therapeutic properties, but when combined, they have a synergistic effect. In this case, the nanoceria acts as a delivery vector, keeping the miRNA intact until needed.

The CNPs also scavenge excess ROS to help suppress the body’s inflammatory response and deliver MiR-146a to the wound site to correct the inflammatory response at the molecular level. The researchers found that when the CNPs deliver miR-146a to a diabetic wound site, the miR-146a acts as a “molecular brake” on the inflammatory response by targeting and repressing the inflammatory pathway. Altogether, the conjugated CNPs shorten the time of diabetic wound closure and help avoid the complications associated with impaired diabetic wound healing.

Seal said that though the nanoceria material is engineered only for a specific function, it is long-lasting and regenerative. “You don’t need multiple doses. That’s one of the advantages. Another advantage is it stays inside the cell—that’s good.”

Nanosilk Fibers to Protect Skin and Treat Injuries

Another healing invention developed by the UCF-CU collaborators employs nano silk fibers from the silk of silkworms or spiders. The patented invention (US11298309B2) includes biocompatible and hypoallergenic compositions to heal, protect and strengthen skin. Like the nanoceria-miRNA invention, this second invention uses a form of the nanoceria and miR-146a combination.

Silk comprises two proteins: fibroin and sericin. The silk core is fibroin, often used to make surgical sutures because it is non-toxic and biocompatible with human tissues. Surrounding the core is sericin, a glue-like protein. Fibroin solution converts to many forms, including films, sponges, gels, and powders.

During their research, the inventors found that applying a layered system of silk fibroin fibers in solution and spun mat formats can effectively protect and strengthen skin, especially in weak areas that are injury-prone or stressed repetitively. Also, they found that when integrated with CNPs conjugated with miR-146a, the silk fibroin fiber solution and mat enhanced wound healing for both diabetics and non-diabetics.

According to Seal, “We are now using biodegradable material to deliver therapeutics in disease sites. Silk ceria composite is one of them—it’s green and sustainable technology.”

Silk cocoons of commercially bred caterpillar silkworm moths. Image source: iStock.

The solution of silk fibroin fibers may be applied in many forms. For example, it can be made into a spray, liquid, film, foam, cream, ointment, or gel. Likewise, the silk fibroin mat can be applied in many forms, including a non-woven mat, sheet, gel, hydrogel, mesh, fabric, powder, or sponge. The invention, which has many cosmetic and dermatological uses, can be used as a protective layer to improve the skin’s elasticity, thus preventing or reducing injury, even minor blisters and skin ulcers. It can treat a variety of wounds, including burns, cuts, major/minor bruises, penetrating and surgical wounds, contusions, and crushing injuries. Additionally, it can be used to treat injuries to subcutaneous tissue caused by, for example, pressure sores from extended bed rest and trauma.

Tissue Regeneration for Wounds and Heart Attack

Like the two previous inventions, the UCF-CU collaborators, along with a collaborator from the University of Pennsylvania, developed another invention that uses the microRNA-nanoceria conjugate to promote wound healing. However, the third invention’s design and structure also promote tissue regeneration, a key process needed for angiogenesis, the growth of new blood vessels.

“Angiogenesis is a very interesting biological function,” said Seal about the invention’s added benefit. “You need angiogenesis. You need blood vessels to grow,” he said. For instance, after a heart attack (also known as myocardial infarction or MI), the invention aids recovery by reducing the body’s inflammatory response and helping it to generate new tissue for blood vessels.

As with diabetic wounds, heart attacks can cause the body to produce excess reactive oxygen species (ROS) and increase oxidative stress and inflammation. Also, the ROS build-up can negatively affect a patient’s recovery by causing adverse ventricular remodeling—that is, changes in the size, shape, or function of the heart, which can worsen outcomes and lead to heart failure. A key factor in recovery is the ability to reduce left ventricular end-diastolic volume (LVEDV) in a patient following an MI, since increased volume can lead to unwanted remodeling.

Offering both treatment and prevention, the patented invention (US11833172B2) can significantly mitigate heart damage and prevent adverse ventricular remodeling during recovery.

In one study, the researchers found that treatment with the invention’s nanoceria/microRNA conjugate was able to reduce ventricular dilation at eight weeks post-infarction, highlighting the synergistic effect of the components. They saw similar results at the two-week time point, although the effects were not as dramatic. The findings indicate that though heart damage can continue after an MI, the invention can help lessen the damage.

Conjugated CNPS that Treat and Prevent Lung Injury

The final CNP/miR-146a invention developed by the UCF-UC researchers suppresses lung inflammation, promotes lung repair, and can help treat or prevent symptoms of pulmonary diseases or conditions. Examples include pulmonary fibrosis, obstructive pulmonary disease (COPD), emphysema, asthma, idiopathic pulmonary fibrosis, pneumonia, tuberculosis, cystic fibrosis, bronchitis, pulmonary hypertension, and lung cancer.

Seal said that his earlier work 10-15 years ago on lung injury and cancer therapy radiation helped in developing the invention. “We have papers where you’re saying that during the lung cancer treatment, of course, everything dies, right?” He said that radiation therapy produces a lot of radicals. “Radicals kill the cancer cells, but they also kill your good cells,” he said.

“When you treat the lungs with nanoceria, the good cells around the lungs are protected from the radiotherapy while the radiotherapy is killing the cancer cells,” he noted. “The cerium oxide has this bifunctionality to protect the good cells from the radiation.”

He explained that the nano cerium oxide has multivalent states. “The particle has those openings, and I can exchange when I want to exchange between the electrons. When I don’t want to exchange, I shut it off,” he said. “And that’s when the engineering of the nanoparticles comes into play.”

“In cancer cells, it acts as an anti-angiogenesis, because you don’t want the blood vessels to grow. Whereas in tissue engineering wound repair, it will act as pro-angiogenesis.”

He likened the technology to two neighbors exchanging food or who have different opinions. “I have a neighbor in my apartment complex and sometimes we exchange foods that we like. Sometimes, we don’t exchange food because I may not like that particular food, but we are still neighbors. We are still living happily next to each other.”

In other words, Seal said that the invention’s nanoparticles can stay silent when they want to and stay active when needed. “What we have seen in nanoscale depends on the microenvironment in the cell. It can switch back and forth.” He added that very few materials can switch their valence states to provide anti-angiogenesis and pro-angiogenesis.

iStock image of lungs.

The CNP-micro-RNA compositions of the invention can be administered as a pharmaceutical in different forms. Some examples include aerosol, a metered dose inhaler, a pre-compression pump, and an intranasal spray.

Ongoing, Future and Related Work

Seal briefly discussed plans for his current and future projects.

“My goal is to see that our technology, our UCF technology—at least the nanoceria platform—is being used by humankind at some point. That means you get through the FDA and other folks, another trial which is quite challenging.” Related to this goal is his interaction and work with Ceria Therapeutics. He said that the company wants to take the technologies to the clinical testing level for applications that help to heal diabetic wounds and lung injuries. “I’m quite excited about the future of this University of Colorado spin-out,” he said.

He also plans to continue promoting the commercialization aspect of technology developed within his department. “I’m really a proponent of people creating new IPs and taking them to the next level. I think every department should have an entrepreneurial/entrepreneurship type of course.”

As for the future, Seal says: “My two cents to the world is to take it one step at a time. The world of nanomaterials is quite intriguing. It is quite challenging, and it needs a good understanding. Don’t do things in a rush. The potential benefit of the nanomaterials, nanotechnology is immense.”

According to Seal, basic science is the key to knowing how to make a technology, how to use it, and how to understand its function. “It’s all in the research and preparation,” he said. “It might take some time, but the time is necessary for success later on.”

He also mentioned the importance of “good chemistry” among collaborators. “There is always a two-way street, as well as complementary expertise.” His collaborators over the years include students, post-docs, and other faculty researchers in and outside the university. “I thank them for the help and inspiration they gave on the journey.”

Finally, what sage advice does the Chair of the Department of Materials Science and Engineering have?

“Never say never again,” he smiled.

Researcher’s Credentials

UCF Pegasus Professor, UCF Trustee Chair, Sudipta Seal is Chair of the Department of Materials Science and Engineering. Seal joined the Department of Materials Science and Engineering and the Advanced Materials Processing Analysis Center, which is part of UCF’s College of Engineering and Computer Science, in 1997. He has an appointment at the College of Medicine and is a member of UCF’s prosthetics cluster Biionix. He is the former director of UCF’s NanoScience Technology Center and Advanced Materials Processing Analysis Center. Dr. Seal received his doctorate in materials engineering with a minor in biochemistry from the University of Wisconsin (UWM), Milwaukee and was a postdoctoral fellow at the Lawrence Berkeley National Laboratory at the University of California Berkeley.

His research encompasses the following:

  • Nanomaterials processing and characterization
  • Nanobiotechnology
  • Materials for optics, sensors, coatings, fuel cells
  • Oxidation/corrosion
  • Surface science and engineering
  • Chemical mechanical planarization

Technology Available for License

To learn more about Seal’s work and potential licensing of these UCF technologies or for more information about sponsored research opportunities, contact Andrea White (andrea.white@ucf.edu) at (407) 823-0138.