Scientists Uncover How Molecule Improves Appearance of Surgery Scars (Medicine)

In a new study led by Rob Gourdie, researchers discovered that the alphaCT1 molecule may help repair the skin’s collagen matrix by altering how scar-forming cells behave.

Surgical scars treated with a molecule called alphaCT1 showed a long-term improvement in appearance when compared to control scars, according to multicenter, controlled Phase II clinical trials – a finding that could help surgeons improve patient outcomes.

Now, a public-private research team led by Rob Gourdie, professor and director of the Center for Vascular and Heart Research at the Fralin Biomedical Research Institute at VTC, has revealed clues about why and how it improves the appearance of scars.

The study, scheduled to appear in the August issue of the Federation of American Societies for Experimental Biology (FASEB) Journal, describes how the drug influences the behavior of collagen-producing cells called fibroblasts. The findings reveal a previously unreported feature of scar formation and could help advance wound healing treatments for patients undergoing surgical procedures.

The researchers analyzed scars from 49 healthy volunteers in a randomized, double-blind Phase I clinical study. Each volunteer had 5-milimeter punches of skin biopsied from each of their inner biceps. One arm’s wound was treated with the alphaCT1 molecule in a gel, and the other received a nonmedicated control gel. The wounds healed for 29 days, at which point the scars were photographed and biopsied again.

Under the microscope, the untreated scars’ collagen – a protein produced by cells called fibroblasts – formed parallel strips, which makes the tissue less pliable. By contrast, scars that were applied with the drug had a collagen matrix resembling unwounded skin. Related experiments were repeated using guinea pig and rat models and yielded similar results.

The researchers also analyzed human skin cells cultured in a dish to watch how the drug influenced cellular activity in real time. They discovered that the presence of the molecule caused fibroblasts to stretch out like a rubber band, then snap back into shape and change direction.

“We call it the fibroblast dance,” said Gourdie, who is also the Commonwealth Research Commercialization Fund Eminent Scholar in Heart Reparative Medicine Research and a professor of biomedical engineering and mechanics in Virginia Tech’s College of Engineering.

This unusual fibroblast behavior in the treated tissue appears to have a positive effect on scar formation, Gourdie said.

“In unwounded skin, the collagen is enmeshed, allowing the tissue to move and stretch in all directions. The fibroblasts’ directional changes appear to influence how the collagen matrix forms during scarring,” Gourdie said.

Fibroblasts treated with alphaCT1 respond by doing what Gourdie describes as the “fibroblast dance.” The cells undergo pivoting motions that result in frequent direction changes. Gourdie speculates this unusual pattern of cellular movement dictates how the cells knit the collagen bundles together that will form the scar. (Gourdie Lab / Virginia Tech)

More than 300 million surgical procedures are performed in the United States each year – often resulting in noticeable scarring on patients. Methods to reduce scarring after operations are sought after.

“This is some of the most exciting basic science research in wound healing I’ve seen in a long time,” said Kurtis Moyer, chief of plastic and reconstructive surgery for Carilion Clinic and a professor of surgery at the Virginia Tech Carilion School of Medicine. Moyer was not involved in the study, but has collaborated with the Gourdie lab on wound healing research for 20 years.

“This shows real promise and could potentially revolutionize what we do in plastic surgery,” Moyer said.

AlphaCT1 influences wound healing by temporarily interrupting cell signaling functions of connexin 43, a gap junction channel protein.

Gourdie and his lab invented the molecule and discovered its useful effects on wound healing with his former postdoctoral associate, Gautam Ghatnekar, a decade ago. Together they formed a biopharmaceutical company, FirstString Research Inc., to bring alphaCT1 to market.

The molecule is currently being evaluated in Phase III clinical testing in bilateral breast surgery patients.

“These findings validate that the drug’s mechanism is playing out as we thought it would,” said Ghatnekar, FirstString’s president and chief executive officer.

The company has closed $55 million in Series B, C, and D Funding since 2018 and is evaluating the drug’s use in a variety of applications, including surgical wound healing, chronic wound healing, radiation therapy wound healing, and corneal tissue repair.

“We alter how the human body responds to injury by shifting the balance from healing by scarring to healing by regeneration. The medical applications for our technology are far-ranging,” Ghatnekar said.

Gourdie and Ghatnekar were joined on the study by its first author, Jade Montgomery, a former graduate student in Gourdie’s lab at the Fralin Biomedical Research Institute and in Virginia Tech’s Department of Biomedical Engineering and Mechanics; William Richardson, an assistant professor of bioengineering at Clemson University; Spencer Marsh, a postdoctoral associate in Gourdie’s lab; Matthew Rhett, a staff scientist at the Medical University of South Carolina at the time of the study; Francis Bustos, a former medical student; Katherine Degen, a former graduate student in Gourdie’s lab at the Fralin Biomedical Research Institute and in the Virginia Tech – Wake Forest School of Biomedical Engineering and Sciences; Christina Grek, senior director of research and development at FirstString; Jane Jourdan, Gourdie’s lab manager; and Jeffrey Holmes, dean of engineering at the University of Alabama.

Featured image: In a new study, Fralin Biomedical Research Institute at VTC scientists discovered that the alphaCT1 molecule may help repair the skin’s collagen matrix. Microscopic imaging of 29-day scar biopsies from the same patient reveals the molecule’s effects on collagen organization. Collagen bundles in the untreated scar, right, are more aligned compared to the alphaCT1-treated tissue’s collagen, which is more randomly arranged in swirls that resemble unwounded skin. (Gourdie Lab / Virginia Tech)

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Reference: Montgomery, J, Richardson, WJ, Marsh, S, et al. The connexin 43 carboxyl terminal mimetic peptide αCT1 prompts differentiation of a collagen scar matrix in humans resembling unwounded skin. The FASEB Journal. 2021; 35:e21762. https://doi.org/10.1096/fj.202001881R

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Provided by Virginia Tech

Asteroid’s Scars Tell Stories Of Its Past (Planetary Science)

Impact craters left by space debris in the boulders on asteroid Bennu’s rugged surface allowed researchers to reconstruct the history of the near-Earth object in unprecedented detail.

By studying impact marks on the surface of asteroid Bennu – the target of NASA’s OSIRIS-REx mission – a team of researchers led by the University of Arizona has uncovered the asteroid’s past and revealed that despite forming hundreds of millions of years ago, Bennu wandered into Earth’s neighborhood only very recently.

This image shows four views of asteroid Bennu along with a corresponding global mosaic. The images were taken on Dec. 2, 2018, by the OSIRIS-REx spacecraft’s PolyCam camera, which is part of the OCAMS instrument suite designed by UArizona scientists and engineers. ©NASA/Goddard/University of Arizona.

The study, published in the journal Nature, provides a new benchmark for understanding the evolution of asteroids, offers insights into a poorly understood population of space debris hazardous to spacecraft, and enhances scientists’ understanding of the solar system.

The researchers used images and laser-based measurements taken during a two-year surveying phase in which the van-sized OSIRIS-REx spacecraft orbited Bennu and broke the record as the smallest spacecraft to orbit a small body.

Presented at the opening day of the American Astronomical Society’s Division for Planetary Sciences meeting on Oct. 26, the paper details the first observations and measurements of impact craters on individual boulders on an airless planetary surface since the Apollo missions to the moon 50 years ago, according to the authors.

The publication comes just a few days after a major milestone for NASA’s University of Arizona-led OSIRIS-REx mission. On Oct. 20, the spacecraft successfully descended to asteroid Bennu to grab a sample from its boulder-scattered surface – a first for NASA. The sample has now been successfully stowed and will be returned to Earth for study in 2023, where it could give scientists insight into the earliest stages of the formation of our solar system.

Impact Craters on Rocks Tell a Story

Although Earth is being pelted with more than 100 tons of space debris each day, it is virtually impossible to find a rockface pitted by impacts from small objects at high velocities. Courtesy of our atmosphere, we get to enjoy any object smaller than a few meters as a shooting star rather than having to fear being struck by what essentially amounts to a bullet from outer space.

Planetary bodies lacking such a protective layer, however, bear the full brunt of a perpetual cosmic barrage, and they have the scars to show for it. High-resolution images taken by the OSIRIS-REx spacecraft during its two-year survey campaign allowed researchers to study even tiny craters, with diameters ranging from a centimeter to a meter, on Bennu’s boulders.

On average, the team found boulders of 1 meter (3 feet) or larger to be scarred by anywhere from one to 60 pits – impacted by space debris ranging in size from a few millimeters to tens of centimeters.

“I was surprised to see these features on the surface of Bennu,” said the paper’s lead author, Ronald Ballouz, a postdoctoral researcher in the UArizona Lunar and Planetary Laboratory and a scientist with the OSIRIS-REx regolith development working group. “The rocks tell their history through the craters they accumulated over time. We haven’t observed anything like this since astronauts walked on the moon.”

This composite image of a boulder on Bennu’s surface shows the cascading rim of one of the asteroid’s ancient craters that originated while Bennu resided in the asteroid belt. The image combines photos from OSIRIS-REx and reconstructed shape models built from the OSIRIS-REx laser altimeter instrument. The overlaid colors highlight the topography of the boulder (warmer colors are higher elevation). ©University of Arizona/Johns Hopkins APL/York University.

For Ballouz, who grew up during the 1990s in post-civil war Beirut, Lebanon, the image of a rock surface pitted with small impact craters evoked childhood memories of building walls riddled with bullet holes in his war-torn home country.

“Where I grew up, the buildings have bullet holes all over, and I never thought about it,” he said. “It was just a fact of life. So, when I looked at the images from the asteroid, I was very curious, and I immediately thought these must be impact features.”

The observations made by Ballouz and his team bridge a gap between previous studies of space debris larger than a few centimeters, based on impacts on the moon, and studies of objects smaller than a few millimeters, based on observations of meteors entering Earth’s atmosphere and impacts on spacecraft.

“The objects that formed the craters on Bennu’s boulders fall within this gap that we don’t really know much about,” Ballouz said, adding that rocks in that size range are an important field of study, mainly because they represent hazards for spacecraft in orbit around Earth. “An impact from one of these millimeter to centimeter-size objects at speeds of 45,000 miles per hour can be dangerous.”

Ballouz and his team developed a technique to quantify the strength of solid objects using remote observations of craters on the surfaces of boulders – a mathematical formula that allows researchers to calculate the maximum impact energy that a boulder of a given size and strength could endure before being smashed. In other words, the crater distribution found on Bennu today keeps a historical record of the frequency, size and velocity of impact events the asteroid has experienced throughout its history.

“The idea is actually pretty simple,” Ballouz said, using a building exposed to artillery fire as an analogy to boulders on an asteroid. “We ask, ‘What is the largest crater you can make on that wall before the wall disintegrates?’ Based on observations of multiple walls of the same size, but with different sized craters, you can get some idea of the strength of that wall.”

The same holds true for a boulder on an asteroid or other airless body, said Ballouz, who added that the approach could be used on any other asteroid or airless body that astronauts or spacecraft may visit in the future.

“If a boulder gets hit by something larger than an object that would leave a certain size cater, it would just disappear,” he explained. In other words, the size distribution of boulders that have persisted on Bennu serve as silent witnesses to its geologic past.

A Newcomer to Earth’s Neighborhood

Applying the technique to boulders ranging in size from pebbles to parking garages, the researchers were able to make inferences about the sizes and type of impactors to which the boulders were exposed, and for how long.

The authors conclude that the largest craters on Bennu’s boulders were created while Bennu resided in the asteroid belt, where impact speeds are lower than in the near-Earth environment, but are more frequent and often near the limit of what the boulders could withstand. Smaller craters, on the other hand, were acquired more recently, during Bennu’s time in near-Earth space, where impact speeds are higher but potentially disruptive impactors are much less common.

Based on these calculations, the authors determine that Bennu is a relative newcomer to Earth’s neighborhood. Although it is thought to have formed in the main asteroid belt more than 100 million years ago, it is estimated that it was kicked out of the asteroid belt and migrated to its current territory only 1.75 million years ago. Extending the results to other near-Earth objects, or NEOs, the researchers also suggest that these objects likely come from parent bodies that fall in the category of asteroids, which are mostly rocky with little or no ice, rather than comets, which have more ice than rock.

While theoretical models suggest that the asteroid belt is the reservoir for NEOs, no observational evidence of their provenance was available other than meteorites that fell to Earth and were collected, Ballouz said. With these data, researchers can validate their models of where NEOs come from, according to Ballouz, and get an idea of how strong and solid these objects are – crucial information for any potential missions targeting asteroids in the future for research, resource extraction or protecting Earth from impact.

References: Ballouz, R., Walsh, K.J., Barnouin, O.S. et al. Bennu’s near-Earth lifetime of 1.75 million years inferred from craters on its boulders. Nature (2020). https://doi.org/10.1038/s41586-020-2846-z link: http://dx.doi.org/10.1038/s41586-020-2846-z

Provided by University of Arizona