Injectables of the Future
It’s been nearly 20 years since the very first hyaluronic acid (HA) filler won FDA approval, forever changing the face of aesthetics and all who succumb to its charms. The field of injectables has subsequently exploded, yielding dozens of unique formulas designed to deliver nuanced effects and tackle concerns beyond run-of-the-mill wrinkles. In the hands of seasoned pros, our current cache of fillers can sculpt the face, reshape our features, enhance a profile, and discreetly reposition skin that has shifted with time.
While you’ve perhaps seen headlines forecasting the fall of fillers—and a wave of celebs allegedly dissolving their plumped lips and cheeks—the numbers tell a different story. If statistics reflect societal preferences, the demand for injectables has never been greater. To wit, more than 1.8 million filler procedures were performed in the United States in 2021, per The Aesthetic Society. Only muscle-relaxing neuromodulators, like Xeomin, outrank fillers on the nonsurgical charts—a trend we’ve seen, year over year, for as long as anyone’s been tracking treatments.
Despite their many boons and constant popularity, fillers aren’t without shortcomings. For starters, “patients have certain concerns, like skin laxity and loss of elasticity, that we can’t target with standard HA injectables,” Amelia Hausauer, a board-certified dermatologist in Campbell, California, and clinical investigator/adviser to multiple injectable and regenerative medicine companies, says. When injected in a traditional manner, gel fillers typically act as placeholders—synthetic substitutes for the collagen, fat, and bone we lose over time. They’re not powered to improve the skin’s health or function to truly rejuvenate in a real way.
Moreover, while hyaluronic acid fillers are billed as temporary and reversible, researchers have learned they don’t actually disappear on a predictable timetable—in six months, or nine or 18 or whatever figure your injector throws out when you ask how long your results will last. In fact, “recent publications show that when facial surgery is performed, whether for aesthetic purposes or medical reasons, it’s not uncommon to see filler in the skin that was injected over 10 years ago,” Hema Sundaram, a board-certified dermatologist in the Washington, D.C., area and a clinical investigator/consultant for several filler, neuromodulator, and regenerative medicine technologies, adds. Recent MRI studies have shown the same—HA lingering for a decade plus. Over time, residual gel can migrate, swell, and pile up, affecting muscle mechanics and creating a puffy, unnatural appearance. (Here’s a secret injectors rarely share: Your exclusive relationship with HA fillers is somewhat finite and requires a thoughtful approach. Too-frequent top-offs will eventually do you wrong.)
Injectable tech is rapidly evolving, however, and the hottest products in the pipeline promise to do more than just sit there, taking up space. Forthcoming formulas boast novel regenerative properties, with the goal of “stimulating the production of the types of tissue that have been lost due to aging,” Sundaram says. In many cases, “this is a true age-repair process, as the tissue that’s produced harmonizes with what’s already in the skin.”
Of course, the notions of regeneration and biostimulation aren’t entirely new to aesthetics, board-certified dermatologist Saranya Wyles*, a regenerative medicine specialist at the Mayo Clinic Center for Aesthetic Medicine and Surgery in Rochester, Minnesota, notes. “When it comes to injectables, we already have this alluded to in the form of Sculptra and Radiesse, which stimulate natural collagen formation,” she says. But some of the most groundbreaking up-and-coming products will work in a revolutionary way, harnessing the body’s own tools for regeneration rather than relying on synthetic substances to galvanize the skin.
Ahead, doctors reveal the injectables of tomorrow—from buzzy exosomes to next-gen HAs and futuristic gene therapies—all striving to make skin look and act younger by imbuing it with the ability to repair and replenish for improved bounce, elasticity, glow, hydration, and more.
Filler with Benefits
While scientists have long suspected that conventional hyaluronic acid injections can subtly ramp up collagen synthesis, the latest crop of fillers is engineered to amplify these effects. One that’s expected to pursue FDA approval is HArmonyCa, a hybrid formulation that suspends calcium hydroxylapatite spheres (like those found in Radiesse) in a hyaluronic-acid base to give both immediate volume and long-term collagen gains in areas like the cheeks and jawline. While the calcium component is more synonymous with regeneration, Sundaram points out that HA has the potential to spark fresh collagen and elastin by interacting with specific receptors in the skin and its underlying tissue.
Also on the horizon: so-called skin boosters, an innovative clutch of non-volumizing HAs proven to refine the skin’s texture when injected very superficially in minuscule droplets across the face. “Filler injected in this way has a chance to integrate into the tissue and, provided it has the right scientific properties, become one with it,” Sundaram says. “There is, then, more of a chance of it being able to turn on the signals that can stimulate skin repair”—which is what gives these skin-quality injectables a regenerative bent.
Though the FDA has yet to approve any booster-type injectables, certain ones, like Restylane Vital and Juvéderm Volite, are already in use elsewhere in the world. In a recent study on Volite, the gel “induced hydration and firmness with ultimately better tissue quality,” Hausauer adds.
Injectable Exosomes
Exosomes, skin care’s darling du jour, are being investigated as potential injectables. Secreted by all manner of cells throughout the body, these microscopic, lipid-bound sacs are essentially messengers, shuttling their contents—growth factors, DNA, and the like—between nearby cells. “What an exosome is is defined by where the exosome is coming from,” Wyles says. “Its source really matters,” she stresses, since its cell of origin—be it a platelet, a stem cell, a cancer cell—determines the nature of the message being communicated and its overall safety.
“After exosomes are released, they’re actively taken up by surrounding cells, where they trigger different responses based on their cargo,” Sundaram explains. They may order their host to make more antioxidants, collagen, or elastin to help with wrinkles or brown spots. “Exosome messages can activate some cells and block the activity of others,” she adds. “In this way, they are master controllers of the balance of what the skin is made of and how it functions.”
But don’t dial your derm just yet. At the moment, there are no FDA-approved exosome injectables on the market, Wyles says, as they’re still in the earliest, experimental stages of testing and development. Though some are showing promise for aesthetic purposes, “we don't yet have solid proof of what exosomes can do for skin and hair,” Sundaram notes, and more controlled clinical trials are needed.
In lieu of injecting exosomes for skin rejuvenation, some cosmetic providers are reportedly applying off-the-shelf exosome serums to freshly microneedled or lasered skin—disrupting the skin barrier to enhance the product’s penetration—but even this work-around isn’t sanctioned by the FDA, Wyles insists. Which could spell trouble for the providers performing such services.
“The FDA is starting to get much more strenuous with their regulations in this realm,” Hausauer cautions. Since 2019, the administration has issued multiple alerts, stating that while it does regulate regenerative medicine products, like exosomes, none has been formally approved for use and that the safety and efficacy of unvetted products are suspect at best. If the agency finds a provider using illegal exosomes outside of approved research purposes, Hausauer says, they can report that person to the medical board, putting them at risk of losing their license.
A Shot of Elastin
Currently in development with the Sydney-based biotech company Elastagen is a first-of-its-kind injectable aiming to restore skin’s elastic fibers, the springy structural proteins that break down with age, leading to laxity, crinkling, and sagging.
“Our own elastin is only produced with a normal, youthful structure before we are born and for a short time afterwards,” Sundaram shares. “More elastin can be made later in life, but it tends to be abnormal or disorganized, as we see in sun-damaged or scarred skin. So in any regenerative strategy, it’s very important to replace elastin.”
Enter: recombinant tropoelastin, a precursor (or building block) of elastin that’s identical to what’s found in human tissues. Think of it like a next-level retinoid, feeding skin what it needs to produce more plumping proteins. “This is a completely human-based molecule,” Hausauer says, underscoring, yet again, a shift to injectable ingredients that are native to our bodies.
What’s jaw-dropping about this one is it appears to build proteins that resemble those found in young skin. In recent studies, when researchers injected tropoelastin into the dermal layer of living skin models and into the skin of rats, they saw it restore “youthfully organized collagen and elastin networks, as well as derivatives of hyaluronic acid,” Sundaram says.
With research still in its infancy, we won’t see this shot in doctors’ offices for several years.
Skin Gene Therapy
Imagine a needle penetrating the nuclei of your skin cells to replace or reprogram the pesky gene responsible for your deepening crow’s feet or crepey neck. While it sounds utterly sci-fi, clinical trials exploring this radical form of aesthetic gene therapy are well underway, courtesy of the trailblazing biotech company Jeune.
“The idea here is to introduce a synthetic gene that turns the clock back in aging skin cells by stimulating them to start making more type 3 collagen, which is abundant in baby skin but decreases with age,” Sundaram explains. This particular protein is key to youthful skin, she says, not only by virtue of its mere presence, which buoys skin’s structure, function, and strength, but in terms of how it influences the output of other kinds of collagen.
In a number of small, company-funded studies, researchers injected the gene into the sun-damaged skin of subjects’ knees and cheeks, and measured significant improvements in thickness, elasticity, fine lines, and redness following a series of treatments. Side effects were mostly mild and included injection-site reactions (like bruising), headache, fatigue, and chills.
In order to target fine lines and improve the quality of the skin, Hausauer notes, the gene has to be placed high up in the dermis, “where your body has the machinery to translate it.” If this gene-based treatment is eventually approved—phase two trials are expected to start in 2023—she envisions using it in a skin-boosting fashion, dotting tiny doses across the treatment area to create a sweeping change.
With data still being collected, it’s unclear how quickly the gene will elicit results or precisely how long they’ll last. “What we can say is that, based on the mechanism of action, we wouldn't expect immediate results,” Sundaram says. “The idea is to switch on regenerative mechanisms, so it will take time for the results to manifest.” On the upside, since improvements are rooted in new collagen, they should be quite durable. “The clock of aging continues to tick, however, so maintenance treatments are likely to be needed with any regenerative therapy,” she adds.
Regenerative Neuromodulators
With injectables going next-level natural to more harmoniously sync with our bodies, “we now have the very real promise of being able to rebuild skin better, stronger, and faster than with previously available rejuvenative treatments,” Sundaram says. But what about neuromodulators like Xeomin or Botox—the yin to fillers’ yang? How might they adapt to the regenerative landscape? According to our experts, botulinum toxins already fit quite nicely into this world.
“Neuromodulators are a game-changer treatment with a multitude of effects through various signaling pathways,” Sundaram tells us. “There is growing evidence that this includes regenerative effects on the skin, through the stimulation of new collagen and elastin production, which explains the progressive improvement in skin quality and elasticity that we see in patients who continue their neuromodulator treatments over years or decades.”
In the future, neurotoxins will likely play a pivotal role in transforming the skin’s tone and texture while also working alongside a variety of cutting-edge regenerative treatments to create what Wyles calls “that ideal aesthetic effect.”
One Final Point
The success of any regenerative treatment hinges not only on evidence of safety (hello, clinical trials), but also stability: Will that sexy gene or exosome degrade within hours if not stored at North Pole temps? As well as scalability: Does test-tube efficacy translate in human beings, and can the product be affordably produced so as not to drain patients’ wallets? Addressing these complexities takes time—it will, no doubt, be years before we see some of these shots—but we’re predicting they’ll be worth the wait.
*The views expressed by Wyles throughout this story do not necessarily reflect the policy or position of the Mayo Clinic.
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