Biostimulators: A therapy for the ages
A historical review and forecast of the products, procedures — plus the pros and cons.
Consumer preferences and expectations have driven demand for regenerative aesthetics and cosmetics, and medical advancements in biostimulators have helped to make this possible.
The seemingly steep learning curve for preparing and administering biostimulator injections in addition to inconsistent or unregulated protocols can be overwhelming or discouraging to current and future dermatologists. Understanding the genesis of and outlook for biostimulator agents will better inform physicians and prepare them to incorporate the range of medicines into their patient offerings.
At the beginning
According to Mara Dacso, MD, MS, FAAD, biostimulators were first introduced for facial wrinkles at the end of the 20th century in Europe as New-Fill®, containing poly-L-lactic acid (PLLA). Subsequently, PLLA-SCA (Sculptra®) was introduced and approved by the U.S. Food and Drug Administration (FDA) to treat lipoatrophy — loss or redistribution of fat and volume — in patients with HIV. Since then, the FDA has approved its use for nasolabial folds, facial wrinkles, and, most recently, cheek wrinkles.
Dr. Dacso is a clinical dermatologist and dermatopathologist who has been successfully implementing biostimulators in her Plano, Texas, practice. She is passionate about moving the field of anti-aging and aesthetic medicine forward in the United States, and she anticipates continued progress with the expanded armamentarium of injectables, which includes on-label and off-label uses of these products in facial and off-facial indications.
Mara Dacso, MD, MS, FAAD
Historically, hyaluronic acid fillers have been the most common and versatile injectable in aesthetics. They are relatively inexpensive, produce immediate effects, and can be reversed with hyaluronidase. Dr. Dacso said more patients are seeking procedures that avoid an “overfilled face” and instead create a more natural appearance. Although results are not always instantly visible with injectable biostimulators, she said they can produce longer-lasting regenerative properties than traditional fillers.
“The bioregenerative effect can last for several years, perhaps requiring a once annual maintenance treatment,” said Dr. Dacso. “Patients can expect more natural results, where the skins elasticity, glow, and even pigmentation can improve over time.”
Where are we now?
Today, dermatologists have a full toolkit of aesthetic injectables, which has transformed therapeutic options for patients.
PLLA-SCA
PLLA-SCA has come a long way since its initial use circa 2004, according to Dr. Dacso. She said it originally required a significant waiting period after reconstitution. But recent trials and research validated that forcefully shaking the product for one minute prior to injection doesn’t alter the chemical makeup or clinical outcomes, thereby allowing it to be used immediately after reconstitution.
Dr. Dacso said many cosmetic physicians tailor the dilution and injection technique of PLLA-SCA (e.g., subdermal fanning versus supraperiosteal retrograde bolus) to achieve desired outcomes in facial and off-facial presentations, even to improve the appearance of cellulite. She has been impressed with the regenerative capabilities and results of PLLA-SCA when injected in targeted regions of the face and in deeper tissue planes, including supraperiosteal.
Supraperiosteal Injection Technique using PLLA-SCA (After 1 treatment - 2 vials).
Around the world, PLLA-SCA is used to improve contours and skin quality in off-facial locations, such as the décolletage, inner arms, knees, thighs, and buttocks with the potential for more approved indications soon, said Dr. Dacso.
Calcium hydroxylapatite (CaHA)
CaHA (Radiesse®) is a well-known regenerative product that has been approved for volume replacement in the face and hands for more than 20 years. It also is used to treat rejuvenation and enhancement in off-facial applications.
After two treatments with Hyperdilute CaHA (1:4), 8 weeks apart.
“We have sophisticated studies demonstrating how CaHA stimulates fibroblasts to produce collagen I, collagen III, elastin, and proteoglycans that support the ECM,” Dr. Dacso said. “In vitro studies have shown that it promotes neocollagenesis, and clinical studies confirm these findings by showing improvements in skin thickness and skin quality.”
Dr. Dacso said CaHA is diluted (1:1 ratio) or hyperdiluted (≥1:2 ratio) to stimulate collagen rather than solely act as a dermal filler. Off-label, CaHA is used in off-facial locations to improve the elasticity and quality of the skin. She has seen especially impressive results using hyperdilute CaHA for neck rejuvenation.
PLLA-SCA vs. CaHA
‘Is one better than the other?’ is a frequently asked question, said Dr. Dacso, and the answer, in her opinion, is no. Both are first-rate products, and each serves an important role in regenerative medicine.
Figure 1. Dilution of CaHA to transform volume restoration into regeneration. Source: Casabona G, Plast Reconstr Surg Glob Open, 2017.
More recent research has examined gene expression of these two products and has shown differences in the expression of certain genes encoding wound healing, collagen production and inflammation in both PLLA-SCA and CaHA.
Adding more to your plate(let)
Additional biostimulatory products include platelet-rich plasma (PRP) and platelet-rich fibrin matrix (PRFM) which are derived from a person’s blood via centrifugation. These therapies harness and heighten the body’s natural growth factors and wound-healing properties. Dr. Dacso said these treatments have demonstrated increased collagen production and improved skin quality, although research is limited.
Adipose allograft matrix is another readily available class of biostimulator that consists of cadaveric adipose tissue. It preserves growth factors for use in adipogenesis and angiogenesis, said Dr. Dacso. Given the demand for more natural aesthetic outcomes, she expects its demand to grow due to the surge of antidiabetic and anti-obesity injectables, such as Ozempic, which can produce rapid fat and volume loss.
Although adverse events are rare, Dr. Dacso said it is important to understand and plan for undesirable outcomes like inflammatory nodules by using injectable corticosteroids and other treatments, such as fluorouracil (5-FU), as needed. As with any injectable product, clinicians need to have a thorough understanding of anatomy and proper injection technique to avoid vascular occlusion. They also need to properly screen patients prior to pursuing any treatment to confirm candidacy. People who are immunocompromised or take immunomodulators may not pass muster.
Forward progress
There is no shortage of regenerative products and modalities on the horizon, Dr. Dacso said. This includes a ready-to-inject biostimulator that is currently being developed and trialed as well as future indications for CaHA and PLLA-SCA that will expand the scope of body contouring and rejuvenation options for patients. Exosomal therapy is another buzzworthy development in the dermatologic field.
“Injectable biostimulators are powerful tools in the realm of anti-aging science, however some dermatologists may be hesitant to offer them,” she said. “There are some exciting ongoing and future clinical studies that will hopefully provide guidance to those who are interested in adding them to their practices.”
Indeed, Dr. Dacso said, the regulatory hurdles and shortage of defined protocols can be a deterrent. The most immediate next step is to obtain funding and approval for more randomized controlled trials that demonstrate long-term efficacy and safety to contribute proven outcomes and apply the science behind biostimulators that translates to optimal results. Additionally, she said comprehensive education for physicians and patients can only further the possibilities of regenerative aesthetics.
“We are at the tip of the iceberg in terms of understanding the molecular mechanisms with which these biostimulators function in vivo, and the structural benefits are likely far greater than we can currently detect,” Dr. Dacso said. “As more and more of our cosmetic patients request non-surgical, natural treatments to help them maintain their youthfulness through the years, who better to champion these regenerative therapies than dermatologists, who are the true skin experts?”