Cheryl Guttman Krader, BS, Pharm

The evolving field of regenerative aesthetic medicine (RAM) is likely to become a growing part of dermatology practice, according to William P. Werschler, MD, FAAD, FAACS.

“In recent years, the amount of knowledge, types of procedures, and uptake of RAM have all increased and done so rapidly as growing general awareness of RAM has led practitioners to learn more about these procedures and then to try them,” he noted in his presentation at Maui Derm Live. The in-person dermatology continuing medical education (CME) conference in Hawaii was held concurrently with Maui Derm Connect, a virtual CME conference, in January.

“Regenerative modalities will likely not replace our current rejuvenating procedures in most of our practice lifetimes, but I believe RAM will significantly impact what dermatologists do and how we do it within the next 5 years,” added Weschler, an assistant clinical professor at the University of Washington in Spokane, a founding member of Spokane Dermatology Clinic and Werschler Aesthetics, and a 

Werschler described RAM as a collection of disparate products, techniques, and procedures that have in common the use of autologous or allogenic biomaterials. As part of the portfolio of aesthetic medicine, RAM addresses patient demand for results that are more natural and longer lasting, he said.

“RAM represents the fifth column of aesthetic practice, after cosmetic surgery, energy devices, injectables, and medically directed skin care [cosmeceuticals],” Werschler said.

As it stands, RAM principally comprises procedures utilizing either platelet-rich plasma (PRP) and a host of related products or adipose-derived stem cells (ADSCs). However, exosomes are assuming a growing place in RAM, he noted. The leading areas in which RAM is being applied in dermatology include hair restoration, wound healing, scar reduction, and anti-aging/rejuvenation procedures for improving skin laxity, texture, and tone.

Werschler explained that understanding the various RAM modalities comes down to 3 key concepts: cell type, growth factors, and tissue matrix. For example, PRP and its derivatives provide an array of growth factors and signaling proteins that activate cells and stimulate cell differentiation, growth, proliferation, and migration within a fibrin matrix.

“PRP is the gateway to initiating the healing cascade, and it accommodates a variety of aesthetic needs,” Werschler said. “It’s like a dermal filler that’s turbocharged.”

There is no standard protocol for preparing PRP, but the main principle is to increase the concentration of platelets in a blood sample to between 2 and 5 times the normal physiological value. The final material is then delivered to tissue via microneedling, direct injection, or other open direct applications. The PRP sample is sometimes also mixed with another material such as a dermal filler that will act as a matrix to maintain the PRP at the site of delivery.

Stem cells used in RAM are predominantly mesenchymal stem cells derived from fat that communicate via paracrine mechanisms using exosomes, which are extracellular vesicles that act as messengers. In addition, the bulge in hair follicles is a rich source for epithelial and melanocytic stem cells.

The popularity of ADSCs is explained by their abundance in fat and by the relative ease with which fat can be obtained. Nevertheless, clinicians need to pay attention to the techniques used for fat harvesting, fat processing/sizing, and subsequent reinjection to generate the most optimal results.

“Variability in the performance of these steps probably explains the variability in results achieved,” Werschler said. “There is no single best way yet determined to perform ADSC therapy. Different practitioners have different techniques and subsequently different outcomes. Over time, there will be further standardization of techniques either through rigorous investigation and clinical trials or through mandated regulatory oversight.”

Werschler is a consultant or independent contractor for AbbVie, Suneva Medical, Inc, and Ultherapy. He receives grants or research support from Allergan, Amgen, Boehringer Ingelheim, DermAvance, Galderma, Genentech, Janssen Pharmaceutical Companies of Johnson & Johnson, Kythera Biopharmaceuticals, Pfizer Inc, Suneva Medical, Inc, and Ultherapy. He has received honoraria from AbbVie, Allergan, Celgene Corporation, continuED Medical LLC, Leo, Merz Therapeutics, Prescriber’s Choice, and Sunev. He is a speaker for AbbVie, Allergan, Celgene Corporation, Aclaris Therapeutics, Leo, Merz Therapeutics, Prescriber’s Choice, Pfizer Inc, Ultherapy, and Xoft.

Hot topic: regeneration will replace rejuvenation 2021-

 Presented at: Maui Derm Live In-Person Dermatology CME Conference and Maui Derm Connect Virtual Dermatology CME Conference; January 25-29, 2021; Maui, Hawaii; virtual. 

Articles

While regenerative medicine is still in its infancy, patient demand and ease of use are growing its popularity among aesthetic physicians. However, regulatory issues raise concerns.

Regenerative Medicine Gains Popularity

New treatment modalities and novel compounds are expanding the armamentarium for managing melasma and preventing relapse, said Pearl E Grimes, MD, in her update on this challenging skin disease at Maui Derm 2021.

’ editorial advisory board member, is the director of The Grimes Center for Medical and Aesthetic Dermatology, director of the Vitiligo and Pigmentation Institute of Southern California, and clinical professor of dermatology at the David Geffen School of Medicine at UCLA, all in Los Angeles.

Her presentation highlighted new solutions to optimize melasma management and identified cautions that could negatively impact outcomes.

Photoprotection from ultraviolet light has been a long-standing element in the melasma management algorithm. However, findings from recent studies indicating that visible light is also a trigger for the pathogenic pathway have spurred research showing the benefits of photoprotection strategies using iron oxide sunscreens that block visible light, Grimes noted.

“Using these modalities in our practice, we are seeing they have a significant positive impact in patients with melasma,” Grimes said. “Oral Polypodium leucotomos extract has also been investigated as a novel photoprotective agent in melasma. Recent data suggest that [it] also blocks visible light, and it has shown benefit as an adjunctive modality for melasma patients in several randomized studies.”

Current evidence from histological studies suggesting that melasma likely represents a phenotype of photodamage carries implications for long-term management, Grimes noted.

In addition to photoprotection, topical lighteners have a cornerstone role in managing melasma. Most lighteners used currently act via tyrosinase inhibition. Hydroquinone has been the major workhorse in this category for 60 years. However, new and emerging agents are showing substantially greater efficacy, according to Grimes.

Newer options for treating hyperpigmentation include cysteamine, methimazole, silymarin, tranexamic acid (TA), glutathione, melatonin, and new combination formulations. Most of these agents also inhibit tyrosinase activity, but some have different or multimodal mechanisms of action and have been used with varying routes of administration, Grimes said.

TA is one example. This antifibrinolytic agent suppresses angiogenesis, mast cells, and arachidonic release. It has been used orally, topically, and intralesionally with good results, she said. However, Grimes pointed out some concerns with TA—including an almost-universal risk for relapse after treatment is stopped and a risk for inducing thromboembolic phenomena.

“Although thromboembolic events are uncommon or rare in studies investigating TA for dermatologic conditions, patients should be screened for thromboembolic risk factors,” she advised.

Procedural interventions are strategic partners in the multimodality approach for melasma.

Chemical peels are part of the armamentarium for treating melasma as a second-line regimen, and superficial peels are preferred for treating melasma in darker-skinned patients.

“Findings from a meta-analysis showed that for patients with Fitzpatrick phototypes IV to VI, increasing the depth of the peel also increases the risk of more [adverse] effects or deleterious outcomes,” Grimes said.

Maximizing outcomes with peels requires a combination approach, in which a topical lightener is used for 2 to 4 weeks preceding the peel and between procedures, she said, adding that in her opinion, the daily regimen is key to achieving best-possible results.

Grimes pointed out that multiple recent studies also show that microneedling can have a role in melasma treatment when used in combination with a topical lightening agent. But there are certain caveats.

“In my experience, it is essential to have patients on a daily topical lightening agent when using microneedling. Without it, there is a significant risk for development of postinflammatory hyperpigmentation,” Grimes said.

Light-based treatments using lasers or intense pulsed light (IPL) sources may target deeper pigmentation along with a vascular component of melasma that is much more prominent than previously thought.

“Very tiny telangiectasia can often be seen when closely examining patches of melasma,” said Grimes. “Although these vessels were once considered a result of what patients had used for treatment, they are now known to be part of the melasma spectrum.”

Only fractional 1550/1540 nm nonablative lasers are approved by the FDA for treating melasma. However, treatment with a low-fluence Q-switched Nd:YAG laser may be the best option for refractory cases of melasma, according to Grimes. Excellent results can also be achieved using IPL sources in Fitzpatrick skin types II, III, and sometimes IV, she added.

However, because of the risk for significant complications, IPL should be used with extreme caution in darker-skinned patients. “The Q-switched ruby and erbium:YAG lasers are best avoided completely,” she said.

Despite the expanding number of therapeutic interventions, the fact remains that melasma is a chronic and therapeutically challenging disease for which there is no cure. Moreover, relapses are almost universal, said Grimes. Therefore, establishing realistic expectations for outcomes remains a critical aspect of the therapeutic consultation.

“Whereas we can cure postinflammatory hyperpigmentation of the face often caused by acne by treating the inciting condition, it is essential to articulate to patients with melasma that their pigmentary disorder requires long-term management,” Grimes said. “Meanwhile, we continue to have hope that the quest to find new therapies for this psychologically devastating condition will lead to options that are more durably efficacious.”

Grimes has conducted clinical research and/or served as a consultant for Procter & Gamble, Clinuvel Pharmaceuticals Ltd, L’Oréal, Johnson & Johnson, LaserOptek, VT Technologies, Incyte, Pfizer Inc, and DermaForce.

1. Grimes PE. Update 2021: disorders of pigmentation. Presented at: Maui Derm Live In-Person Dermatology CME Conference and Maui Derm Connect Virtual Dermatology CME Conference; January 25-29, 2021; Maui, Hawaii; virtual.

An array of agents for blocking visible light and lightening skin are joining the armamentarium to treat melasma. Despite this expanding number of therapeutic interventions, melasma is a chronic, therapeutically challenging disease for which there is no cure, so treatment plans should address both management of the disease and patient expectations.

Emerging Agents Augment Melasma Modalities

Regenerative aesthetic medicine (RAM) is becoming an increasing popular addition to dermatologists’ practices. Its evolving menu of procedures and applicability in addressing such key concerns as hair restoration, wound healing, scar reduction and anti-aging/rejuvenation address patient demand for natural-looking and longer lasting results.

Mastering the range of modalities is just part of the learning curve in maximizing RAM’s potential. Understanding and complying with relevant regulatory issues is also essential, William P. Weschler, MD, pointed out in his presentation on the topic at Maui Derm Live. The in-person dermatology continuing medical education (CME) conference in Hawaii was held concurrently with Maui Derm Connect, a virtual CME conference, in January.

 features his remarks and comments from an interview in an overview on regenerative medicine to be featured in its April 2021 edition.

Werschler, an assistant clinical professor at the University of Washington in Spokane, a founding member of Spokane Dermatology Clinic and Werschler Aesthetics, and a 

® editorial advisory board member, cautioned that the premise that, as an autologous procedure, RAM is not subject to FDA oversight is false.

The 21st Century Cures Act signed into law in 2016 addressed RAM. It was designed to accelerate medical product development and bring new innovations and advances to patients who need them faster and more efficiently, and it gave the FDA statutory authority over aspects of RAM by establishing the Regenerative Medicine Advance Therapy program.

But that is just one of the regulatory issues to consider. “RAM procedures and materials do not undergo the traditional process of FDA review and approval as do the drugs, biologics, and devices that we use,” said Werschler. “However, there are FDA guidelines that create guardrails around the conduct of regenerative medicine. Anyone who is using platelet rich plasma (PRP) or stem cells should be fully aware of these rules so that they do not run afoul of the FDA.”

The equipment used in the preparation and administration of the materials—such as the centrifuges used to prepare PRP or the needles, tubing, and syringes used for injection, etc—are FDA-cleared devices, usually class 1 or 2. To date, the FDA has not officially “approved” the autologous use of ADSC or PRP as a medical procedure.

Additionally, under the Public Health Service Act (PHSA) section 361, the FDA has the authority to regulate procedures that may spread communicable diseases. This is intended to minimize infectious disease risks associated with the use of human cells, tissues, and cell- and tissue-based products (HCT/P). Section 361 applies to regenerative aesthetics when the HCT/P is “minimally manipulated and for homologous use only and does not involve the combination of the cells or tissues with another article except for water.”

Section 351of the PHSA is of particular interest to dermatologists who want to offer RAM because it gives the FDA oversight on the use of any HCT/P that are more than minimally manipulated. Essentially, if the regenerative technique does not meet the criteria of section 361, it falls under section 351, which requires a biologics license application.

“When these autologous products are manipulated beyond their original structure and function, they move from just beyond FDA purview to essentially a clinical investigation with institutional review board [IRB] oversight,” Werschler explained. “Physicians are not prohibited from using these techniques, but those who wish to do so must first describe their intent by submitting a study protocol and obtaining IRB approval for the study before they proceed.

“That’s how we learn, through the scientific method,” Werschler said.

William P. Weschler, MD, offers tips on understanding and complying with regulations governing regenerative medicine. 

Regulatory Issues in Regenerative Medicine

The so-called feel-good hormone may also have benefits for the skin. In results of a pilot study, high oxytocin (OT) levels correlated with more youthful-looking skin, as measured by skin age score (SAS).

“This research links previous findings on the neuropeptide hormone’s role in preventing the release of certain proinflammatory cytokines, which may lead to skin aging, with clinical evidence of OT levels’ effect on skin’s appearance. Together, the clinical and preclinical evidence identify the OT signaling pathway as a potential target for strategies to protect against photoaging and, possibly, intrinsic aging of the skin,” according to Nicole Hayre, MD.

Hayre, graduate of Massachusetts Institute of Technology, and founder of Cosmetic Dermatology Center in McLean, Virginia, undertook the pilot study based on clinical observations of skin appearance. “I have been impressed that people who are in love generally look fantastic and seem to have a glow to their skin that is absent in people who are going through divorce or suffered the death of a spouse,” she told 

 “Granted, a person’s mood and whether they are caring for themselves are important contributors to appearance, but I was curious about whether there was some biochemical explanation.”

The observation that factors such as social bonding, mental state, and enjoyment of intimacy in personal relationships differentiate the 2 cohorts turned Hayre’s attention to OT—also called the “love hormone.”

“Searching the literature, I found several basic science studies on oxytocin and the skin.

 The research showed that both oxytocin and its carrier protein are synthesized in keratinocytes,” she said. “In addition, there was evidence that fibroblasts express an OT receptor and that binding of OT to this receptor suppresses a senescence-associated secretory phenotype composed of an array of proinflammatory cytokines, chemokines, extracellular matrix-remodeling proteases, and growth factors.”

To explore the relationship between OT levels and skin aging, Hayre designed a clinical pilot study. Participants included 6 women aged 48 to 61 years with Fitzpatrick skin types II to IV. Individuals were excluded if they had undergone cosmetic procedures/treatments in the previous 6 months, were using topical anti-aging products, or were on hormone supplements. All participants had an average body mass index and were nonsmokers.

Each woman provided a 24-hour urine sample for OT measurement and completed a questionnaire on sunscreen use and ultraviolet light (sun/tanning) exposure. Hayre used data from each participant’s history to calculate sun exposure score (possible range, 1 [least] to 7 [greatest]). Using photographs taken with a medical imaging camera and software system (Canfield Scientific, Parsippany, NJ), she used the images to grade facial skin aging for each subject and calculate their SAS. From that value and the expected SAS score, which correlates with chronological age, she calculated an estimated percent change of SAS, she said. (

Sun exposure scores for the 6 participants ranged from 1 to 7, OT levels ranged from 86 to 306 pmol/L per 24 hours, and actual SAS scores ranged from 23 to 53. The results for estimated percent change of SAS showed that the actual score for all participants was lower (more youthful) than expected. A plot of each woman’s OT level against the percent change showed an inverse, almost linear relationship between the 2 variables—the higher the OT level, the greater the percent change in SAS.

“It was interesting to find that several patients with high OT levels had SAS that correlated with more youthful skin in spite of high sun exposure scores, whereas others with lower OT levels and minimal sun exposure had higher SAS scores,” Hayre says. “This evidence connects clinical findings with previously published benchwork research showing that OT binding to receptors in fibroblasts can halt skin degradation by inhibiting SASP.”

Hayre would like to expand the pilot study and further explore the OT’s potential importance in the skin. She is now working with a pharmaceutical company to evaluate a safe, nonhormonal, botanical that appears to have an OT-like effect on the skin.

In the meantime, it may be possible to take advantage of OT’s potential benefits by encouraging certain behaviors, she said. “For skin health, dermatologists tell patients to wear sunblock, use appropriate skin care products, and avoid smoking,” Hayre said. “Perhaps our counseling should also include advice about making time for love and affection. Research shows that aside from intimacy and hugging partners, family, and friends, snuggling a pet and even caressing the skin can release OT.”

“Higher OT levels protecting the skin and making subjects appear healthier and more youthful likely promotes further social interaction. This OT Social Exchange System appears to work as a positive feedback loop which I speculated likely affects more than just the skin.” Hayre adds that this theory intrigued her to search the literature for information on other biological effects of OT. “I found preliminary research involving every system in the body and how it is positively affected by OT,” she says. “We have always known that love and affection improve mental and emotional well-being, but I am amazed that after centuries of medicine we are just learning about the importance of our social interactions on physical health.”

“To me, all of this is evidence that we really do need to take time out every day from our busy modern lives to enjoy one another’s company,” adds Hayre. “It is essential to our good health.”

The author reports no relevant disclosures or financial interests.

1. Hayre N. Oxytocin levels inversely correlate with skin age score and solar dam- age. 

. 2020;19(12):1146-1148. doi:10.36849/JDD.2020.5063

2. Denda S, Takei K, Kumamoto J, et al. Oxytocin is expressed in epidermal keratino- cytes and released upon stimulation with adenosine 5’-[γ-thio] triphosphate in vitro. 

3. Deing V, Roggenkamp D, Kühnl J, et al. Oxytocin modulates proliferation and stress responses of human skin cells: implications for atopic dermatitis. 

4. Lotti T, Hautmann G, Panconesi E. Neuropeptides in skin. 

Patients with high oxytocin levels had significantly lower (more youthful-looking) skin age scores than expected, even with strong histories of lifetime sun exposure, according to a recent study.