Biological Aging Modulation: Mechanisms, Interventions, and Therapeutic Perspectives

The skin of color (SOC) population in the United States continues to grow, and these patients are undergoing various cosmetic and surgical procedures at increasing rates. There is a paucity of data on the potential complications associated with surgical and cosmetic procedures in this patient population. We aim to educate dermatologic surgeons and clinicians on surgical and cosmetic procedures in patients of color and increase awareness of the potential complications unique to this patient population. A thorough PubMed literature search was performed to conduct this review. There are a number of complications in SOC that require special attention, including keloids, postoperative infections, postinflammatory hyperpigmentation, and hypopigmentation. There are also various precautions to consider when performing cosmetic procedures, such as neurotoxin and filler injections, laser therapy, microneedling, and chemical peels. Dermatologists should be aware of the potential cosmetic and surgical complications of this growing patient population to provide optimal evidence-based medical care.

The occurrence of subacute thyroiditis (SAT) after vaccines or after hyaluronic acid skin fillers is very rare and might be related to genetic susceptibility. We suggest that the co-administration of both products could potentially increase the possibility of development of SAT. A 58-year-old Caucasian healthy female initially presented with chills, myalgia, dysphagia, sore throat, dry cough, fatigue, and intermittent fever of 38.5°C orally after simultaneous injection of an influenza vaccine and a dermal filler containing hyaluronic acid. Ten days later the patient developed palpitations and neck pain radiating to the left jaw. She was diagnosed with SAT on day 16 after her first visit and responded promptly to etoricoxib treatment. The patient progressed clinically from hyperthyroidism to euthyroid state and eventually to hypothyroidism and further testing showed she had HLA B-35 haplotype. Physicians should be aware that SAT might be associated with the administration an influenza vaccine and this possible association might increase if the vaccine was co-administered with a dermal filler.

Introduction: Cosmetic procedures have been growing recently among men and women. Cosmetics procedures refer to both surgical and non-surgical procedures. For example, rhinoplasty (nose surgery), surgical face-lifts, abdominoplasty (tummy tuck), and liposuction, etc. referred to surgical procedures. In contrast, procedures such as chemical peels, filler, and botulinum toxin injections, laser skin resurfacing, vein removal, and laser hair removal are collectively referred to as non-surgical procedures. In recent years cosmetics surgeries have decreased while people have moved towards non-invasive cosmetic procedures. Objective: Knowledge, Attitude, and Practice of Cosmetic procedure among the population of Al-Majmaah, Saudi Arabia, 2019-2020. Methodology: This is an observational cross-sectional study targeted Al- Majma’ah population. Half of the participants were asked to complete an electronic questionnaire and the remaining completed a paper-based questionnaire. The questionnaire was divided into four parts: Socio-Demographic Data, Knowledge, Attitude, and Practice of cosmetic procedures. Data were analyzed by using SPSS v.25. In addition, Pearson Chi-square tests applied to determine associations between qualitative variables. Results: Most of the participants were aged between 18-25 years. The majority were female. All of them have heard about cosmetic procedures. Social media was the most common source of information. More than half of the participants recognized different types of cosmetic procedures. More than two-thirds of them believed low self-esteem affects decisions about cosmetic procedures. Only 146 reported undergoing cosmetic procedures, where most of them underwent liposuction and hair removal. Personal desire was the primary source of motivation.,Whereas self satisfaction was the commonest cause for not considering such procedures. 244 of the participants reported their relatives had undergone cosmetic procedures Conclusion: Most of the participants had poor to moderate levels of knowledge regarding Cosmetic procedures. Most of the participants had a positive attitude regarding such a procedure. The prevalence of cosmetic procedures is somewhat uncommon as about one-third of the participants underwent surgical and non-surgical procedures. Keywords: Cosmetic Procedures, Knowledge, Attitudes, Practice, Majmaah, Saudi Arabia

Event Abstract Back to Event Hyaluronic acid hydrogels cross-linked by polyethylene glycol diglycidyl ether (PEGDE) for long-lasting dermal filler applications Ho-Yong Lee1*, Seol-Ha Jeong1, Jae-Uk Baek1, Ju-Ha Song1 and Hyoun-Ee Kim1 1 Seoul national university, Materials science and engineering, Korea Statement of Purpose: Dermal fillers have been widely used for cosmetic applications such as wrinkle management and plastic surgery. Hyaluronic acid (HA) has been regarded as the best candidate for dermal fillers due to its non-immunogenicity and biodegradability[1]. HA for commercial dermal fillers is often chemically cross-linked by 1,4-butanediol diglycidyl ether (BDDE) for enhanced mechanical properties and biostability[2]. However, BDDE-crosslinked HA fillers is known to lose their mechanical integrity within 6 months in vivo by enzymatic degradation[3]. Therefore, in this study, we have incorporated polyethylene glycol diglycidyl ether (PEGDE) into HA hydrogels as a chemical cross-linker to further enhance mechanical and biological stability as compare to BDDE. Moreover, we investigate in vitro and in vivo biological behavior of PEGDE-crosslinked HA fillers. Methods: HA hydrogels were cross-linked using PEGDE (Mn = 2000 Da) or BDDE. 20 wt. % HA solution was prepared by dissolving 0.1 g HA (Mn = 2.2 MDa) in 0.5 mL 0.3 N NaOH aqueous solution. 5 µL BDDE was added to the HA solution. Likewise, the molar equivalent amount (0.15 mol crosslinker/ 1 mol HA) of PEGDE to BDDE was added to the HA solution. The reactions were performed at 25 oC for 24 h. Rheology measurement was carried out using parallel plate rheometer. Swelling test was performed with fully swollen samples in PBS at 37 ºC. In vitro degradation was performed in Hyaluronidase/PBS (100 U/ml) solution. In vitro cell test was performed by culturing L929 fibroblasts on the gel surface. Results: Rheological behavior of cross-linked HA hydrogels by BDDE and PEGDE were shown in Fig. 1a. The storage modulus of PEGDE-cross-linked HA hydrogel was higher than that of BDDE-crosslinked HA hydrogel, meaning higher elasticity in PEGDE-cross-linked HA hydrogel. Swelling behavior was inversely correlated to storage modulus (Fig. 1b). Degradation stability by hyaluronidase was evaluated by volumetric and shape change, showing PEGDE-cross-linked HA hydrogel is more resistant to degradation than BDDE-cross-linked HA hydrogel (Fig. 2). Between time intervals, the hydrogels maintained their initial shape. Cell spreading was observed for both gels (Fig. 3). On PEGDE-cross-linked HA hydrogel, fibroblasts spread well almost “spindle-like” phenotype, whereas “spherical” shape on BDDE-cross-linked HA hydrogel, implying cell-matrix interaction is higher on PEGDE-cross-linked HA hydrogel surface. Conclusions: PEGDE-cross-linked HA hydrogel was fabricated with more efficient cross-linking effect as compared to BDDE-cross-linked HA hydrogel. Higher elasticity and biostability can be obtained by using PEGDE rather than BDDE. Moreover, the hydrogel can controllable in mechanical properties and degradability by the amount of cross-linker with minimally modified. Exploiting great biocompatibility of PEG/HA hydrogel can be a good candidate for long-lasting dermal filler applications. Small and Medium Business Administration, Republic of Korea (S2174750)

Amyloid β and Tumorigenesis: Amyloid β-Induced Telomere Dysfunction in Tumor Cells

Primary care physician (PCP) perceptions regarding expertise in cutaneous surgery and cosmetic procedures are unknown. An internet-based survey was administered to physicians in primary care medicine residency programs in the United States. Respondents were asked to select the specialist most qualified to perform different cutaneous cosmetic and surgical procedures. Five hundred sixty-one PCPs undertook the survey. Dermatologists were identified as the most qualified specialist to evaluate and biopsy worrisome lesions on the face (95%), perform skin cancer surgery (56%), inject botulinum toxin (61%), inject fillers (55%), and perform laser procedures (75%). Seventy percent of respondents correctly defined Mohs micrographic surgery (MMS), and 60% of respondents selected a fellowship-trained dermatologist as the best physician to perform MMS. U.S. medical school graduates were more likely than foreign medical school graduates to select a Mohs fellowship-trained dermatologist as the most qualified physician to perform MMS (adjusted odds ratio (AOR)=1.52, 95% confidence interval (CI)=1.05-2.21). PCPs without exposure to dermatology in medical school were about half as likely those with exposure to correctly define MMS (AOR=0.51, 95% CI=0.30-0.89). Dermatologists are recognized as the most qualified specialist to perform a variety of cutaneous cosmetic and surgical procedures, including skin cancer surgery, botulinum toxin injections, filler injections, and laser procedures. Mohs fellowship-trained dermatologists were viewed as more qualified to perform MMS than other dermatologists, plastic surgeons, otolaryngologists, or ophthalmologists.

We present the first reported cases of delayed inflammatory reactions (DIR) to hyaluronic acid (HA) dermal fillers after exposure to the COVID-19 spike protein. DIR to HA is reported to occur in the different scenarios including: secondary to poor injection technique, following dental cleaning procedures, following bacterial/viral illness, and after vaccination. In this report of 4 cases with distinct clinical histories and presentations: one case occured following a community acquired COVID-19 infection, one case occured in a study subject in the mRNA-1273 clinical phase III trial, one case occurred following the first dose of publically available mRNA-1273 vaccine (Moderna, Cambridge MA), and the last case occurred after the second dose of BNT162b2 vaccine (Pfizer, New York, NY). Injectable HA dermal fillers are prevalent in aesthetic medicine for facial rejuvenation. Structural modifications in the crosslinking of HA fillers have enhanced the products’ resistance to enzymatic breakdown and thus increased injected product longevity, however, have also led to a rise in DIR. Previous, DIR to HA dermal fillers can present clinically as edema with symptomatic and inflammatory erythematous papules and nodules. The mechanism of action for the delayed reaction to HA fillers is unknown and is likely to be multifactorial in nature. A potential mechanism of DIR to HA fillers in COVID-19 related cases is binding and blockade of angiotensin 2 converting enzyme receptors (ACE2), which are targeted by the SARS-CoV-2 virus spike protein to gain entry into the cell. Spike protein interaction with dermal ACE2 receptors favors a pro-inflammatory, loco-regional TH1 cascade, promoting a CD8+T cell mediated reaction to incipient granulomas, which previously formed around residual HA particles. Management to suppress the inflammatory response in the native COVID-19 case required high-dose corticosteroids (CS) to suppress inflammatory pathways, with concurrent ACE2 upregulation, along with high-dose intralesional hyaluronidase to dissolve the inciting HA filler. With regards to the two vaccine related cases; in the mRNA-1273 case, a low dose angiotensin converting enzyme inhibitor (ACE-I) was utilized for treatment, to reduce pro-inflammatory Angiotensin II. Whereas, in the BNT162b2 case the filler reaction was suppressed with oral corticosteroids. Regarding final disposition of the cases; the vaccine-related cases returned to baseline appearance within 3 days, whereas the native COVID-19 case continued to have migratory, evanescent, periorbital edema for weeks which ultimately subsided.

Background: Hyaluronic acid (HA) formulations are used for aesthetic applications. Different cross-linking technologies result in HA dermal fillers with specific characteristic visco-elastic properties. Objective: Bio-integration of three CE-marked HA dermal fillers, a cohesive (monophasic) polydensified, a cohesive (monophasic) monodensified and a non-cohesive (biphasic) filler, was analysed with a follow-up of 114 days after injection. Our aim was to study the tolerability and inflammatory response of these fillers, their patterns of distribution in the dermis, and influence on tissue integrity. Methods: Three HA formulations were injected intradermally into the iliac crest region in 15 subjects. Tissue samples were analysed after 8 and 114 days by histology and immunohistochemistry, and visualized using optical and transmission electron microscopy. Results: Histological results demonstrated that the tested HA fillers showed specific characteristic bio-integration patterns in the reticular dermis. Observations under the optical and electron microscopes revealed morphological conservation of cutaneous structures. Immunohistochemical results confirmed absence of inflammation, immune response and granuloma. Conclusion: The three tested dermal fillers show an excellent tolerability and preservation of the dermal cells and matrix components. Their tissue integration was dependent on their visco-elastic properties. The cohesive polydensified filler showed the most homogeneous integration with an optimal spreading within the reticular dermis, which is achieved by filling even the smallest spaces between collagen bundles and elastin fibrils, while preserving the structural integrity of the latter. Absence of adverse reactions confirms safety of the tested HA dermal fillers.

Safety of cosmetic procedures in pregnant women has not been extensively studied. Maternal and fetal health risks are important to consider in any procedure performed. With the increasing popularity of cosmetic procedures, dermatologic surgeons will be faced with scenarios necessitating knowledge regarding the safety of such procedures during pregnancy. Furthermore, dermatologic surgeons may inadvertently perform cosmetic procedures during the first trimester, before the patient is aware of the pregnancy. To investigate the safety of cosmetic procedures during pregnancy and the postpartum period. A literature search of PubMed and Google Scholar was conducted of all English-language articles published from 1960 through 2012. Definitive recommendations on the safety of procedures such as chemical peels, injectables, fillers, and most laser therapies during pregnancy cannot be made. The safety of onabotulinum toxin usage is well documented in the neurology literature, although isolated events of miscarriage have been reported with high doses of toxin in women with a previous history of miscarriage. Carbon dioxide laser therapy for genital condylomas has considerable evidence supporting its safety during pregnancy. There is a lack of controlled trials addressing the safety of cosmetic procedures during pregnancy and postpartum periods. It is advisable to delay elective cosmetic procedures until after the baby is born.

Biophysical and biochemical data on hyaluronan (HA)-based dermal fillers strongly support their optimal use and design to meet specific requisites. Here, four commercially available (in Europe) HA “volumetric” fillers, among the most used in the clinical practice, have been characterized in vitro. Analyses revealed the highest amounts of water-soluble HA reported so far and provided hydrodynamic data for these soluble polymeric fractions. Volumetric gels exhibit a wide range of rigidity with most of them showing G’ values around 200-300Pa. They greatly differ in cohesivity. 1mL of gel hydrates up to 2.4–3.2mL. The products completely solubilize due to Bovine Testicular Hyaluronidase (BTH)’s action, thus predicting in vivo complete resorption. For the first time, filler degradation due to reactive oxygen species (ROS) was studied by rheological measurements and a rank in stability was established. Studies using Human Dermal Fibroblasts (HDF) indicated a positive biological response to the HA networks. Further, gel capacity to prompt collagen I, elastin and aquaporin3 synthesis was demonstrated, thus suggesting a positive effect on skin elasticity and hydration, besides the physical volumetric action. The findings are the first wide assessment of features for the volumetric class of HA-fillers and include first data on their resistance to degradation by ROS and biological effects on HDF. The study represents a valuable contribution to the understanding of HA-fillers, useful to optimize their use and manufacture.

Individuals with skin of color are underrepresented in studies of lip and perioral enhancement. To examine the effectiveness and safety of hyaluronic acid (HA) dermal filler treatment for lip and perioral enhancement in subjects with skin of color. Data were pooled from subjects with Fitzpatrick skin phototypes IV, V, or VI in 2 pivotal studies of HA dermal fillers. Photonumeric scales were used to assess lip fullness (5-point scale) and perioral lines and oral commissures severity (each 4-point scales). Safety was assessed by injection site responses recorded in patient diaries and adverse events (AEs). The cohort comprised 72 subjects (median age: 49.5 years; 95.8% female). Mean lip fullness improved from baseline by 1.1 points at 3 months after treatment; 85.0% of subjects were responders (≥1-point improvement). Of subjects treated for perioral lines (n = 12) and oral commissures (n = 56), 90.9% and 46.4%, respectively, were responders. Injection site responses were generally mild or moderate in severity, resolved within 2 weeks, and were consistent with those expected for HA dermal filler treatment. The most common AEs were injection site mass (19.4%) and bruising (12.5%). Lip and perioral enhancement with HA dermal fillers is effective and safe in subjects with skin of color.

INTRODUCTION: Dermal fillers are effective for temporary volume augmentation, especially for deep features like NLFs. This is due to volume expansion, with relatively little precision in placement. Neurotoxins are effective at treating rhytids, but can have undesirable effects on facial expression. Available fillers and neurotoxins are not always optimal for treating fine or long, linear wrinkles, such as necklace lines, transverse forehead wrinkles, and lip contouring. To address these clinical needs, a novel hyaluronic acid (HA) product has been developed which is comprised of a dehydrated, solid HA thread attached to a 27 gauge straight needle. The HA thread is implanted by being pulled into position by the needle, whereupon the thread hydrates and slowly reverts back to a gel. METHODS: A first-in-human prospective multi-center study was conducted in Canada. The primary endpoint was safety, and the secondary endpoints were aesthetic result as assessed by the Investigator, Independent Reviewer, and subject. Photographic documentation was captured by CanfieldScientific. NLFs were rated by a Wrinkle Severity Scale and any other area was rated by a Global Aesthetic Improvement Scale. Subjects received bilateral treatment in one area; NLF, forehead, perioral (including vermillion boarder), necklace lines or crow’s feet. One retreatment was allowed at the 2-week follow-up. Follow-ups were at 1, 3 and 6 months. RESULTS: 72 patients were enrolled and completed this study. At least 10 were enrolled in each of the 5 treatment areas. There were no severe or unanticipated adverse events. Overall, the adverse event rates were comparable or better than published rates for HA dermal fillers. Almost all subjects demonstrated improved aesthetic outcomes despite conservative implantation methods initially. Many subjects demonstrated aesthetic improvement between the 1 and 3month follow-ups. CONCLUSION: The results from this clinical study demonstrate that HA threads are safe, and can be effective in treating difficult areas such as necklace lines, horizontal forehead lines, vermillion boarders, as well as more common areas such as NLFs and crow’s feet. The product lends itself well to features that are linear in nature, whether fine or deep. HA threads are a highly novel, differentiated product that complements injectable fillers and neurotoxins for minimally invasive facial rejuvenation.

Hyaluronan is known to act as a filling material of extracellular matrices and as an adhesive substrate for cellular migration. Consequently, it is widely used in aesthetic medicine and surgery, and it would be expected to be used in nanomedicine. Previous clinical case reports associated hyaluronic acid implants to delayed immune-mediated adverse effects. A series of experiments to evaluate immune cell activation supported by this dermal filler and nanomedical biomaterial were performed. The study comprised a total of 12 individuals. Four healthy individuals, none with cosmetically injected dermal filler, were considered as control. Five individuals carried injections of hyaluronic acid dermal filler. Three individuals carried injections of hyaluronic acid dermal filler and presented delayed adverse effects related to the dermal filler. Hyaluronic acid-stimulated peripheral blood mononuclear cells (PBMC) produced low levels of pro-inflammatory cytokines. Phytohemagglutinine (PHA)-stimulated PBMC from patients with hyaluronic implants presenting adverse effects showed a slight increase in the production of interferon (IFN)-gamma and higher expression of CD25, CD69, or CD71. In conclusion, hyaluronic acid administration elicited a laboratory evidence of immune cell activation. Production of low levels of proinflammatory cytokines in vitro could be an observation for low-grade inflammation in vivo resulting in T cell activation.

A novel, biocompatible, and nontoxic dermal filler using hyaluronic acid (HA) hydrogels was successfully developed for tissue augmentation applications. Instead of using highly reactive cross-linkers such as divinyl sulfone (DVS) for Hylaform, 1,4-butanediol diglycidyl ether (BDDE) for Restylane, and 1,2,7,8-diepoxyoctane (DEO) for Puragen, HA hydrogels were prepared by direct amide bond formation between the carboxyl groups of HA and hexamethylenediamine (HMDA) with an optimized carboxyl group modification for effective tissue augmentation. The HA-HMDA hydrogels could be prepared within 5 min by the addition of HMDA to HA solution activated with 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC) and 1-hydroxybenzotriazole monohydrate (HOBt). Five kinds of samples, a normal control, a negative control, a positive control of Restylane, adipic acid dihydrazide grafted HA (HA-ADH) hydrogels, and HA-HMDA hydrogels, were subcutaneously injected to wrinkled model mice. According to the image analysis on dorsal skin augmentation, the HA-HMDA hydrogels exhibited the best tissue augmentation effect being stable longer than 3 months. Furthermore, histological analyses after hematoxylin-eosin (H&E) and Masson's trichrome staining revealed the excellent biocompatibility and safety of HA-HMDA hydrogels. The dermal thickness and the dermal collagen density in wrinkled mice after treatment with HA-HMDA hydrogels for 12 weeks were comparable to those of normal mice. Compared with HA-DVS hydrogels and Restylane, the excellent tissue augmentation by HA-HMDA hydrogels might be ascribed to the biocompatible residues of amine groups in the cross-linker of HMDA. The HA-HMDA hydrogels will be investigated further as a novel dermal filler for clinical applications.

The new 20 mg/mL hyaluronic acid (HA) dermal filler is a smooth, highly cohesive, viscous formulation developed to restore volume in aesthetic facial rejuvenation. OBJECTIVE Evaluate clinical experience with 20 mg/mL HA dermal filler to date and comment on its current and potential uses within the facial rejuvenation treatment paradigm. In this paper, the authors review the unique physical and chemical properties of 20 mg/mL HA dermal filler as well as clinical experience with the product to date. Overall, the 20 mg/mL smooth, cohesive, viscous HA filler was especially effective in restoring volume in the malar region and chin. Volume loss resolved significantly in patients in clinical trials(1) and treatment effects were observed to be maintained from six to 18 months.(2) Physicians reported the agent was highly effective as well as easy to inject, sculpt and mold. The treatment was generally well tolerated and no instances of product migration from the injection site have been reported. Patient satisfaction was high, with the vast majority of trial participants acknowledging they would return for additional treatment and recommend the treatment to friends.(1,2) Initial experience shows the 20 mg/mL smooth, cohesive, viscous HA filler to be a useful addition to the facial rejuvenation armamentarium when used both alone and in combination with BTX-A.