Author: MJ Yuan

With the popularization of anti-aging treatments, for some people simple cosmetic modification is not sufficient. There is a growing preference for more permanent aesthetic medicine methods.

Frost & Sullivan data show that China has become the world’s second largest aesthetic medicine market in 2017. In 2018, the number of aesthetic medicine treatments surpassed the US, bringing China to first place [1].

Among them, non-surgical cosmetics such as injections and fillers have become popular due to their low risk and low price. According to the New Oxygen 2019 white paper, the current proportion of injection-based aesthetic medicine represents 57% of China’s total consumption. Among them, botulinum toxin and hyaluronic acid the two most commonly used for aesthetic injections [2].

Hyaluronic acid

Background

According to ISAPS data, in 2017, there were 8.572 million injection-based aesthetic medicine projects worldwide, of which 3.298 million used hyaluronic acid. Hyaluronic acid is also called hyaluronan. In 1934, biochemists Karl Meyer, a professor at Colombia University, and John Palmer first separated it from the vitreous body of a bull’s eye. Hyaluronic acid is also a natural filler widely present in the skin of the human body, which maintains the skin’s elasticity and moisture by binding water.

Current research has found that hyaluronic acid has more than ten applications used in the aesthetic medical industry.

In a clinical trial, 80 subjects were divided into three groups and received different types of hyaluronic acid injections to treat nasolabial folds, commonly known as “laugh lines”. The research results show that all three types of hyaluronic acid injection used in the trial lessened the nasolabial folds’ depth. Furthermore, about 78-90% of the subjects could maintain the improvements gained from repeated injections to the nasolabial folds for about 1 year [3].

▲ After repeated injections of hyaluronic acid, the improvements were present for about a year (Source: Smith et al.)

In another comparison test between hyaluronic acid and other commonly used injections, the anti-wrinkle and anti-scarring ability of hyaluronic acid injection is stronger than that of gelatin matrix and polytetrafluoroethylene. Meanwhile, its effect is equivalent to that of collagen injections, but the use of hyaluronic acid is simpler than collagen and does not require skin testing [4].

Hyaluronic acid is also known to stimulate the regeneration of collagen by promoting the stretching of dermal fibroblasts.

▲ The injection of hyaluronic acid (blue in the picture) activates fibroblasts (yellow), thereby stimulating the regeneration of collagen (red). (Image source: Wang et al.)

Cross-linking agents and hyaluronic acid

Natural hyaluronic acid has a linear structure: there is no intersection between the molecular chains. This kind of hyaluronic acid is easily metabolized and cannot provide shaping and wrinkle removal effects. Therefore, the linear molecules must be connected through a cross-linking agent to enhance its hardness and stability. However, the cross-linking agent is an organic solvent. When it is not combined with hyaluronic acid molecules, it has a strong toxicity.

▲ Linear hyaluronic acid molecules are bound by a cross-linking agent (Source: fosyderm）

Cross-linking agents are to be considered as a double-edged sword. The use of cross-linking agents can elongate the effect of hyaluronic acid, but at the same time increases the risk of adverse reactions.

Therefore, excellent cross-linking technology is at the core of the hyaluronic acid industry. Generally speaking, the main difference between high-end brands and low-end brands is that the crosslinking agent in the higher-end product is safer and more reliable.

The latest hyaluronic acid products worldwide

• Hyaluronic acid-microneedle injection without syringe

The injection of hyaluronic acid is inevitably accompanied by pain and the risk of infection. Its safety also depends on the technical level of the physician. In recent years, the development of hyaluronic acid microneedles has allowed people to “inject” hyaluronic acid themselves without going to the hospital. This approach avoids the fear of syringe injections and also reduces the risk of poorly skilled physicians. Through the small holes left by the microneedles in the epidermal stratum corneum, hyaluronic acid can effectively enter the deep layers of the skin. The effect lasts longer than creams and masks. One company that uses microneedles is the German company Dermaroller.

▲ Hyaluronic acid microneedle

• Juvéderm Vycross series

The Juvéderm Vycross series produced by the American company Allergan uses a patented cross-linking process called Vycross to combine hyaluronic acid molecules of different molecular sizes. This combination not only balances the elasticity of the gel but also improves cohesion; it is easy to shape after injection.

Vycross technology can also reduce inflammation and have a longer service life. In a clinical trial of 270 subjects, more than 75% of the subjects were able to maintain the effect for more than 2 years after receiving the Vycross series of hyaluronic acid injections. The Vycross series is also the only hyaluronic acid approved by the FDA for deep cheek injection [5].

• The combination of hyaluronic acid and polynucleotide (HA-PN)

The purified polynucleotide (PN) extracted from the germ cells of salmon and other fish is a new type of filler material, which has the advantages of increasing skin elasticity and promoting collagen synthesis. The latest test proves that compared with pure hyaluronic acid (HA), the mixture of hyaluronic acid (HA) and PN (HA-PN) can better promote the migration of fibroblasts, increase collagen synthesis and skin elasticity, and accelerate wound healing. The addition of polynucleotide is expected to further improve the all-round performance of hyaluronic acid. 【6】

• HAYMAR

Haohai Biological is a domestic Chinese company with single-phase cross-linking technology. In August 2020, Haohai officially released its new high-end hyaluronic acid product “HAYMAR”. This product adopts a new non-particulate cross-linked hyaluronic acid gel preparation method, which belongs to the fifth-generation cross-linking technology.

The hyaluronic acid prepared this way has a non-granular structure and is not easy to deform and shift after injection. It can also slow down the biodegradation of hyaluronic acid and prolong the effects. At the same time, the non-particulate structure can prevent biofilm production, thereby reducing the immune response and improving product safety.

Botox: Rejuvenation surgery or the initiator of facial paralysis?

Background

The full name of botox is botulinum toxin, which is a type of neurotropic exotoxin produced by the bacterium botulinum growing under anaerobic conditions. It causes flaccid muscle paralysis by inhibiting the release of acetylcholine at the neuromuscular junction. At the cellular level, botulinum toxin inhibits the fusion of vesicles and the release of acetylcholine by cutting the synaptic fusion protein SNAP-25.

Botulinum toxin is currently the most toxic biological toxin known. But small doses of it can be used to treat various diseases including strabismus, cervical dystonia, migraines, hyperhidrosis and muscle cramps. After being approved by the FDA in 2002 for cosmetics, it has gradually become highly used within the aesthetic medicine field.

What is the difference between botulinum toxin and hyaluronic acid?

Hyaluronic acid injection is mainly used to “pull up” wrinkles by filling them while botulinum toxin paralyzes nerve endings so that it cannot affect the corresponding muscles. In other words, it brings upon “facial paralysis”.

Therefore, botulinum toxin is very effective for wrinkles caused by facial muscle activity, such as forehead wrinkles and crow’s feet. For wrinkles caused by gravity and loose skin, such as nasolabial folds, it has little effect.

▲ People with more dynamic wrinkles and fewer static wrinkles are the most suitable to use botulinum toxin for wrinkle removal (left); people with obvious static wrinkles are not suitable to use botulinum toxin to remove wrinkles (right) (Source: REBECCA SMALL, MD)

The advantage of botulinum toxin injections is that it takes effect quickly. Generally, there’s a noticeable difference the third day after injection. However, as the synaptic protein SNAP25 is regenerated, muscle contraction function is gradually restored. Usually three to four months after treatment, another injection is required. To maintain the effect, it needs to be injected 2-3 times a year for the best results.

The latest botulinum toxin products worldwide

• Botox versus Hengli

Before 2020, the China Food and Drug Administration approved only two types of botulinum toxin for injection, namely the domestic Hengli and the American-imported Botox.

Botox comes from the American company Allergan. It was first approved in 1989 for the treatment of facial spasms and strabismus. In 2002, it was approved by the FDA for the treatment of frown lines. This is also the first time that botulinum toxin has entered the field of aesthetic medicine.

In the following 30 years, Botox has been approved to treat 11 indications including upper limb spasms, chronic migraines, neurogenic urinary incontinence, overactive bladder and others.

Hengli is produced by China Lanzhou Institute of Biological Products and is the only botulinum toxin product developed and listed by a domestic Chinese company. Its name translates to “balancing strength” is derived from the concept of drug mechanisms-relaxing muscles and balancing muscle strength. As a state-owned enterprise, it shoulders the important tasks of national epidemic prevention, biological scientific research, and national medical reserves, and therefore difficult for it to compete with foreign company. However, Hengli, as a domestic product, seizes half of the Chinese market. 【8】

• Dysport

Dysport, a type A botulinum toxin produced by the British company Ipsen, was approved by China’s National Food and Drug Administration in June 2020 and is the third botulinum toxin brand approved in China.

In a clinical trial of 520 Chinese patients with moderate to severe glabellar lines (lines that form between the eyebrows), Dysport at a dose of 50U was better than the placebo and the same as Botox at a dose of 20U. In another trial for the treatment of forehead wrinkles, when a dose ratio of 2.5:1.0 was used, Dysport showed a significantly longer effect than Botox [9].

In the trial to treat forehead wrinkles, Dysport has a longer action time than Botox, with Botox injected on the left forehead and Dysport on the right (Source: Nestor MS, et al.)

• Jeuveau

In 2019, Evolus’s type A botulinum toxin product Jeuveau was approved by the FDA to eliminate frown lines. Jeuveau has performance comparable to Botox. It and Botox are the only botulinum toxin products with a large molecular weight of 900kDa in the world.

Jeuveau is also the first 900kDa botulinum toxin other than Botox approved by FDA in the past 30 years. In a 150-day multi-center, double-blind, controlled Phase III clinical trial. 540 adult patients with moderate to severe glabella were treated with Jeuveau and Botox. The results showed that a 20 U unit of Jeuveau treatment is safe and effective and is not inferior to 20 U of Botox. Furthermore, the price of Jeuveau is usually 20% to 30% lower than that of Botox [10].

• RT002

RT002 is a new weak diffusion type A botulinum toxin for injection developed by Revance in the US. It has the company’s proprietary stabilized excipient peptide technology, and its biggest feature is that the effect is long lasting. Positive results have been achieved in the Phase 3 study of the treatment of moderate to severe frown lines.

In a clinical trial that recruited 609 patients, the treatment effect on glabellar lines was maintained for an average of at least 24 weeks. The current trial of RT002 to treat crow’s feet and forehead lines is underway (11).

▲ The effect of using RT002 to treat glabellar lines can be maintained for 24 weeks (Source: Bertucci V et al.)

Revance plans to receive FDA approval this year. CEO Dan Browne said, “We intend to set new standards in neuromodulators and are committed to providing patients with a safe solution to reduce wrinkles by only performing two or fewer treatments per year. “

Fosun Pharma has obtained the exclusive right to sell RT002 in China, which means that folks will have the opportunity to enjoy its benefits in the future.

Radio Frequency: The Secret Weapon to Stop Aging

RF is the abbreviation of radio frequency, an alternating current electromagnetic wave with a frequency between 300KHz and 300GHz. Radio frequency is very common in our lives, microwave oven and wifi are two types of radio frequency.

Collagen is the most common protein in the human body. It gives the skin its firmness. As we age, the collagen produced by the cells decreases, leading to sagging skin and wrinkles. Several studies have shown that raising the skin temperature to above 46°C and maintaining that temperature for at least 3 minutes triggers the release of heat shock protein (HSP). This increase will produce new collagen and elastic fibers.

RF can penetrate the epidermis and act on deep tissues. Through the resistance of the tissues to RF waves, the water molecules in the tissues instantly oscillate and generate heat. Increasing the skin temperature stimulates collagen to repair and regenerate, so as to tighten the skin and fight aging. In 1999, the US FDA approved radio frequency technology for aesthetic medicine, and it was quickly popularized [12].

The main uses of radio frequency include wrinkle reduction; pore repair; acne scar repair and body plasticity.

▲ Crow’s feet wrinkles are significantly reduced after frequency radiation treatment (Source: Song Hee Han et al.)

RF Products

• Thermage

Thermage is a unipolar radio frequency device produced by the American company Solta Medical. It was first approved by the US FDA in 2002.

Unipolar radio frequency means that only a single magnetic head releases RF. It is the radio frequency with the strongest energy and the deepest skin penetration.

The skin structure ranges from shallow to deep, including the epidermis, dermis, subcutaneous tissue, and superficial muscular aponeurotic system (SMAS). The SMAS layer is like the foundation of our facial skin. The latest generation FLX of Thermage, launched in 2018, can reach the SMAS layer to enhance the support of the tissue, thereby getting rid of wrinkles and firming the skin.

At the same time, Thermage is also the only FDA-approved unipolar radio frequency device that can achieve wrinkle removal in a single treatment. The treatment time of Remaggi is about 30 to 90 minutes and its effects usually last for a year.

▲ Thermage lessens facial wrinkles and stretch marks (Source: Thermage)

• Golden microneedle

Golden microneedle is a new type of anti-aging and skin tightening technology that combines microneedle and radio frequency. It is mainly used to lessen acne scars or wrinkles. It uses a micro-needle probe made of gold to pierce the epidermis, distribute high-intensity radio frequency energy evenly into the deep tissues, and stimulate the growth of new collagen fibers.

Its advantage is that it avoids the stimulation of the epidermis by radio frequency energy, and at the same time, it can treat different levels of tissue to meet different treatment needs by adjusting the penetration depth of the microneedle.

Currently, the FDA-approved microneedle radio frequency brands are INTRAcel Golden Microneedle Radio Frequency, INFINI Microneedle Radio Frequency, Private Li 360, Endymed3D Phase Control. Cynosure’s Potenza was approved in February this year.

• RF-home radiometer

Household frequency radiometers mainly use multi-pole radio frequency. Multiple electrodes are for different permutations and combinations, manipulating the phase of the current flowing between each pair of electrodes so that the intensity of the electric field can be constantly changed, and the energy can be finely and evenly distributed deep in the skin.

At present, the popular multi-polar household RF beauty devices certified by FDA are TriPollar, NEWA, Silk’n FaceTite. However, for safety and convenience, the device’s power is lowered when used at home and its radio frequency reaches the dermis at most. It needs regular use to maintain the desired effect.

References:

【1】Oriental Fortune Securities Research Institute: HA fillers take the beautiful journey express

【2】New Oxygen 2019 White Paper of Medical Beauty Industry

【3】Smith SR, Jones D, Thomas JA, Murphy DK, Beddingfield FC 3rd. Duration of wrinkle correction following repeat treatment with Juvéderm hyaluronic acid fillers. Arch Dermatol Res. 2010;302(10):757-762. doi:10.1007 /s00403-010-1086-8

【4】4. Streit M, Brand CU, Braathen LR. Weichteil-Augmentation zur Falten- und Narbenbehand-lung im Gesicht [Soft tissue augmentation for treatment of wrinkles and scars of the face]. Ther Umsch. 1999;56(4) :212-218. doi:10.1024/0040-5930.56.4.212

【5】JUVÉDERM VOLLURE™ XC Patient Labeling, 2017

【6】Kim JH, Kwon TR, Lee SE, et al. Comparative Evaluation of the Effectiveness of Novel Hyaluronic Acid-Polynucleotide Complex Dermal Filler. Sci Rep. 2020;10(1):5127. Published 2020 Mar 20. doi:10.1038 /s41598-020-61952-w

【7】Sohu News: New domestic high-end hyaluronic acid power! Haohaishengke’s self-developed “5G” memory hyaluronic acid “Haimei” was launched

【8】Comparison of imported and domestic botulinum toxin: Botox vs Heng Li

【9】Nestor MS, Ablon GR. Duration of action of abobotulinumtoxina and onabotulinumtoxina: a randomized, double-blind study using a contralateral frontalis model. J Clin Aesthet Dermatol. 2011;4(9):43-49.

【10】Rzany BJ, Ascher B, Avelar RL, et al. A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Single-Dose, Phase III, Non-Inferiority Study Comparing PrabotulinumtoxinA and OnabotulinumtoxinA for the Treatment of Moderate to Severe Glabellar Lines in Adult Patients. Aesthet Surg J. 2020;40(4):413-429. doi:10.1093/asj/sjz110

【11】Bertucci V, Solish N, Kaufman-Janette J, et al. DaxibotulinumtoxinA for Injection has a prolonged duration of response in the treatment of glabellar lines: Pooled data from two multicenter, randomized, double-blind, placebo-controlled, phase 3 studies (SAKURA 1 and SAKURA 2). J Am Acad Dermatol. 2020;82(4):838-845. doi:10.1016/j.jaad.2019.06.1313

【12】Liu Lihong, Yang Rongya. The principle of radio frequency technology and its application progress in dermatology and aesthetics. Chinese Journal of Laser Medicine. 2008(04)

【13】Cook J, Waughtel J, Lennox KP, P ozner JN. Fractional radiofrequency microneedling for skin rejuvenation. Dermatological Reviews. 2020; 1:16-19 doi:10.1002/der2.10

About the author:

MJ Yuan is an Investment Analyst at MyBioGate and a PhD student at Boston University School of Medicine, majoring in nutritional epidemiology. One of the founders of the Boston University Biotechnology Business Club, a former consultant of the MIT Consulting Club, active in the pharmaceutical science industry in the Greater Boston area.