Summary

With the increasing number of different cosmetic products and procedures available, skin rejuvenation is a hot topic nowadays. Skin rejuvenation refers not only to the special techniques or procedures which are aimed at minimizing unwanted effects of the ageing skin, but also to the preventive strategies that are recommended for maintaining good skin care. Are these products and procedures benefiting our patients according to the best available evidence? In this paper, a preliminary review was performed to assess what the evidence show.

摘要

隨著不同美容產品和方法不斷問世，嫩膚成為現今一個熱點論題。嫩膚不僅涉及減少皮膚老化的特殊技術或方法，還包括保持皮膚健康的預防性措施。從實證醫學角度來看，這些方法對病人有益嗎？本文對有關證據作了初步綜述。

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Introduction

Skin ageing

Basically, there are two processes which account for skin ageing. First, it is the natural ageing process, which is also known as chronological ageing. A combination of genetic factors is believed to play a role, e.g. innate property of skin, the thickness of the skin, hormonal effect, etc. Changes seen in chronological ageing include degeneration of elastic and collagen fibers of skin thinning and drying of the skin, decrease in hair growth, and loss of melanocyte and enlargement of sebaceous glands. Unfortunately, these are not amenable to being modified. On the other hand, external factors such as chronic ultraviolet (UV) light exposure, smoking, excessive facial expression, and low humidity environment are also important causes of skin ageing. Among them, photoageing is considered the most important. Characteristic features of photoageing skin consist of thickened skin, uneven pigmentation, appearance of lentigines or telangiectases, and development of skin tumours.¹

Common features of skin ageing

Pigmentary skin changes are particularly more common in dark skin people like Asians while wrinkles are more predominant in lighter skin individuals. Other characteristic features commonly found are sagging of the cheeks, mouth or jaw, loss of fullness appearance, elastosis, telangiectases and skin tumour growth.¹

Prevention of skin ageing

There is no definitive method to prevent the process of skin ageing. However, some practical tips can be tried to minimize the ageing effects:

• Minimize excessive sun exposure
• Use broad spectrum sunscreen (preferably against both UVA and UVB)
• Avoid smoking
• Healthy diet and regular exercise
• Reduce unnecessary stress
• Prevent unnecessary stretching of the skin, e.g. excessive frowning

Literature searching strategies

The following reference databases were searched, namely the Cochrane Library, Medline, Ovid (including Embase, Clinical evidence and CINAHL). The searching was performed between March and August in 2007. Keywords and MeSH terms were both searched for the following wordings: skin ageing/aging, photoageing, photodamaged skin, skin rejuvenation, wrinkle*, freckles, lentigines, melasma, telangiectasia, rosacea, cherry angioma, sunscreen, tretinoin, retinol, retinyl palmitate, retinal, hydroquinone, azelaic acid, kojic acid, lactic acid, malic acid, citric acid, tartaric acid, vitamin C, ascorbic acid, vitamin E, alpha-tocopherol, tocopherol acetate, glycolic acid, Jessner's solution, alpha-hydroxy acid, AHA, botox, botulinum toxin*, botulinum toxin type A, clostridium botulinum type A, fillers injection, collagen, hyaluronic acid, zyderm, zyplast, cosmoderm, cosmoplast, restylane, perlane, hylaform, hylaform plus, juvederm, artecoll, dermalive, dermadeep, radiance, matridur, sculptra, ablative laser, carbon dioxide laser, erbium-YAG laser, long pulse 1064-nm Nd:YAG laser, Vantage, 1540-nm erbium glass laser, 1320-nm Nd:YAG laser, 1450-nm diode laser, CoolTouch, 1064-nm Nd:YAG laser, SmoothBeam, Q-switched Nd:YAG laser, pulsed dye laser, vascular laser, intense pulsed light therapy, radiofrequency laser, ThermaCool, Aluma, Fraxel, fractional photothermolysis, LED photomodulation and photomodulation. With the help of filter engine, only meta-analysis, systematic reviews and randomized controlled trial were included in this article.

A review on commonly employed products and procedures
Skin rejuvenation cream

(i) Sunscreen

This is one of the most important skin care products that must be used at an early age. Sunscreen products against UVA and UVB are highly recommended as UVA can result in signs of premature skin ageing due to degeneration of collagen and elastin while UVB can cause redness, sunburn and even skin cancer.

Broadly speaking, sunscreen can be divided into physical sunscreen and chemical sunscreen. Physical sunscreen usually contains zinc oxide or titanium oxide which directly reflects and scatters UVA and UVB light. On the other hand, chemical sunscreen against both UVA and UVB contain different constituents, namely oxybenzone, avobenzone or mexoryl for UVA and octyl methocycinnamate, octyl salicylate, phenylbenzimidazole sulfonic acid or octocrylene for UVB.

There are many forms of sunscreen products, e.g. cream, gel, lotion and spray. It should be applied preferably every 4 hours or after facial washing. Additional makeup or powder on top of the sunscreen should not create any problem.

SPF is a well known system used to grade the ability of sunscreen against UVB but there is currently no approved system for protection against UVA. SPF of between 15 and 30 is usually adequate for daily protection but it is highly recommended to use broad-spectrum sunscreen for protection against both UVA and UVB.

Currently, there is no meta-analysis or well conducted randomized controlled trials (RCT) studying the role of sunscreen in preventing photoageing. However, expert opinions are recommending primary prevention programmes to reduce cutaneous photodamage and skin carcinogenesis.²

(ii) Skin lightening cream

This is of particular interest to Asians because our skin is prone to have pigmentation changes due to ageing. It should be applied preferably on the pigmented area.

The most well known product is hydroquinone. It is a strong inhibitor against the melanin production and thus results in lightening of the pigmentation. The usual concentration is 2 to 4%. It must be used with caution because prolonged use of high concentration may result in skin irritation and ochronosis (an uncommon paradoxical darkening side effect). Nowadays, hydroquinone is often mixed with other cosmetic products for better clinical effects, e.g. according to some well conducted RCTs, adjunctive use of hydroquinone can enhance the efficacy of tazarotene in reducing dyspigmentation associated with photodamage³ and combination of hydroquinone with retinol can improve photoageing associated hyperpigmentation.⁴

There are many other substances which are claimed to have skin lightening effect, e.g. azelaic acid, kojic acid, arbutin, locorice extract and mulberry leaf extract but their clinical efficacies remain to be proven by better RCTs. However, it is worth trying if maintenance therapy with hydroquinone is of concern.

(iii) Anti-ageing cream

There are several creams that are claimed to have clinical benefit for anti-ageing, namely tretinoin, alpha-hydroxyl acid (AHA), vitamin C and E.

Vitamin A products and its derivatives are very popular additives to skin rejuvenating products nowadays. Some common examples include tretinoin, retinol, retinyl palmitate, retinyl acetate and retinal. Tretinoin is the only well proven ingredient to have beneficial effects on photodamaged skin according to a meta-analysis.⁵ It can reverse and reduce the early signs of photoageing such as reduction of wrinkles and pigmentation, improvement of skin firmness, etc. It is currently available in different concentrations ranging from 0.01-0.10% and it should be applied at night time only due to the possible sensitivity reaction following exposure to sunlight. Other vitamin A derivatives such as retinol, retinyl palmitate may not be as effective as tretinoin as they are biologically inactive unless the skin has adequate levels of conversion enzymes to change them into an active form.

AHA includes glycolic acid, lactic acid, malic acid, citric acid and tartaric acid. Glycolic acid is the most commonly used and this is supported by several well conducted RCTs to have modest improvements in wrinkles and skin smoothness.^6-8 It is also believed to have better effect when combined with other skin lightening agents because the thinning uppermost dead skin layer allows better penetration of the lightening ingredients. It is generally well tolerated except for occasional redness, irritation and itchiness.

Vitamin C is believed to benefit skin by its collagen synthesis and anti-oxidant properties. The most common form of vitamin C in cosmetic products is L-ascorbic acid. Its role on photodamaged skin is suggested by a recent RCT.⁹ However, its efficacy may be limited by its instability and difficulties in delivering enough vitamin C to become clinically effective.

Since vitamin E is also an anti-oxidant, it is available widely in various cosmetic rejuvenating products, e.g. alpha-tocopherol or tocopherol acetate. However, there are no well conducted studies to prove its effectiveness.

Chemical peeling

It involves the use of chemical solutions, such as AHA (glycolic acid), Jessner's solution and trichloroacetic acid to damage the skin at levels of different depths. A superficial chemical peel removes only the uppermost layer of the skin (the epidermis) while the medium and deep chemical peels act on the skin down to the upper dermis and lower dermis respectively. Upon the healing of the skin layers, the skin will look brighter and healthier with reduction of fine wrinkles. Besides the beneficial effect on photoageing, it is also useful in the treatment of superficial acne scars. The role of glycolic acid is well supported by a RCT8 but the effectiveness of other peel products is not well substantiated.

Priming of the skin with broad spectrum sunscreen, skin lightening cream, and tretinoin or AHA containing cream for 3 to 4 weeks before the procedure is essential for the best effect. The effect of superficial peel is gradual and progressive and hence several treatments are needed initially. Maintenance peels may be needed later at longer time interval to sustain the results.

The procedure is generally safe but possible side effects include pigmentary changes (which can be minimized by a good priming), scarring (therefore patients with history of keloids development should avoid) and prolonged redness (which can be controlled by a mild steroid cream).

Botulinum toxin A

Botulinum toxin A (BTX-A) is produced by the bacterium Clostridium botulinum. It was initially used for medical purpose to reduce muscle spasm. Two commonly used forms are now available in the market, namely Botox and Dysport. The toxin acts on the neuromuscular junction by preventing the release of acetylcholine which results in weakness of the injected muscle. Due to its ability to cause temporary muscle paralysis, it is now widely used in reducing wrinkles, e.g. the role of BTX-A in frown lines on mid forehead/ glabellar lines, crow's feet lines and horizontal forehead rhytides is supported by several well conducted RCTs.^10-16

The procedure is usually performed in the doctor's office setting. The procedure itself is generally safe and minimally painful if correctly trained techniques are used. The group of muscles responsible for causing the wrinkles is first identified. Then the skin is cleansed with antiseptic and the toxin is injected with a very fine needle into the identified group of muscles. After the injections, mild pressure on the injected areas is applied to stop any bleeding. The patient should not lie flat for 6 to 8 hours and he/she must not massage the injected sites as this may cause the toxin to spread to other muscle groups. The effects of toxin will usually start within 3 to 4 days after the injection and observable effects will be seen by the second week. However, the effects will only last for 3 to 6 months and repeated injections may be needed for a sustainable optimal result.

Fillers injection

Soft-tissue fillers can be used to fill in and lift up facial lines and creases found in photoaged skin. It is usually applied together with other cosmetic procedures such as using BTX-A and laser surgery to obtain the best cosmetic effect.^17,18 It is usually performed in an outpatient setting with the use of local anaesthetic (topically applied before the procedure or mixed with the fillers during the procedure). The procedure is generally safe with occasional side-effects such as pain, redness, swelling or even bruising. The results are seen immediately with most of the fillers.

Fillers can be classified into temporary (usually lasting for several months) or semi-permanent (may last for more than one year) depending on the duration of the substance that are used.

Temporary soft-tissue fillers are usually composed of collagen or hyaluronic acid. Collagen based fillers are less used now due to the fear of infection. Common examples include Zyderm, Zyplast, Cosmoderm and Cosmoplast. Hyaluronic acid fillers are more commonly used and they replace the lost hyaluronic acid in our ageing skin. Some examples include Restylane, Juvederm, Hylaform, Hylaform Plus, Perlane and Visagel. Their effects last for 3 to 9 months on average. RCTs showed that hyaluronic acid fillers are better than collagen based fillers.^19,20

Semi-permanent fillers incorporate into the skin tissue and do not break down. They thus create a longer-lasting filling effect and stimulate the skin to produce its own fibrous tissue. However, there may be a higher incidence of unpredictable effects due to this type of stimulation. Hence appropriate selection of candidates by an experienced practitioner is essential. Common examples are Artecoll/Artefill, Radiance, Matridur, Sculptra, Dermalive, Dermadeep, etc. However, only Artefill has been comprehensively studied.²¹

Not everyone is suitable for filler injection. The following situations are some of the contraindications for this procedure: people with active skin infections, people with autoimmune disease, people with allergy to lignocaine, and pregnant woman.

Laser devices

Laser is a monochromatic, collimated light with a single wavelength which can target on the different chromophores on the skin, e.g. water, melanin, oxyhaemoglobin. Different wavelengths will cause selective destructive effect on various problems on the ageing skin, e.g. growths, pigmentary changes, and blood vessels. Hence, no single laser can treat all cosmetic problems.

As there are so many types of lasers available in the market nowadays, only some of the most commonly known devices are briefly outlined here with a review on the available evidences.

(i) Ablative lasers

These are becoming less favourable options for skin rejuvenation due to the long "downtime" but they are still useful in wrinkles around the eyes/mouth, surgical/acne scars and benign growths such as viral warts, seborrhoeic keratoses or actinic keratoses. The commonly used devices include erbium-YAG and carbon dioxide lasers and the light is selectively absorbed by water molecules in the cells resulting in excessive heat generation and eventual destruction of the target tissue.

Post-laser pigmentation is very common in pigmented Asian skin and therefore a small testing area must be performed before the procedure. If there is a low possibility of post-laser pigmentation, the procedure can be scheduled. Laser skin resurfacing can be quite painful and anaesthesia with sedation is required for most patients. After the procedure, oral analgesics, antiviral and antibacterial drugs are prescribed to relieve pain and prevent infection. In addition, proper daily dressing is important for rapid recovery and prevention of skin scarring.

Erythema is a very common complication after the procedure and is most severe in the first 2 weeks of treatment. It will usually fade away in 3 to 6 months.

Pigmentation is another common complication which usually occurs in the first few months after the procedure. It can be minimized by avoiding sunlight exposure and applying skin lightening cream. With proper prevention, it will gradually decrease after 6 to 12 months.

Skin infection after the procedure will cause scarring of the skin. Hence, prophylactic use of antiviral and antibacterial medication is essential to prevent this unfavourable complication.

Regarding its efficacy, ablative laser is effective in laser resurfacing. According to several RCTs,^22-24 variable pulsed erbium-YAG laser may achieve the same effect as carbon dioxide laser but probably with a less adverse sequelae.

(ii) New generation non-ablative lasers

These are the most popular option nowadays for skin rejuvenation. Many new models have been advertised in the market. They target the water molecules in the upper dermis and hence promote the formation of new collagen without the undesirable effect on the epidermal layer. There is minimal or no "downtime" for this procedure. There is less chance of prolonged skin erythema, post-inflammatory pigmentation, skin infection and scarring. Commonly used examples include long-pulse 1064nm Nd:YAG laser (Vantage), 1540nm Erbium Glass laser (Aramis), 1320nm Nd:YAG laser (CoolTouch) and 1450nm diode laser (SmoothBeam). The use of the longer wavelengths allows dermal penetration of light and collagen shrinkening with eventual remodeling.

They are claimed to be particularly useful for fine wrinkles and improvement of skin texture. The procedure usually causes minimal discomfort. It is generally repeated at 4 to 6 weeks interval and optimal cosmetic effect is expected in 6 to 9 months. No special skin care is needed but avoidance of excessive sunlight exposure and application of broad spectrum sunscreen is still recommended to minimize the chance of post-inflammatory hyperpigmentation.

From the evidence-based medicine point of view, no meta-analysis can be found and their efficacies are supported by non-randomized, small trials only. Hence, further larger, well conducted studies are still pending. However, a systematic review can be found to compare the efficacy between ablative and non-ablative laser and this has shown that the erbium-YAG laser or CO2 laser were better than the non-ablative lasers in the treatment of fine lines/superficial scars or deep rhytides/scars.²⁵

(iii) Pigment lasers and vascular lasers

Pigment lasers target at the melanin molecules and are most useful for pigmentary problems such as freckles, tattoos, lentigines and some acquired or congenital pigmented nevus. Some of the most commonly used examples are Q-switched Nd:YAG 532nm laser and Q-switched Alexandrite laser. Its efficacy on facial freckles and lentigines is supported by several well conducted RCT.^26-28 Several treatment sessions under topical anaesthesia are generally needed. However, no good quality or large scale RCTs exists so far for the laser treatment of melasma.

Mild redness and swelling is common after the procedure as the epidermal layer is damaged but this will usually subside in 2 to 4 weeks. Pain and discomfort can be reduced by the use of analgesics and cold-compression. The laser wound should be cleansed regularly with sterile normal saline and antibiotic cream should be applied on the treated sites. The patient should be reminded not to prick, scratch or rub the wound site as this may cause infection and scarring. Moreover, avoidance of sunlight and use of broad-spectrum sunscreen after the wound is healed is recommended.

Vascular lasers target the red blood cells and hence are thought to be beneficial in treating telangiectases. A commonly used example is the pulsed dye laser. Its efficacy is supported by one small-scale RCT.²⁹

Several sessions of treatment are usually required and the number of treatment sessions needed depends on the size, depth and severity of the vascular lesions. Local anaesthesia may be necessary if the patient cannot tolerate the pain. The procedure will initially cause a transient bruising appearance for about 2 weeks and this will gradually fade away without special treatment. The patient should be advised to clean the skin with cool water and avoid strong facial soaps. Again, avoidance of sunlight and the use of broad-spectrum sunscreens are suggested.

Intense pulse light therapy

Generally speaking, this is not a laser because it produces a broad band of light with multiple wavelengths. Initially, the machine produces a range of wavelengths from 500 to 1200nm. With the use of special cut-off filters, only the desirable spectrum of intense light is delivered to the target tissues such as melanin and haemoglobin. It is currently one of the most popular devices for photo-rejuvenation.

It is claimed to be most useful for the treating of telangiectases, freckles and lentigines. However, it is not effective in the removal of deep wrinkles, melasma or scar. In general, 4 to 6 monthly sessions are adequate for improvement with minimal "downtime". The treatment is in general safe under the hands of trained physicians. Topical anaesthesia can be applied to reduce the pain during the procedure. Minimal erythema is common and this will resolve after a few hours. In addition, before and after the procedure, the patient should refrain from sun tanning for at least 4 weeks and broad spectrum sunscreen/ skin lightening cream should be used to minimize the risk of hyperpigmentation.

Regarding its efficacy, 2 well-conducted RCTs showed that intense pulsed light treatments improved skin texture, telangiectasia, and irregular pigmentation but had no effect on rhytides.^30,31 On the other hand, when comparing between IPL and ablative laser, CO2 laser resurfacing induces significantly higher degree of clinical rhytide reduction followed by considerably more side effects.³²

Skin tightening devices

Recent advances in laser technology allow selective heating of the collagen in the dermal layer leading to initial contraction and thickening of the collagen tissue. This initial change is followed by formation of new collagen which results in tighter and smoother skin appearance theoretically.

Currently, the common approaches include the use of radiofrequency (e.g. ThermaCool- monopolar system and Aluma- bipolar system).

The procedure is generally safe in experienced hands. Some pain is expected as there is heat sensation when the hand piece of the device is activated. However, this is usually tolerable because the cooling device will immediately cool down the discomfort. If this is still intolerable, topical anaesthetic cream and analgesics may be given and its use will not affect the clinical result according to one RCT.³³

The number and duration of the procedure depends on the severity of laxity and size of the area being treated respectively. The clinical result will usually be gradually seen in 2 to 6 months. Similar to other non-ablative devices, minimal redness is very common but it lasts for a few hours only. Sun avoidance and use of broad spectrum sunscreen is also recommended to minimize the risk of post-inflammatory hyperpigmentation.

Concerning the evidence available, monopolar system is shown to be effective by a well designed RCT³⁴ but the efficacy of bipolar system is still controversial.

New techniques

One of these is called fractional photothermolysis (e.g. Fraxel). This treatment aims at producing multiple microthermal treatment zones (MTZ) of thermal injury to the skin. The normal skin next to these puncture holes helps to repair the holes and hence new collagen is formed resulting in improvement of wrinkles, scars and pigmentation.

Topical anaesthesia is usually required before the procedure to minimize the pain. After the procedure, mild burning sensation is common but it will fade away within hours. Besides, mild redness and swelling will be seen but they will just last for a few days. The procedure needs to be repeated several times in 1 to 2 weeks interval as each treatment session targets around 20% of the skin. The clinical result is claimed to be observed in 3 to 6 months. However, regarding the best evidences, one clinical trial showed some effect on facial and non-facial photodamage, rhytides and dyspigmentation³⁵ but well conducted RCTs are still pending.

Another new technique is LED photomodulation. It involves the use of narrow band, (590nm) low-energy light source emitting diodes (LEDs), transmitting a fixed frequency to the skin cells. The light will activate the skin cells to produce collagen and the result is a softer, smoother facial complexion with fewer wrinkles and freckles. The procedure is very safe as this is non-thermal and non-ablative. No anaesthesia is needed and the treatment can be repeated twice a week for approximately 4 weeks to obtain the best cosmetic result. However, their safety and effectiveness are supported only by 2 non-randomized controlled trials only.^36,37

Unresolved issues

In the past, cosmetic procedures (especially lasers) were mainly used by dermatologists or plastic surgeons. However, nowadays, due to huge market demands together with lucrative financial incentive and a lack of regulation on the use of different cosmetic products, many beauticians and doctors without formal dermatology training are allowed to perform various types of high risk procedures. Should more stringent restrictions be imposed on this trend which is now causing so much confusion to the general public? Should there be a assessment to be held for practitioners before becoming qualified to perform such procedures? Should non-medical personnels or non-specialists be disallowed or stopped from further practising such aesthetic medicine in the future? Perhaps these and other questions need urgently to be addressed by the government and other relevant professional bodies or organizations.

Limitation

This paper is not intended to give a formal systematic review on the evidences regarding the different techniques and procedures used in facial skin rejuvenation. Instead, only a preliminary search of evidences based on the best study designs was performed. Moreover, bias may be present as the search was confined to literature written in the English language only. In addition, no measures against publication bias and no stringent evaluation of the quality of the evidences were done. Last but not the least, as the articles in this topic are growing so rapidly, the opinions given in this paper may not contain the most accurate or give the most updated information.

Conclusion

Clinical decision-making not only depends on the clinical evidence available, but also on the patients' benefits and interests. In other words, patient safety should always be placed as the first priority. Besides, we must also pay particular attention to the possible biases in many of the published studies, doubtful long-term side-effects after prolonged treatments, premature promotions of new technology by media and stakeholders prior to evidence-based reviews as well as the misleading messages given by the advertising agents or sometimes even by doctors.

Acknowledgement

I would like to express my sincere thanks to Dr Luke Tsang for his kind support in preparing this manuscript for publication.

Key messages

According to the level of evidence, the following impression regarding different treatment modalities for facial skin rejuvenation are:

1. Evidence supported by meta-analysis/systematic review-Tretinoin.
2. Evidence supported by RCTs-Hydroquinone; AHA; Vitamin C; Chemical peels; Botulinum toxin A; Fillers injection (hyaluronic acid based); Ablative laser (erbium-YAG laser and carbon dioxide laser); Pigment laser (Q-switched Nd:YAG laser and Q-switched Alexandrite laser); Vascular laser; Intense pulsed light; Radiofrequency device (Monopolar system).
3. Inconclusive evidence-Vitamin E; New generation non-ablative laser; Radiofrequency device (Bipolar system); Fractional photothermolysis; LED photomodulation.
4. Opinions only from experts but worth following-Sunscreen.

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References