The Effectiveness of Injectable Hyaluronic Acid in the Improvement of the Facial Skin Quality: A Systematic Review

Introduction

The dermis, a layer of skin beneath the surface, is made up of three main components: collagen, elastin, and ground substance. These components, which are largely produced by fibroblasts, are essential for maintaining the normal structure and function of the skin.¹ Each component plays a unique role in maintaining the normal structure and function of human skin.¹ They help keep the skin healthy by performing various physiological functions and biosynthetic activities.²

Table 1 Characteristics of the Studies Using Various Formulations of Hyaluronic Acid (HA) Alone for Improving Facial Skin Quality

Table 2 Characteristics of the Studies Using Various Formulations of Hyaluronic Acid (HA) Along with Other Active Ingredients (Cocktail) for Improving Facial Skin Quality

Skin aging is a complex process that is influenced by both inherited genetic factors and external environmental factors. Recent research has shown that skin aging is not simply a result of the passage of time, but rather it is also influenced by a wide range of external factors known as the “exposome”. The exposome refers to all of the environmental exposures that a person experiences throughout their lifetime, such as UV radiation, pollution, and diet, which can contribute to the aging of the skin. Understanding the various factors that contribute to skin aging can help individuals make informed decisions about how to care for their skin and may potentially help to slow the aging process.³ There are many external factors that can contribute to the aging of the skin, such as environmental exposures, lifestyle habits, and chronic diseases. These factors can accelerate the aging process and should be taken into consideration by dermatologists and other healthcare providers when assessing an individual’s skin aging concerns and determining strategies for minimizing or delaying it. It is important for individuals to be aware of these factors and to take steps to protect their skin from harmful exposures, maintain a healthy lifestyle, and manage any underlying health conditions in order to support healthy, youthful-looking skin.⁴

Hyaluronic acid (HA) is a chemical that plays a key role in maintaining normal skin moisture levels.⁵ HA first gained attention in the medical field in the 1970s and 1980s when it was used in ophthalmic surgery. Since then, its use in dermatology has grown significantly due to its ability to retain moisture, improve skin texture and elasticity, and provide a variety of other benefits. HA is now commonly used in a variety of skin care products, including filler injections and cosmeceuticals, to help improve the overall quality of the skin.^6,7 Clinical studies in dermatology have often focused on evaluating the elasticity and hydration of the skin in order to assess overall skin quality, particularly in relation to aging skin.⁸

HA injectable formulations have been used in recent years as a means of improving skin quality in addition to their traditional use for filling wrinkles and adding volume to the face. These treatments work by injecting HA into the dermis, the layer of skin beneath the surface. HA helps to hydrate the skin and create a stable extracellular matrix, which is a supportive structure that is essential for the normal function of the fibroblasts in the dermis. This can help to improve the overall quality of the skin, including its elasticity, hydration, and texture. The procedure is relatively quick and non-invasive and can be used to address a range of skin concerns related to aging and other factors.⁹ There are a number of ways to improve the structural integrity and appearance of aging skin, and injectable formulations of HA are one option that has been studied extensively. These treatments work by injecting HA into the dermis, the layer of skin beneath the surface, where it helps to hydrate the skin and support the normal function of the fibroblasts, the cells responsible for producing collagen and elastin. This can help to improve the overall quality of the skin. There have been several studies that have evaluated the effectiveness of various injectable HA formulations in improving skin quality, and it is important to review and summarize this evidence in order to understand the potential benefits and risks of these treatments.

Materials and Methods

Study Design

We aimed to include published original clinical research studies that evaluated the therapeutic role of any injectable formulation of HA in improving the quality of facial skin in adult humans. Pre-clinical studies, case reports, case series, reviews, commentaries, view points, or opinions were excluded. Studies that evaluated the therapeutic role of HA on augmentation of the facial contour (eg nasolabial fold augmentation, malar augmentation, lip augmentation, temple hollowness, upper orbital hollowness, deflated earlobes, etc.), those which used topical formulations of HA alone or in combination, those which had evaluated the effect of HA on the quality of skin apart from the face, and those which used an ex vivo explant model were excluded. The primary outcome of this study was the effect of various formulations of HA on facial skin quality. The secondary outcome was the safety of these formulations.

Search Strategy

PubMed, Embase, ClinicalTrials.gov, World Health Organization - International Clinical Trials Registry Platform, Cochrane Library databases [Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL) and Cochrane Methodology Register], and two pre-print servers (medRxiv.org and Research Square) were searched from inception until 31Dec 2022. The search terms used in various combinations were: “cheek”, “face”, “mid-face”, “malar”, “filler”, “hyaluronic acid”, “HA”, “hyaluronan”, “cosmetics”, “cosmeceuticals”, “cosmetology”, “Skin aging”, “aging treatment”, “skinboosters”, “skin boosting”, “boosters”, “exposome”, “Juvederm”, “Restylane”, “Perlane”, and “Belotero”.These search terms were adapted for use with different bibliographic databases in combination with database-specific filters for studies, if available. The search strategy was used to obtain the titles and the abstracts of the relevant studies in the English language, and they were independently screened by two authors, who subsequently retrieved abstracts, and if necessary, the full text of articles to determine the suitability.

Analysis of the Selected Articles

Two authors independently extracted data using a standardized data extraction spreadsheet. The extracted data included the general characteristics of the articles, population, intervention, and outcome of interest (according to the study objectives). During data extraction, no simplifications or assumptions were made. All the studies were critically analyzed. The risks of bias of each study were analyzed by the Cochrane risk of bias tool¹⁰ for the randomized controlled trials andtheNewcastle-Ottawa scale¹¹ for the observational studies. Data related to the key efficacy and safety outcomes related to the use of HA from the included studies were noted. Two authors independently validated the assessment, and discrepancies or disagreements were resolved in consultation with a third author.

Results

A total of 2996 articles were screened and 15 studies^12–26 met our eligibility criteria and were finally included (Figure 1). There was one randomized controlled trial,¹⁵ one non-randomized observational study,²⁵ and 13 observational studies.^{12–14,16–24,26} Eight studies^12–19 evaluated the effect of various formulations of HA alone, while five^22–26 evaluated the effect of various formulations of HA along with other active ingredients (cocktails) on the facial skin quality. The summary of all the included studies is enumerated in Table 1 and Table 2. The risk of bias in the included studies is depicted in Tables s1 and s2 (Supplementary Material). Most of the studies had a moderate risk of bias.

Figure 1 Study flow chart depicting the steps of the synthesis of evidence from the literature.

Most of the studies used subjective endpoints, such as Global Aesthetic Scale, Subject Global Impression of Change Scale, Wrinkle Severity Rating Scale, Allergan Skin Roughness Scale, Allergan Fine Lines Scale scores, etc. Some of the studies used histology and immunohistochemistry. Some studies have used biophysical evaluations, such as noninvasive suction skin elasticity meter or cutometer (to measure elasticity), corneometer (to measure skin hydration), spectrocolorimeter (to measure skin pigmentation), high-resolution camera (to measure skin surface morphology), and ultrasound scanner (to measure skin thickness and density).

Regarding the use of HA monotherapy, stabilized HA-based gel of non-animal origin, cross-linked HA, and small particles of HA were most commonly used. The sample size of the studies ranged from 15 to 131 and the age of the patients ranged from 25 to 65 years. More than 80% of the study population was female. All studies showed significant improvement in facial skin quality in terms of skin hydration, skin firmness, skin-tiring effect/fatigue, and skin elasticity. More than 95% of the patients were quite satisfied with the treatment outcomes.

Regarding the use of HA monotherapy along with other active ingredients (cocktail), multivitamins were commonly used along with HA. The sample size of the studies ranged from 6 to 60 and the age of the patients ranged from 29.5 to 75 years. More than 85% of the study population was female. Three studies showed significant improvement in facial skin quality in terms of brightness, texture, radiance, and firmness, while two studies showed no significant clinical or histologic changes in facial skin quality. Patient satisfaction varied. However, two studies^22,24 showed negative results.

All HA formulations were very well tolerated and no major safety issues were noted in any studies. The most common adverse events included bruising, swelling, and tenderness, which typically lasted for less than two weeks.

Discussion

In this study, we found that facial skin boosting using HA alone could significantly improve skin quality. HA along with other active ingredients also showed beneficial effects and the treatment was found to be quite safe.A majority of the patients, particularly those who received HA monotherapy, were highly satisfied with their results following HA treatment. This reinforces the fact that HA injections are an integral part of facial aesthetics. HA products are similar but not interchangeable.²⁷ Individual patient assessment and an understanding of facial aging are necessary for optimal results with HA injections.

HA is a common ingredient in many cosmetic products due to its ability to retain moisture and improve the texture and elasticity of the skin. It is known for its excellent hygroscopic, rheological, and viscoelastic properties, which make it an effective choice for a range of skin care products. Some research has suggested that HA may have beneficial effects when used topically in dermatological practice, although more studies are needed to fully understand its potential effects.²⁸ There is a growing body of evidence suggesting that HA is well-tolerated and effective when used in combination with various facial rejuvenation procedures, such as botulinum toxin type A, photodynamic therapy, fractional CO₂ laser skin resurfacing, fillers, microneedling, and chemical peeling. Clinical studies have generally found that HA-based cosmeceuticals, which are skin care products that contain HA and other active ingredients, can help to improve skin hydration, rejuvenation, and healing. In addition to advising patients about healthy lifestyle habits and skin protection, dermatologists can recommend the use of HA-based cosmeceuticals as a way to counterbalance the negative impact of external factors on the skin (exposome). These products may be useful for helping to maintain healthy, youthful-looking skin and may be suitable for people of all skin types and concerns.^28,29

HA has been shown to be effective in improving the quality of facial skin, particularly when used in consecutive treatments spaced a few weeks apart. This may be due to the viscoelastic properties of HA, which help to improve skin elasticity and firmness. It is generally recommended that patients with mild loss of skin elasticity and firmness receive a single treatment, while those with more pronounced changes in skin quality may benefit from three consecutive treatments in order to gradually improve skin fatigue and firmness.¹⁹ Some studies have shown negative results when using a cocktail regimen of HA, which may be due to differences in the concentration and particle size of the HA used. Overall, HA appears to be a promising option for improving skin quality and addressing a range of skin concerns related to aging and other factors.

HA is thought to play a role in skin rejuvenation due to its viscoelastic properties. When applied to the skin, HA forms a condensed network within the connective tissue that helps to attract water into its matrix. This can improve skin turgor, or firmness, and stimulate the production of collagen fibers, which are important for maintaining the structure and elasticity of the skin. Additionally, HA may help to modulate the elongation of collagen fibers, which can help to improve the overall quality and appearance of the skin.³⁰ It is well-established that collagen fibers in the extracellular matrix, which is a supportive structure in the skin, have a faster turnover rate than elastin fibers. This means that collagen is more quickly replaced in the skin than elastin, which is a protein that helps to give the skin its elastic properties.¹⁹ HA products with larger particles and higher densities are typically injected into the upper subcutaneous layer of the skin, while those with smaller particles and lower densities are typically injected into the dermis. The subcutaneous layer is the layer of tissue beneath the skin that contains fat cells and blood vessels, while the dermis is the layer of skin beneath the surface that contains collagen, elastin, and other supporting structures. In general, smaller HA particles are able to attract and hold more water in the skin, without adding volume, compared to larger particles.¹³

Skin boosting with small HA particles is a new method of skin rejuvenation. There are several studies and case reports proving the skin boosting idea as a novel treatment for skin improvement using injectable cross-linked HA.^31,32 “Skin boosting”, has been shown to have a number of potential benefits for the skin. By increasing the hydration of the skin, skin boosting with HA may help to delay or reverse the aging process, reduce the appearance of aging indicators such as wrinkles and sagging skin, and improve the overall quality of the skin.

There are several commercial products available that contain small particles of HA and are designed to be injected into the dermis to boost skin hydration. These products typically have a concentration of HA ranging from 13.5 to 20 mg/mL and are administered in small aliquots using a series of punctures in order to distribute the product evenly over the treated area. Once injected, the HA attracts water into the skin matrix, which can help to improve skin turgor, add extra volume, and refine the skin structure.³²

The goal of using small particle HA injections, or “microinjections”, as a skin treatment is not just to increase hydration, but also to stimulate the activity of fibroblasts, the cells responsible for producing collagen and elastin. The skin’s mechanical behavior is not purely elastic, but rather it is viscoelastic, meaning that it exhibits both elastic and viscous behavior. This is due to the presence of collagen and elastin fibers in the skin, which respond to mechanical stresses in different ways. By injecting cross-linked HA into the dermis, it is thought that the extracellular dermal scaffold, which is the supportive structure in the skin, may be restored more diffusely and uniformly, compared to more localized injections used for correcting wrinkles or adding volume. This may help to improve the overall quality and appearance of the skin, including its elasticity, hydration, and texture.¹² According to a review of the available evidence, skin boosting with small particle HA injections may have a number of beneficial effects on the skin, including improving hydration, elasticity, anisotropy, roughness, and radiance.¹² To achieve these effects, it is generally recommended that patients receive a series of monthly treatments in order to adequately stimulate and restore the extracellular matrix, which is the supportive structure in the skin. The specific number and frequency of treatments will depend on the individual’s skin concerns and goals and may vary from person to person. Skin boosting with HA injections may be suitable for people of all skin types and concerns and may be used as a standalone treatment or in combination with other skin care procedures.

Regarding the safety aspect, HA treatment in the face was generally mild and self-limiting.³³ While generally safe and well-tolerated, skin boosting with HA injections can carry the risk of certain complications, such as lumpiness, nodules, and extrusion of the filler material. The incidence of these complications may vary depending on the type of HA product used and the individual’s specific skin concerns and goals. Some research suggests that the risk of nodule formation may be lower with HA compared to other skin boosters, such as poly-L-lactic acid, although more research is needed to confirm this.³⁴ The formation of nodules after skin boosting with HA injections may be due to a number of factors, including a delayed inflammatory reaction, an infectious biofilm process, the location of the injection, and the volume of the injection. To reduce the risk of nodule formation, it is important to thoroughly clean the skin with an antiseptic prior to injecting the HA.³⁵ Furthermore, placing injections deep into the muscle in the upper cheeks and the deep subcutaneous in the lower cheeks may prevent nodule formation.³⁶

There were a few limitations to the included studies. Some of the studies enrolled very few patients and these studies could have a high fragility index. Most of the studies were not randomized controlled trials, the risk of bias in some of the studies was high, and hence, the quality of evidence generated was low.Most of the studies did not use any hard endpoint. The long-term treatment outcomes were not reported in any study. There were a few limitations to our review process as well. Data for all outcomes of interest were unavailable, and hence, either could not be included in the review. Not withstanding these limitations, to the best of our knowledge, this is the first systematic review to demonstrate the effectiveness of HA as skin booster in the improvement of the quality of facial skin.

Conclusion

Skin aging is a complex biological process affected by both genetic and extrinsic factors. HA has nowadays been used extensively in dermatology due to its hygroscopic, rheological, and viscoelastic properties. The clinical evidence on the use of various injectable formulations of HA alone in the improvement of the quality of facial skin, in terms of hydration, firmness, skin-tiring effect/fatigue, brightness, texture, radiance, and elasticity, is quite promising. The effect of HA monotherapy was more pronounced than that of the cocktail ingredients. However, the results need to be confirmed in robust and large randomized controlled trials.