Lydia Badia explores the art of facial rejuvenation beyond hyaluronic acid and botulinum toxin 

Ageing transforms the face to create an appearance that does not always reflect the vibrant person within. Maintaining a youthful appearance can have a profound effect on self-esteem, as well as personal and professional relationships. 

This article gives an overview of the core non-surgical interventions with special attention directed at collagen stimulation products, which I believe provide better longevity for rejuvenation and more natural results but are also extremely useful for injured or scarred tissue after trauma.

The causes of ageing in relation to facial appearance may be intrinsic or extrinsic. Intrinsic skin ageing is caused by the same genetic pathways that lead to ageing of all the other organs of the body. Intrinsic ageing of the subcutaneous tissues is also highly relevant as bone resorption, muscle atrophy, and variable atrophy of the fibrous layers leads to ptosis of the soft tissues, sagging, hollowing, and rhytids. Extrinsic skin ageing is caused by lifestyle and environmental factors, which result in lines and wrinkles from a loss of elastin and collagen fibres. Photoaging also affects skin colour and tone.

Patients are typically concerned about looking fatigued, dull, angry, and negative. If they have suffered injuries, they wish to improve the contouring. Most people want to appear ‘well’ for their chronological age.

Broadly speaking, non-surgical treatment modalities may be considered by anatomical layer depending on whether they address changes in the epidermis, atrophy and inelasticity of the dermis, dynamic facial lines caused by the pull of the underlying muscle, or loss of volume at sites of fat or bone resorption.


Topical treatments are popular among consumers seeking skin (epidermis) improvement because of their convenience, low cost, and excellent safety profile. While results may be modest, the market is saturated with promising non-prescription topical products. Of the prescription products, retinoids are the most powerful, effective, and evidence-based topical anti-ageing products available. They should form the cornerstone of any topical rejuvenation plan. The profound biological effect of retinoids on the skin results from their direct action on a family of nuclear hormone receptors — the retinoic acid receptors (RAR) and the retinoid X receptors (RXR). These receptors are found in all cells, though the key targets are keratinocytes and melanocytes in the epidermis and fibroblasts in the dermis. Activation of retinoid receptors leads to a molecular chain of events that changes protein transcription and modifies cellular function. Histologically this leads to epidermal hyperplasia and impaction of the stratum corneum (producing smoother skin with a ‘glow’); increased dermal collagen type I, III, and VII synthesis; reduced collaged breakdown and normalisation of elastic tissue organisation (improving coarse wrinkling and crepe-like skin texture); a reduction in melanin synthesis, and transfer of melanosomes to keratinocytes (improving solar pigmentation)1. Epidermal effects are seen within six months of use, while dermal effects may take a year or longer to become apparent. Treatment ought to be continued indefinitely for continued benefit.

A concentration of tretinoin of 0.025% is considered therapeutically effective while minimising side-effects. Chemical peeling is the topical application of chemical agents to cause controlled destruction of part of the epidermis. This leads to desquamation, liquefaction of the affected layers, followed by inflammation and finally, regeneration. Glycolic acid and salicylic acid peels have a similar profile and are frequently delivered at two to four weekly intervals. Trichloracetic acid (TCA) has a higher depth of penetration and, in high concentrations, also a higher risk of scarring.

Botulinum toxin 

Botulinum toxin has been the most revolutionary anti-ageing treatment in recent years, two to five days after injection it produces muscle paresis, which prevents the skin from being pulled or stretched by the muscle movements. The subjective duration of action in a given patient seems to be stable, but there is considerable variability between individuals. In the European market, three different branches of BTX-A are officially registered: Botox®/Vistabel® (Allergan), Dysport® (Ipsen)/Azzalure® (Galderma), and Xeomin®/Bocouture® (Merz). The units are not directly comparable. The products either have varying amounts of complexing proteins or are free of these proteins altogether (i.e., Xeomin®/Bocouture®). The diffusion of the various drugs seems to be dependent on concentration. BTX-A has an excellent safety profile and has been used extensively for facial rejuvenation with a focus on hyperkinetic wrinkles and to improve facial wound healing after surgery2. Microbotox is the injection of multiple microdroplets into the dermis with the intention of decreasing sweat and sebaceous gland activity and thus improving skin texture and sheen.


Injectable fillers can be inserted under the skin, in different layers to improve contours, angles, scars, folds and flaccidity. Fillers can be divided into autologous or synthetic. Autologous fat grafting is the filler that has a long-term effect. This technique was popularised and modified by Coleman3. However, there are several issues surrounding fat transfer; one of which is that the injected fat can grow. There have been patients who have gained weight after their fat injections and their faces have enlarged. Another issue is that it is difficult to remove. Fat is not reliable, and the adipocyte survival can be unpredictable; hence, it may work better on one side of the face than the other, so touch-up procedures are often necessary.

Autologous platelet-rich plasma injections (PRP) promote tissue remodelling by increasing the expression of Type I collagen in human dermal fibroblasts4. This is the evidence and reasoning behind the ‘vampire facelift’.

Although regenerative medicine is the current topic of the day, the use of blood products in roles other than transfusion began almost a half-century ago when fibrinogen was used as a type of glue, to put tissue together. Platelets, neither a cell, like the red or white blood cell, nor a metabolite, like fibrinogen, is a cell fragment (no nucleus). It is deeply involved in tissue repair, helping to form clots to fix a leaky blood vessel and containing a number of growth factors that signal and stimulate cell proliferation and remodeling — enhance healing.

The use of synthetic fillers for soft-tissue augmentation has increased dramatically in recent decades, progressively supplanting surgery as a result of its improved safety and efficacy, the short recovery time, and the lower treatment costs. Different types of soft-tissue fillers can be distinguished: non-biodegradable (e.g., polymethylmethacrylate) and biodegradable (e.g., hyaluronic acid [HA]) products. A new generation of biodegradable products has also emerged: the soft-tissue fillers — calcium hydroxylapatite (CaHA), poly-l-lactic acid (PLLA), and polycaprolactone (PCL), which possess bio-stimulatory properties. 

Permanent artificial fillers are, in my view, no longer recommended, as the widely accepted long-term safety effect has not been established. Temporary fillers are metabolised by the human body and consist of different substances. Hyaluronic acid, also known as hyaluronan or hyaluronate, is a carbohydrate, more specifically a mucopolysaccharide occurring naturally in the human body. It is the most common temporary filler used today; it has a high tolerability profile, and cross-linking gives HA fillers a life span of six to eighteen months5. Although there is some evidence that HA stimulates new collagen, the main effect is from its hydrophilic properties. When not bound to other molecules, it binds to water giving it a viscous quality similar to ‘jello’. In my view, this is the main drawback of HA; it can result in an unnatural overinflated look. The HA produces multiple anechoic pseudocystic structures. The bright hyperechoic spots noticed in PCL represent microspheres with collagen-stimulating properties.  

Ellanse®, Radiesse® and Sculptra® are particle based dermal fillers. The constitution of these fillers is mainly carboxymethylcellulose solution; it acts as a carrier gel for the particles and microspheres. The particles of these three different fillers are the part of the filler that functions as a subdermal scaffold after injection and stimulates neocollagenesis around the particles.

Ellansé®, Radiesse®, and Sculptra® are all made from resorbable materials. The particles/microspheres are made from: 

  • ELLANSÉ®: Polycaprolactone (PCL): (C6H10O2)n 
  • Radiesse®: Calcium Hydroxylapatite (CaHA): Ca10(PO4)6(OH)2. 18H2O 
  • Sculptra®: Poly-L-Lactic Acid (PLLA): (C3H4O2)n. 

It is well known that the surface morphology of implanted particles has an effect on the biocompatibility of the implant to the surrounding tissue6. Smooth surfaces of embedded particles contribute to a gentle reaction of the body to the implant, without inducing an inflammatory response. Particle size distribution is also important after implantation. Particles smaller than 20 μm can be phagocytosed and transported to the lymph nodes. 

Ellanse and Radiesse are very comparable fillers and are very different from Sculptra, which contains large amounts of particles smaller than 20 μm and many fragments are larger than 50 μm. All three have bio-stimulatory properties, but Radiesse lacks the long-lasting results7, and Sculptra the immediate effect8.

The author believes Ellanse combines durability and immediate outcome. It is composed of microspheres of a bioresorbable polymer, polycaprolactone (PCL) (30%), in an aqueous carboxymethyl cellulose (CMC) (70%) gel carrier. 

The PCL microspheres are 25–50 μm in size and are thus protected from phagocytosis. They are spherical and perfectly smooth. PCL biodegradation and bioresorption occur via hydrolysis of the ester linkages, leading to the end products CO2 and H2O that are eliminated from the body9–13.

The CMC gel carrier has an immediate effect and is gradually resorbed by macrophages in 6–8 weeks, the PCL microspheres stimulate neocollagenesis14,15.  Deposition of newly synthesised collagen around the PCL microspheres was demonstrated by histological and histochemical analysis of skin biopsies from treated animals, showing that collagen type I becomes progressively predominant over collagen type III, thereby achieving earlier and superior qualitative results than other resorbable products with a long-lasting effect14. The collagen stimulatory effect has recently been confirmed in humans on skin biopsies from treated subjects15.


The safety of PCL injections has been demonstrated in clinical studies, and recommendation on injection techniques are provided for the upper, mid and lower face, and zone by zone for each of these areas16. 

In non-surgical facial rejuvenation, an approach targeting the whole face is better than trying to get rid of individual facial lines. Avoid creating and unnatural, overinflated appearance by restoring volume and redefining contours. 

  Declaration of interest None