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Beyond Fillers: Rejuvenation through collagen stimulation

Hot quotes:

-Hyaluronic acid is hydrophilic; it gives an unnatural overinflated look.

-Collagen contributes to the scaffolding and keeps the skin tight.

-With Botox, less is more!

Take home message:

Avoid getting rid of individual facial lines. Focus on appearing ‘well’ for the chronological age. With Botolunim toxin, avoid creating unnatural folds and a frozen face. Hyaluronic acid binds up to 1000 times its weight in water, it is a good lubricant ‘jello’ but when injected in the dermis it can cause pseudocysts and can give an overinflated look.  The newer generation polycaprolactone based collagen stimulator restores volume and redefines contours making it the author’s first choice for natural facial rejuvenation.

Biodata:

Lydia Badia  FRCS (ORL_HNS) was appointed as Consultant Surgeon in Rhinology at The Royal National, Throat, Nose and Ear Hospital (UCL) in 2001 after she finished her fellowship in Facial Plastic Surgery. Her main interest is in Rhinoplasty surgery and has always had a passion for facial aesthetics. ‘Patients who were happy with the nose result wanted more treatments’. She wrote a chapter for the latest edition of the textbook Scott Brown on non-surgical rejuvenation of the ageing face. She resigned her NHS post in 2012 to dedicate her time exclusively to private practice and together with Charles East founded Rhinoplasty London to promote excellence in nose surgery.

BEYOND FACIAL FILLERS; REJUVENATION THROUGH COLLAGEN STIMULATION

 Ageing transforms the face to create a look that often does not reflect the vibrant person inside. Maintaining a youthful appearance can have a profound effect on self-esteem, and personal and professional relationships.

I would like to give an overview of the core of non-surgical interventions and focus on collagen stimulation products which I believe provide better longevity for rejuvenation and more natural results but also extremely useful for injured and scarred tissues 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 life-style and environmental factors, which result in lines from loss of elastin and collagen fibres. The photoageing also affects the skin colour and tone.

Patients are typically concerned about looking fatigued, dull, angry, negative. If they have suffered injuries, they wish to improve the contouring. Most people want to appear “well” and optimum 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, and loss of volume at sites of fat or bone resorption.

1.Topical treatments are popular among consumers seeking skin (epidermis) improvement because of their convenience, low cost and excellent safety profile. Whilst results may be modest, the marked is saturated with promise through 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), and 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 whilst 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.

2.Botulinum toxin has been the most revolutionary anti-ageing treatment in recent years, two to five days after injection it produces muscle paresis and it therefore stops pulling on the skin. The subjective duration of action in a given patient seems to be stable, but there is great variability between different people. On the European Market, three different branches of BTX-A are off icially registered: Botox®/Vistabel® (Allergan), Dysport® (Ipsen)/Azzalure® (Galderma), and Xeomin®/Bocouture® (Merz). The units are not directly comparable. The products have different amounts of complexing proteins or are free of complexing proteins (ie, Xeomin®/Bocouture®). The diffusion of the different 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 surgery. [2] 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.

  1. Fillers. By fillers, I understand the different products, which 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. The filler with long-term effect is autologous fat grafting. This technique was popularized and modified by Coleman [3] There are several issues surrounding fat transfer. One of them is that the injected fat can grow. The have been patients who has 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 may be working 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 remodeling by increasing the expression of Type I collagen in human dermal fibroblasts. [4]. This is the evidence for the “vampire facelift”.

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

Permanent artificial fillers are in my view no longer recommended, as the widely accepted long-term effect safety has not been established. Temporary fillers are metabolized by the human body and consist of different substances. Hyaluronic acid (HA) 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. Cross-linking gives HA fillers a life span of six to eighteen months. [5]. Although there is some evidence that HA stimulated 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 give an unnatural overinflated look. Figure 1. Shows a comparison sonogram between PCL and HA.  [6] The HA produces multiple anechoic pseudocystic structures. The bright hyperechoic spots noticed in PCL represent microspheres with collagen stimulating properties. Collagen contributes to the scaffolding and keeps skin tight.

Figure 1. Comparison of sonographic morphology between

polycaprolactone versus hyaluronic acid. A, Polycaprolactone. The filler consists of a matrix with hypodermal hypoechoic deposits (*) that contain bright hyperechoic spots with mini-comet-tail artifact (arrows). B, Hyaluronic acid.

demonstrates multiple hypodermal deposits conformed by oval-shaped, anechoic pseudocystic structures. Notice that there are no bright hyperechoic spots within the deposits (o).

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 . 18 H2O

Sculptra®: Poly-L-Lactic Acid (PLLA): (C3H4O2)n

It has been well known that the surface morphology of implanted particles has an effect on the biocompatibility of the implant to the surrounding tissue. [7]. Smooth surfaces of implanted particles contribute to a gentle reaction of the body to the implant, without inducing an overreaction 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 based fillers and they are very different from Sculptra which contains large amounts of particles smaller than 20 um and many fragments are larger than 50 um. All three have biostimulatory properties but Radiesse lacks the long-lasting results,[8] and Sculptra the immediate effect [9].

Ellanse combines durability and immediate outcome. This unique product is composed of microspheres of a totally 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 totally spherical and perfectly smooth .PCL biodegradation and bioresorption occur via hydrolysis of the ester linkages, leading to the end products CO2  and H2 O that are totally eliminated from the body.[10-14]

The CMC gel carrier has the immediate effect and is gradually resorbed by macrophages in 6–8 weeks, the PCL microspheres stimulate neocollagenesis.[15,16]  Deposition of newly synthesized 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 effect.[15 ] The collagen stimulatory effect has recently been confirmed in humans on skin biopsies from treated subjects.[16].

The PCL-based safety 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 areas. [17].

  1. Darlenski R, Suber C, Fluhr JW. Topical retinoinds in the management of photodamaged skin: from theory to evidence-based practical apporach. Br J Dermatol 2010; 163: 1157-65.
  2. Badia, L. The use of Botulinum Toxin in Facial Rejuvenation. ENT News. Feature article. 2006; Volume 14 Number 6:59-63.
  3. Coleman S.R.: Structural fat grafts: The ideal filler. Clin. Plast. Surg.,2001; 28: 111.
  4. Kim DH, Jin Je Y, Kim CD, et al. Can platelet-rich plasma be used for skin rejuvenation? Evaluation of effects of Platelet-rich plasma on human dermal fibroblast. Annals of Dermatology. 2011 Nov; 23(4): 424-431
  5. Beer K. Lupo MP. Making the right choices: attaining predictable aesthetic results with dermal fillers. J Drugs Dermatol 2010; 9 (5):458-465
  6. Wortsman K, Quezada N: Ultrasound morphology of Polycaprolactone filler. J Ultrasound Med 2017;00:00-00
  7. Lemperle G et al. Migration studies and histology of injectable microspheres of different sizes in mice. Plastic and Reconstructive Surgery. 2004;113(5): 1380-90.
  8. Jacovella PF. Use of calcium hydroxylapatite (Radiesse) for facial augmentation. Clin Interv Aging. 2008;3(1):161–174.
  9. Redaelli A, Rzany B, Eve L, et al. European expert recommendations on the use of injectable poly-L-lactic acid for facial rejuvenation. J Drugs Dermatol. 2014;13(9):1057–1066.
  10. Pitt CG. Poly-epsilon caprolactone and its polymers. In: Chassain M, Langer R, editors. Biodegradable Polymers as Drug Delivery Systems.Vol. 45. New York, USA: Marcel Dekker; 1990:71–119.
  11. Pitt CG, Gratzl MM, Kimmel GL, Surles J, Schindler A. Aliphatic polyesters II. The degradation of poly (DL-lactide), poly (epsilon-caprolactone), and their copolymers in vivo. Biomaterials. 1981;2(4):215–220.
  12. Taylor MS, Daniels AU, Andriano KP, Heller J. Six bioabsorbable polymers: in vitro acute toxicity of accumulated degradation products. J Appl Biomater. 1994;5(2):151–157.
  13. Ma G, Song C, Sun H, Yang J, Leng X. A biodegradable levonorgestrelreleasing implant made of PCL/F68 compound as tested in rats and dogs. Contraception. 2006;74(2):141–147.
  14. Sun H, Mei L, Song C, Cui X, Wang P. The in vivo degradation, absorption and excretion of PCL-based implant. Biomaterials. 2006;27(9):1735–1740.
  15. Nicolau PJ, Marijnissen-Hofsté J. Neocollagenesis after injection of a polycaprolactone based dermal filler in a rabbit. Eur Cell Mater. 2013;3(1):19–26.
  16. Kim JA, Van Abel D. Neocollagenesis in human tissue injected with a polycaprolactone-based dermal filler. J Cosmet Laser Ther. 2015;17(2):99–101.
  17. De Melo F, Nicolau P et al. Recommendations for volume augmentation and rejuvenation of the face and hands with the new generation polycaprolactone-based collagen stimulator (Ellanse). Clinical, Cosmetic and Investigational Dermatology. 2017: (10):431-440

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