Skin rejuvenation without a scalpel. I. Fillers

Fillers are an important tool in the armamentarium of the physician combating aging phenomena. A wide variety of filler substances are now available that meet many, but by far not all, needs in aesthetic medicine. The most commonly used substances now are hyaluronic acid and collagen preparations that have slightly different indications, but collagen requires pre-use testing to rule out inflammatory complications. Poly-L-lactic acid has gained its place in the filling of adipose tissue wasting in HIV-infected patients. Autologous fat is easy to harvest and inject and has virtually no risk of adverse side effects. Permanent fillers may be of advantage but carry the risk of permanent adverse reactions. Skillful combination of different fillers as well as with botulinum toxin injections and other cosmetic procedures may give optimal results.     

Comparison of polycaprolactone and calcium hydroxylapatite dermal fillers in a rat model

Polycaprolactone (PCL) and calcium hydroxylapatite (CaHA) are semipermanent dermal fillers that are frequently preferred in the last decade. This study aims to compare the effects of these two fillers in the rat skin. A total of 30 female rats were divided into; control, PCL, and CaHA group. Tissue samples taken at the second and fourth month were stained with hematoxylin‐eosin, Masson trichrome, collagen type 1, and 3 immunohistochemical antibodies. Collagen density was quantitatively compared using the Image J computer program. At 2 and 4 months, the density of collagen increased in both filler groups compared to the control group. There was no significant difference between collagen density or type 1 and type 3 collagen H scores in the filler groups. The number of fibroblast nuclei was significantly higher in the PCL group at 4 months compared to the other two groups. Dermis thickness was found to be superior in both filler groups compared to the control group at the fourth month, there was no significant difference between the filler groups. We compared the effect of CaHA and PCL filler on collagenization histologically and immunohistochemically. We found that PCL and CaHA fillers are effective in increasing dermal collagen density, type 1 and type 3 collagen amount, and preventing dermis atrophy and showed that they have no advantage over each other in this respect. We have shown that PCL filler provides more fibroblast increase compared to CaHA filler and the effect of stimulating fibroblast proliferation takes longer.     

High‐frequency sonography of temporary and permanent dermal fillers

Background: Dermal fillers are used widely; some have a permanent effect, whereas others are temporary. The aim of this study is to describe the ultrasonographic features of permanent and temporary fillers injected into patients for cosmetic purposes. Materials and methods: Between December 2006 and April 2009, 36 subjects, aged 25–45, who had received lips or nasolabial fold filler augmentation, were enrolled for a high‐frequency sonographic examination by a blinded investigator. The criteria for exclusion were a history of autoimmunity, infection, neoplastic diseases or episodes of local reactions to the injected filler. Twenty patients underwent a sonographic exam after the injection of a temporary filler (collagen or hyaluronic acid) by FRG; the rest were enrolled among patients seeking a consultation for further cosmetic reasons, but had been treated with an identifiable filler before. Results: It was always possible to identify the filler at the site of injection. Seldom was it possible to discover a silent inflammatory reaction, otherwise unsuspected. The sonographic images differed according to the temporary or the permanent nature of the filler. Conclusion: Ultrasonography has proved to be a useful, non‐invasive tool for the identification of the presence and type of the filler injected.     

Neocollagenesis in human tissue injected with a polycaprolactone-based dermal filler

A novel dermal filler containing polycaprolactone (PCL) has been introduced into the aesthetic market. A recently published study has shown that the PCL-based dermal filler induces neocollagenesis, a process associated with improvement in appearance of the skin, in rabbit tissue. In this pilot study, we investigated whether the PCL-based dermal filler induces neocollagenesis in human tissue by histological analysis. Two patients who were enrolled in the study, and were willing to undergo temple lifting surgery, were injected intra-dermally with the PCL-based dermal filler. Thirteen months post-injection, biopsies were obtained for subsequent histological analysis. Histological analysis of tissue obtained from the biopsies (13 months post-injection) revealed that the PCL-based dermal filler shows collagen formation around the PCL particles and, therefore, supports similar findings previously shown in rabbit tissue. In conclusion, PCL particles are maintained in their original state 13 months post-injection.     

Hyaluronic acid fillers in facial rejuvenation

Nonsurgical procedures have become very popular for the rejuvenation of the aging face. Trends now are for less invasive procedures as well as for more preventative intervention to slow the damage from ultraviolet light and environmental factors, as well as from intrinsic aging. The goal of these procedures is to eliminate or delay the need for corrective surgery. The regular use of sunscreens; retinoids and improved cosmeceuticals; injectable neurotoxins; soft-tissue augmentation products; and minimally invasive laser, light, and radiofrequency treatments are decreasing and delaying need for invasive procedures. Injectable fillers entered mainstream cosmetic medicine with the development of bovine collagen injections in the 1980s. The availability of improved fillers that are less allergenic and longer lasting has resulted in a renaissance in filler techniques. No single filler has proven to be more popular than the category of hyaluronic acids (HA). This article will review the use of the hyaluronic acid fillers that are currently approved for use by the Federal Drug Administration in the United States and describe the significant differences between them to assist the practicing cosmetic physician in choosing and using this category of dermal filler.     

Ästhetische Dermatologie

Younger and younger patients are undergoing aesthetic procedures to achieve "wrinkle-free" aging. This has had great impact on the field of aesthetic dermatology. The rapid development of new indications and filler materials requires a critical approach to the available substances particularly concerning side effects and long-term effects. The quality of the chosen approach depends on the applied filler substance, clear indication the compliance of the patient and the experience of the physician. The growing expectations of patients require a critical analysis of the available therapy options. Botulinum toxin A is one of the preferred treatments for wrinkles secondary to facial expression. In addition there are a variety of biologically inert and completely resorbable filler materials such as collagen and hyaluronic acid and autologous materials such as fat implants or plasma gel available. This article gives an overview about the most common fillers and their use in aesthetic dermatology.     

In vivo stimulation of de novo collagen production caused by cross-linked hyaluronic acid dermal filler injections in photodamaged human skin

OBJECTIVE: To determine whether endogenous synthesis of new extracellular matrix may contribute to the degree and duration of clinical benefits derived from cross-linked hyaluronic acid dermal filler injections. DESIGN: In vivo biochemical analyses after filler injections. SETTING: Academic referral center. PARTICIPANTS: Eleven healthy volunteers (mean age, 74 years) with photodamaged forearm skin. Interventions Filler and vehicle (isotonic sodium chloride) injected into forearm skin and skin biopsy specimens taken 4 and 13 weeks later. MAIN OUTCOME MEASURES: De novo synthesis of collagen, the major structural protein of dermal extracellular matrix, was assessed using immunohistochemical analysis, quantitative polymerase chain reaction, and electron microscopy. RESULTS: Compared with controls, immunostaining in skin receiving cross-linked hyaluronic acid injections revealed increased collagen deposition around the filler. Staining for prolyl-4-hydroxylase and the C-terminal and N-terminal epitopes of type I procollagen was enhanced at 4 and 13 weeks after treatment (P<.05). Gene expression for types I and III procollagen as well as several profibrotic growth factors was also up-regulated at 4 and 13 weeks compared with controls (P<.05). Fibroblasts in filler-injected skin demonstrated a mechanically stretched appearance and a biosynthetic phenotype. In vitro, fibroblasts did not bind the filler, suggesting that cross-linked hyaluronic acid is not directly stimulatory. CONCLUSIONS: Injection of cross-linked hyaluronic acid stimulates collagen synthesis, partially restoring dermal matrix components that are lost in photodamaged skin. We hypothesize that this stimulatory effect may be induced by mechanical stretching of the dermis, which in turn leads to stretching and activation of dermal fibroblasts. These findings imply that cross-linked hyaluronic acid may be useful for stimulating collagen production therapeutically, particularly in the setting of atrophic skin conditions.     

Generalized livedo reticularis induced by silicone implants for soft tissue augmentation

Silicone is one of the most widely used filler for facial cosmetic correction and soft tissue augmentation. Although initially it was considered to be a biologically inert material, many local and generalized adverse effects have been reported after silicone usage for cosmetic purposes. We present a previously healthy woman who developed progressive and persistent generalized livedo reticularis after cosmetic surgery for volume augmentation of buttocks. Histopathologic study demonstrated dermal presence of interstitial vacuoles and cystic spaces of different sizes between the collagen bundles, which corresponded to the silicone particles implanted years ago. These vacuoles were clustered around vascular spaces and surrounded by a few foamy macrophages. General examination and laboratory investigations failed to show any evidence of connective tissue disease or other systemic disorder. Therefore, we believe that the silicone implanted may have induced some kind of blood dermal perturbation resulting in the characteristic violet reticular discoloration of livedo reticularis.     

Dermal fillers

The new bioengineered human collagen products and the various hyaluronic acid (HA) fillers are all safe and effective agents for soft tissue augmentation. There is no one best filler for all purposes and optimal results are achieved by using these products in various combinations. In my opinion, HA-containing products provide volume while collagen products are better suited to provide structural support. Less downtime is associated with the collagen products, due to the platelet-aggregating effects of collagen and the eosinophil-stabilizing effects of lidocaine. Using collagen in combination with HA, during the same office visit, may help reduce some of the bruising and swelling seen with HA alone.     

Inflammatory Nodules Following Soft Tissue Filler Use: A Review of Causative Agents, Pathology and Treatment Options

Nodule development is a common complication following the use of fillers for soft tissue augmentation and is commonly categorized as inflammatory or non-inflammatory in nature. Inflammatory nodules may appear anywhere from days to years after treatment, whereas non-inflammatory nodules are typically seen immediately following implantation and are usually secondary to improper placement of the filler. Although inflammatory nodules are more common with permanent fillers such as silicone, inflammatory nodule development following administration of temporary fillers such as hyaluronic acid and collagen has also been reported. Treated many times with corticosteroids due to their anti-inflammatory properties, inflammatory nodules may be secondary to infection or biofilm formation, warranting the use of alternative agents. Appropriate and prompt diagnosis is important in avoiding delay of treatment or long-term complications for the patient. This paper addresses the etiology, development, and studied treatment options available for inflammatory nodules secondary to each of the major classes of fillers. With this knowledge, practitioners may expeditiously recognize and manage this common side effect and thus maximize functional and aesthetic benefit.     

Filler migration to the forehead due to multiple filler injections in a patient addicted to cosmetic fillers

Filler migration is a potential complication following the injection of multiple fillers. With the increasing popularity of multiple filler injections, migrated granulomas should be an essential differential diagnosis for newly growing facial lumps. It is important for all physicians to be aware that complication induced by dermal fillers can occur in locations other than the planned injected sites. We described a case of filler migration to the forehead in a patient addicted to cosmetic fillers. To our knowledge, it has never been published in dermatology literature so far. A detailed history of cosmetic procedures from the patient addicted to filler injections is necessary for accurate diagnosis. Because account of previous cosmetic filler injections is not always reliable, an early skin biopsy with pathological examination is the gold standard for determining whether multiple filler injections have been performed.     

Clinical Use of RESTYLANE

There is no ideal filler, nor will there be a single product that can satisfy all requirements. However, RESTYLANE, a non-animal, stabilized hyaluronic acid (NASHA, Medicis), is a very versatile augmenting agent. It has been in clinical use for 8 years and experience has shown it to be close to the ideal filler in many respects. This review will outline the background to the use of RESTYLANE, and will focus on the clinical use of this material.     

Hereditary skin diseases of anchoring fibrils.

Remarkable progress has been made in the last few years in understanding the functions of the anchoring fibrils, polymers of collagen VII, that connect the epidermal basement membrane with the dermal connective tissue. Novel insights into the biology of these fibrils have been gained from studies on dystrophic epidermolysis bullosa (DEB), a group of inherited blistering disorders caused by abnormalities of the anchoring fibrils. Mutations in the COL7A1 gene encoding collagen VII have been disclosed in a number of DEB families, and the mutation analyses and studies on genotype-phenotype correlations in DEB have revealed an unusual complexity of the gene defects and their biological consequences. In analogy to heritable disorders of other collagen genes, predictable phenotypes of COL7A1 mutations causing premature termination codons (PTC) or dominant negative interference have been observed. However, collagen VII seems to be unique among collagens in that many mutations lead to minimal phenotypes, or to no phenotype at all. Furthermore, the mild DEB phenotypes can be severely modulated by a second mutation in individuals compound heterozygous for two different COL7A1 defects. Therefore, not only definition of mutations with diagnostic analyses, but also cell biological, protein chemical and suprastructural studies of the mutated molecules are required for understanding the pathomechanisms underlying DEB.     

Peripheral anchorage of dermal equivalents

Human fibroblasts can induce collagen gel contraction with different kinetics depending on the number of cells and on the collagen concentration within this lattice, which has been considered as a dermal equivalent. Skin equivalent is a combined culture of dermo-epidermal layers which may be of therapeutic value in the treatment of burn patients. However, the current production of the dermal equivalent component gives results that present many drawbacks for their eventual clinical use as a first step in obtaining a skin equivalent. These include: (i) final surfaces which are very small; less than 20% of the initial size (ii) excessive thickness which may hamper successful graft take (iii) fibroblasts that do not have an arrangement comparable with normal dermal tissue. We propose, as a solution to these problems, the utilization of a 5-mm-wide fibre-glass filter ring peripherally attached to the surface of the Petri dishes to prevent inordinate contraction while the fibroblasts reorganize the collagen gel. Using this technique the initial surface was preserved and the dermal equivalent contracted only in thickness. Histological analysis of these anchored equivalents confirmed an alignment of fibroblasts and collagen fibres resembling normal dermal tissue. We consider this method useful in the development of dermo-epidermal sheets for clinical purposes.     

Management of noninflammatory nodule in chin after a large volume bolus injection of hyaluronic acid filler

As most Asian women desire to have an “inverted triangle” appearance for face, there is an increasing trend to give a large volume bolus (LVB) injection in the submental region of the chin for its lengthening. Hyaluronic acid (HA) dermal fillers are very popular for facial contouring and reshaping, including the chin area. Filler injection in the submental area has been a popular method to lengthen the chin. Placing an LVB of HA filler material at one place can present as the formation of lump or nodule after injection. We present a case of formation of a nodule in the submental area after injection of a single LVB of filler. The nodule was injected with hyaluronidase 3 months after its formation, and a near‐complete resolution was seen immediately. Complete disappearance of the nodule was found at follow‐up after 10 days. LVB of HA filler can give rise to the formation of noninflammatory nodules after filler injection in the immediate post‐injection period. Knowledge of the type of filler material and presenting features can help in instituting the correct line of treatment for the resolution of signs and symptoms. Also 0.5 mL of filler can be recommended as maximum size of single LVB, based on the mathematical calculations.     

Facial volume restoration of the aging face with poly-l-lactic acid

The purpose of this article is to discuss current techniques used with poly-l-lactic acid to safely and effectively address changes observed in the aging face. Several important points deserve mention. First, this unique agent is not a filler but a stimulator of the host's own collagen, which then acts to volumize tissue in a gradual, progressive, and predictable manner. The technical differences between the use of biostimulatory agents and replacement fillers are simple and straightforward, but are critically important to the safe and successful use of these products and will be reviewed in detail. Second, in addition to gains in technical insights that have improved our understanding of how to use the product to best advantage, where to use the product to best advantage in facial filling has also improved with ever-evolving insights into the changes observed in the aging face. Finally, it is important to recognize that a patient's final outcome, and the amount of product and work it will take to get there, is a reflection of the quality of tissues with which they start. This is, of course, an issue of patient selection and not product selection.     

Biocompatibility of microparticles into soft tissue fillers

The increasing need for long-lasting injectable soft tissue fillers for the treatment of wrinkles and folds requires a critical discussion of the biocompatibility on a scientific background. Since biological fillers made of collagen and hyaluronic acid will be resorbed over time, copolymer biomaterials with microparticles have been developed in recent years. The microparticles followed special and essential demands because of the interaction with the tissue. In search of an ideal soft tissue filler substance, a variety of biomaterials with microparticles suspended have been created for injecting into dermal defects, into the urethra of patients with urinary incontinence, and in patients with vocal cord insufficiency. The particles differ in chemical composition, surface structure, surface charge, and particle size and evoke different host reactions, accordingly.     

Pathophysiology of fibroses. Progressive systemic scleroderma as a model disease

Fibrosis is characterized by excessive deposition of connective tissue in the involved organs. Although the prime event in the pathogenesis is still poorly understood, several mechanisms are discussed, which finally result in the activation of fibroblasts. Recent studies have demonstrated that immunocompetent cells play a crucial role during the initial phases of the development of fibrosis. Therefore, several mediators have been characterized, which are secreted by platelets, lymphocytes and macrophages and which can attract fibroblasts, induce proliferation and collagen synthesis in mesenchymal cells. These include PDGF, EGF, TGF--beta and many others. In addition, gamma-interferon has been shown to inhibit chemotaxis of fibroblasts and to reduce collagen mRNA levels. A controlled interaction of all the different mediators is required to guarantee a normal functioning of connective tissue. Alterations in these regulation steps can result in excessive deposition of connective tissue and the development of fibrotic processes.     

Effects of minoxidil on human skin fibroblasts in culture

Collagens are a family of extracellular proteins that have evolved to serve many specialized biologic functions. Fifteen collagen types with at least 18 genetically distinct polypeptide chains have been identified.¹ In skin, eight of these collagens make up a major portion of the extracellular matrix including specialized structures such as basement membrane (Type IV collagen) and anchoring fibrils (Type VII collagen). All collagens are synthesized as procollagen precursor molecules. In addition to synthesis and precise association and alignment of the three polypeptide chains, biosynthesis involves many posttranslational modifications.^2,3 These include synthesis of hydroxyproline catalyzed by prolyl hydroxylase and synthesis of hydroxylysine catalyzed by lysyl hydroxylase. Hydroxyproline is essential for maximum helical stability, and hydroxylysine participates in collagen cross-link formation as well as synthesis of specific glycosides catalyzed by collagen glycosyl transferases. Other enzymes incorporate into the procollagen molecule complex carbohydrate residues typical of glycoproteins. Following secretion from the cell, amino and carboxyterminal propeptides of the procollagen molecule are cleaved by separate enzymes. Certain lysyl and hydroxylysyl residues are then modified by lysyl oxidase to corresponding aldehydes, which interact with certain hydroxylysine residues to form intermodular cross-links.     

Comparative effects of various absorbable threads in a rat model

Background: Conventional procedures including botulinum toxin and filler injections have their limitations in improving deep wrinkles and decreasing tissue laxity, and possess the propensity for vascular accidents. Absorbable thread is a recently commercialized field, but there is little evidence on comparative superiority. Objectives: We observed the effects of polydiaxanone (PDO) threads with different number of strands in relation to collagen production and histopathology in a rat model. Materials and methods: Dorsal skin of rat was divided into five different compartments and four different PDO threads and monofilament poly-lactic acid (PLA) thread were inserted. Tissue samples were obtained at week 1, 2, and 12 after the procedure for histopathologic review and real-time PCR for quantification of collagen. Results: Multiple PDO filaments produced more collagen at 2 weeks. Single-stranded PLA thread insertion resulted in more Col1α1 levels than the double PDO thread and also showed the most Col1α3 production at week 2. The amount of collagen showed a sharp decline at week 12. Histologic evaluation showed retained threads surrounded by fibrous capsule-like structure at week 12. Conclusion: We were able to observe more collagen production in multiple stranded PDO threads compared to a single strand and that increasing number of threads leads to more collagen synthesis.