Injections in Aesthetic Medicine: Atlas of Full-face and Full-body Treatment

Part I

General Aspects

© Springer-Verlag Italia 2014

Mario Goisis (ed.)Injections in Aesthetic Medicine10.1007/978-88-470-5361-8_1

1. Fillers in Aesthetic Medicine

Mario Goisis¹  , Alessandro Di Petrillo¹  , Claudio Rinna¹, Chiara Brillante¹, Magda Guareschi¹ and Doris Ali Youssef¹

(1)

Maxillo-Facial and Aesthetic Surgeon, Doctor’s Equipe, via Carducci 19, 20123 Milan, Italy

Mario Goisis (Corresponding author)

Email: mariogoisis@yahoo.it

Alessandro Di Petrillo

Keywords

Body enhancementBody modellingBotoxBotulinBreast augmentationCollagenFillerHyaluronic acidHydroxylapatiteIsogenicMacrolanePlatelet-Rich PlasmaRadiesseVistabexWrinkles

1.1 Permanent Fillers

Doris Ali Youssef

The pursuit of beauty and the effort to reverse the effects of ageing dates back to many centuries. Facial volume depletion and facial rhytids are a natural and inevitable part of ageing. Over the last 100 years, various attempts to restore volume to the face with the use of injectable devices have been described.

The prologue to this story must start with the development of the appropriate technology, namely the syringe. The hollow needle was invented in 1844 by Irish physician Francis Rynd [1].

The fillers history begins in 1830, when a German chemist, Baron Karl Ludwig von Reichenbach, discovered a material created by the dry distillation of beech-wood tar. He noted this substance to be very unreactive and named it paraffin, from the Latin parum (barely) and affinis (affinity). The first reported use of a material injected into the body for ‘cosmetic’ purposes was by Robert Gersuny (1844–1924) [2]; Gersuny injected mineral oil (liquid paraffin) to create a testicular prosthesis in a patient with tuberculous epididymitis who had been treated by castration. Paraffin was enthusiastically embraced by the medical community and became the treatment of choice for nasal augmentation. However, in 1901, a case was reported of a 39-year-old woman who underwent paraffin injection for urinary incontinence and developed pulmonary and cerebral paraffin emboli [3]. The sequelae associated with paraffin injections were outlined in 1911 by Kolle [4], who described inflammation, infection, embolism, and yellowish skin plaques at the site of the injection. In the following years, the term paraffinoma was used to describe the granulomatous foreign-body reaction that developed as a result of paraffin injection.

The most famous account of the complications of paraffin injection was that of the Duchess of Marlborough [5]. This American-born, dazzling beauty was preoccupied with the ‘kink’ of her nose and underwent paraffin injections to her nasal dorsum. The paraffin subsequently migrated into her chin producing paraffinomas throughout her face. She became so disfigured she did not permit mirrors in her house, and she died a recluse in 1977. The biology of injected paraffin is now well understood. There is an initial inflammatory phase, followed by a latent phase that can last for decades [6] Over time, the fatty tissue calcifies and develops hyaline sclerosis, producing yellowish skin nodules. These lesions can become infected or fistulize. Because the paraffin is inert, it remains completely unchanged in the body and can migrate through the fatty tissue, stopped only by fascial planes.

Over the subsequent years, similar injectables such as vegetable oil, mineral oil, lanolin and beeswax have been used for cosmetic injections but were abandoned due to undesirable complications including migration, granuloma formation and scarring. A tragic example of such injections was described in the London Daily Telegraph (November 11, 2008). A Korean woman received silicone injections from a physician who also gave her syringes to self-administer. After she ran out of silicone, she substituted cooking oil for self-injection and ultimately became severely disfigured.

1.1.1 Liquid Silicone

In the 1960s, liquid silicone injection became a popular cosmetic treatment [7–10]. Like paraffin, silicone is an inert, clear, oily substance that is easily injected and, unfortunately, had similar disastrous sequelae. Silicone, a polymer of dimethylsiloxanes, was first used in Japan during the 1940s for breast augmentation. This practice spread to the United States (California, Texas and Nevada), in 1965, Dow Corning developed a purified silicone that could be used for injection, called MDX4–4011. In subsequent years, it was noted that the injected silicone would migrate and fistulize, and it had resulted in several deaths. Some patients with severe complications required mastectomies. Because of the complications encountered in the Las Vegas showgirls injected with silicone, Nevada was the first state to ban the use of injectable silicone. In 1964, Weiner coined the term siliconoma to describe the soft tissue granuloma that developed from injected silicone. These disfiguring inflammatory responses could sometimes be seen decades after silicone had been injected. Although medical-grade silicone was also used to treat facial wrinkles and augment the lips, the U.S. Food and Drug Administration (FDA) considered it an investigational device and never approved silicone for cosmetic use. In 1964, the FDA regulated the use of injectable silicone as a drug, and the Medical Device Amendments of 1976 restricted the use of silicone as a device. After reports of the sequelae of injected silicone, in 1979, the FDA and the American Medical Association condemned the use of injectable liquid silicone. Although today medical-grade silicone is available for ophthalmic use in the treatment of detached retinas, its cosmetic use is considered illegal in some states. In spite of the problems encountered with injectable liquid silicone, silicone injections are still performed in Europe, Canada, Mexico and by some physicians in the United States. Since 1994, two medical-grade silicone products were available to treat detached retinas, and use of these products cosmetically is considered ‘off-label’. Even though the use of injectable silicone for cosmetic purposes is federally banned and illegal in some states, some physicians feel that in the hands of experienced surgeons, injections can be extremely efficacious. They purport the ‘microdroplet’ injection technique using a small needle and deep injection into the dermis and subcutaneous fat. These injections are performed in multiple treatments over 1- to 3-month intervals. The authors strongly suggest not to use liquid silicon and to consider this use illegal.

1.2 Collagen

1.2.1 Heterologous Collagen

Giorgio Persichetti, Valentina Isgrò

Bovine collagen has been the most widely used filler material in the early 2000s (See Table 1.2). Three products have been manufactured and distributed by Inamed: Zyderm I, Zyderm II, and Zyplast. Inamed has been acquired by Allergan at the end of 2005. Allergan continued marketing these products until the end of 2010. In June 2008, Johnson & Johnson patented their own product, Evolence, derived from porcine collagen. The production of Evolence has been suddenly discontinued in November 2009.

Zyderm I corrected fine lines quite well, particularly fine perioral and crow’s-feet lines. Zyderm II, designed to correct average lines, offers an average duration of 3–6 months. Zyplast was designed to correct deep wrinkles in thick skin and to restore facial volume (lips and outline of the face). It generally lasted 6–12 months [11].

Evolence has been recommended for the treatment of moderate to deep wrinkles, fold and lines, including hard-to-treat nasolabial folds.

Due to the possible allergic reactions concerning the use of heterologous collagen, a preliminary test was mandatory before injection.

A double test was recommended because positive reactions to treatment have been reported in 0.3–1.5 % of patients even after clinical selection and initial testing [12, 13].

Pons-Guiraud [14] recommends the following protocol, which can take up to 7 weeks to complete. The first injection (0.1 mL) is given in the anterior aspect of the forearm, followed by a reading at 72 h. A positive reaction is characterized by a change in the contour of the injected implant, erythema, oedema, occasionally pruritus and, rarely, by an indurated papule or inflamed dermal nodule. All positive reactions contraindicate collagen injections. A second injection is given 15 days later, followed by readings 3 days and 4 weeks later. Any positive reaction to the test or double test contraindicates the collagen injection. If there is any doubt, bovine (ACACB) and human (ACACH) anticollagen antibodies must be measured.

Concerning complications, a study performed by Castrow and Krull [15] on behalf of 316 practitioners, covering approximately 7,000 patients who demonstrated negative test results revealed a side-effect rate at the injection site of 1.5 %.

The reactions were mostly limited to the injection site: erythema, induration, itching, and pain. In general, these reactions lasted 4–6 months; in a few cases, they lasted more than 1 year. Other reactions included arthralgia (6.5 %) and local granulomas (5 %, confirmed in 4 of 5 cases through biopsy). In rare cases, severe allergic reaction (anaphylactic shock) that requires immediate emergency medical assistance occurred.

Abscesses were reported at a frequency of 4 cases per 10,000 patients [16]. These reactions develop, on average, 8–12 weeks after the injection, after 1 or more collagen injections. They are characterized by a nodule or papule at the injection site, severe swelling, erythema and induration of the surrounding tissues. The abscess is different from the collagen hypersensitivity reaction, which is also characterized by induration and erythema but is not fluctuant. Cases of necrosis have been reported at a rate of 9 per 10,000 [16]. The local necrosis reaction after injection of collagen is not related to the implant itself but to obstruction of a blood vessel or ischaemic necrosis.

According to ASAPS member statistics, use of heterologous collagen decreased starting from 2004 (Table 1.1).

Table 1.1

ASAPS member statistics year on year comparisons for dermal filler products

During 2009, law firm McPhadden Samac Tuovi announced a proposed class action against Johnson & Johnson and related companies relative to the injectable collagen dermal filler Evolence. It is alleged that Johnson & Johnson and related companies failed to warn the public about the potential of these adverse effects. Exactly, during November 2009, Johnson & Johnson announced that it would be discontinuing the porcine collagen product.

The need of a double test and relative waiting time together with the risk of side effects are probably the main reasons leading to a gradual decrease in the mid of 2000s and a definitive loss of popularity of heterologous collagen between 2008 and 2010.

1.2.2 Human Collagen

Implantable materials containing autogenous or isogenous human collagen have a limited presence because preparation of the injectable solutions is relatively difficult, and the cost of these products is relatively high.

1.2.3 Autogenic Human Collagen

Introduced at the end of the 1980s, Autologen (Collagenesis, Inc., Beverly, MA) was the first autologous injectable agent on the market. Autologen is a dispersion of intact collagen fibres and a matrix of collagen tissue obtained from the clean skin of the patient during a plastic surgery procedure (mammaplasty, abdominoplasty, facelift and blepharoplasty). A skin biopsy is inadequate. Because the injected material is autologous and no allergic reactions were reported in a sufficient number of patients, the United States Food and Drug Administration (FDA) does not consider it necessary to perform a test before Autologen injection. The skin excision, placed in a sterile container, is sent to the manufacturer’s laboratory for treatment. As a general rule, 10–13 cm² of excised skin is required to produce 1 mL of Autologen 5 %.

At least 3 injections, a few weeks apart, are needed to obtain a satisfactory result, provided that each treatment is overcorrected by 30 % [17]. The duration of treatment depends on the region treated, the injection technique and the volume of Autologen administered. No significant side effects have been reported. It must be noted, however, that moderately severe erythema may last for 48 h after the injection [18, 19]. Preparation of the autologous collagen from a patient-tissue sample is expensive, and yield varies, depending on the individual and the anatomic areas from which collagen is harvested. Since 1998, autologous fibroblast cultures have been used to correct wrinkles, scars and other skin defects. Boss et al. [20] described a method of injecting autologous fibroblasts obtained from a 3-mm skin excision from the retroauricular area, an area protected from UV light. The sample is immediately placed in a culture medium provided by Isolagen Laboratories (Houston, TX) and must reach the laboratory by the day after sampling in an isothermic container. Six weeks after sampling, an injection test (0.1 mL) is administered to the patient in the forearm; any sign of an allergic reaction is recorded. Two weeks after the test, approximately 1 mL of the autologous material is available for implantation. Overcorrection of 300 % is recommended for suitable aesthetic results [21, 22]. The level of correction achieved depends on the defect, the patient’s age, and the ability of the patient’s fibroblasts to create collagen. Patients older than 60 years are not good candidates for this technique. This technique has several disadvantages. The Isolagen preparation must be injected within 48 h. It offers more effective correction of periorbital wrinkles or perioral wrinkles than of deep furrows [23]. The improvement obtained is poor compared with that of other techniques, such as hyaluronic acid, and correction is not immediate. Fagien and Elson [24] concluded that the results obtained with this technique were rather disappointing. In addition, Isolagen is expensive.

1.2.4 Isogenic Human Collagen

Alloderm (LifeCell, Branchburg, NJ) has been used in the treatment of burns and for transplantation in periodontal surgery. In aesthetic surgery, it is used to increase lip volume, to correct nasolabial folds and to treat scars. Alloderm is an acellular dermal graft material obtained from cadavers or from a tissue bank that provides an acellular matrix of dermal components, including collagen, elastin and glycosaminoglycans. The dermis skin is examined in accordance with FDA requirements and regulations relating to human tissue. No cases of transmissible viral disease have been reported in patients who have received this treatment since its introduction in 1992. Alloderm is offered in the form of sheets that are implanted through an incision in the treatment area. Infection of the incised/sutured sites has been attributed to abscess formation around the suture rather than to the graft itself. Cases of labial herpes have also been reported; prophylactic antiviral therapy must be prescribed for patients with a history of labial herpes. Alloderm is also available in a micronized injectable form, marketed under the name Cymetra (average particle size 123 μm). Cymetra is provided in the form of an aseptic powder reconstituted with lidocaine 0.5 % with 1: 200,000 epinephrine immediately before injection. It is injected with a 26-gauge needle [25]. Dermalogen (Collagenesis Corp., Beverly, MA) is obtained from cadaver tissues that have been carefully selected to help eliminate the risks of viral and bacterial infection. Clinical indications for the use of Dermalogen include correction of obvious nasolabial folds, perioral wrinkles, glabellar wrinkles and depressed scars, as well as increasing lip volume. The injection technique for Dermalogen is the same one used for Autologen: injection into the middle dermis/deep dermis with a 30-gauge needle. Because the injection is painful, use of a local anaesthetic is recommended [26]. Overcorrection of 20–30 % is recommended at each session. An average of 3 injection sessions is required for satisfactory correction. Prolonged erythema and acneiform rashes were noted in 10 % of patients in a study of 130 patients. The manufacturer does not recommend a pretreatment allergy test, although 1 case of foreign-body reaction 4 weeks after a test injection of 1 mL of Dermalogen in the forearm has been described by Moody and Sengelmann [27]. Klein [28] also reported several positive skin tests with Dermalogen and 1 case of secondary reaction characterized by redness, swelling, and hyperpigmentation of the treated sites after Dermalogen implantation.

1.3 Hyaluronic Acid

Chiara Lumini

Hyaluronic acid is a natural substance in the body that was first described in 1934 by John Palmer and Karl Meyer at Columbia University, New York. It was isolated from a cow’s eye, and the name comes from hyalos (Greek word for glass) and the uronic sugar found in the substance. Hyaluronic acid is produced by the cells in the human body, and it plays a key role in numerous functions. It facilitates the cell-division process, it makes the skin elastic and it lubricates the joints. In 2003, the U.S. Food and Drug Administration (FDA) approved the first hyaluronic acid dermal filler for the correction of moderate to severe facial wrinkles and folds, such as nasolabial folds. In the last ten years, numerous products for therapeutic and aesthetic uses have been developed for this versatile natural substance.

1.3.1 What is Hyaluronic Acid?

Hyaluronic acid is a natural complex sugar found in all living animals. It is one of the few elements that is virtually identical in all living organisms. Hyaluronic acid has the capacity to bind great quantities of water, absorbing more than 1,000 times its weight In addition, hyaluronic acid combines with collagen and elastin. The triple binding of elastin, collagen and hyaluronic acid provides elasticity and volume to the skin.

The body’s amount of hyaluronic acid is metabolized quickly and must be newly produced constantly by the cells.

The ageing of the skin, and the exposure to oxidants, to pollutants and to ultraviolet rays, reduce the ability of the cells to produce hyaluronic acid. As a result, the skin begins to reduce its volume, with subsequent formation of facial wrinkles and folds.

1.3.2 What is Cross-Linked Hyaluronic Acid?

In its natural form, hyaluronic acid is a liquid composed of individual polymers (chains) that are broken down in the body in just 12 h. Cross-linking is a process in which the individual chains of hyaluronic acid are cross-linked (chemically bound) together, converting the liquid hyaluronic acid into a gel, a soft solid. The hardness of the gel depends on the degree of cross-linking of the individual hyaluronic acid chains.

The body metabolizes cross-linked hyaluronic acid more slowly than the natural individual chains, resulting in a longer duration of effect.

For this reason, dermal fillers composed of cross-linked hyaluronic acid are used in aesthetic medicine to temporarily replace lost hyaluronic acid and to restore volume of the face and of the body.

Fillers are reticulated hyaluronic acid-based medical devices. They are made of stabilized non-animal hyaluronic acid obtained from bacterial fermentation of_Streptococcus equi strains.

The cross-linking agent generally used for fillers is 1.4-butanediol diglycidyl ether (BDDE), a small molecule that binds to two ends of an HA chain, generating a three-dimensional structure.

The various HA-based fillers on the market have different chemico-physical characteristics, such as particle size, the cross-linking agent used, the degree of cross-linking, the quantity of free HA and the elastic modulus G.

The quantity of hyaluronic acid in a product affects its consistency and longevity. However, it is also important to take into account the quantity of reticulated HA, the quantity of non-reticulated HA and the degree of cross-linking to consider the HA as fully or partially linked. Often, some quantities of free hyaluronic acid are added to increase its ease of injection as it functions as a lubricant.

The cohesive property of the gel depends on the elastic modulus G which measures its resistance to deformation and, therefore, the strength of the gel. Fillers with a high G are considered cohesive gels and are indicated for correction of deeper wrinkles, such as naso-labial folds or for marionette lines, whereas fillers with a lower G′ are indicated for the treatment of larger areas such as the cheekbones and cheeks (See Table 1.2).

Different properties of hyaluronic acid can be resumed in a simple classification:

low viscosity hyaluronic acid, useful for revitalization and small wrinkles

medium viscosity hyaluronic acid: useful for deeper wrinkles, lines and lips

high viscosity hyaluronic acid: useful for larger areas as malar areas.

1.3.3 History of Hyaluronic Acid in Aesthetic Medicine

1987 Q-Med was founded by Bengt Ågerup with a view to commercializing the research that he had carried out around hyaluronic acid.

1996 Restylane® obtained marketing authorization in Europe for use as filler for wrinkles and lip augmentation.

2003 Restylane® is approved in the US.

2003 Corneal group introduces Juvaderm in Europe and Canada.

In 2006, Q-Med launches a new product for lip enhancement treatment, Restylane Lipp™, Q-Med’s first product in the field of body augmentations, Macrolane™, is approved in Europe.

The JUVÉDERM™ dermal filler family of products is approved by the FDA.

2007 Restylane Perlane™ approved for sale in the USA.

2008 Q-Med’s Restylane Vital™ and Restylane Vital™ Light—were launched in Europe.

Allergan introduces in Europe Juvederm Ultra 2, 3 and 4.

2009 Restylane obtained registration approval in China and became the first injectable non-animal hyaluronic acid product on the Chinese market.

Q-Med introduced Restylane® Lidocaine and Restylane Perlane™ Lidocaine.

Allergan introduces Juvaderm Voluma.

2010 By the beginning of 2010 FDA approved Restylane and Restylane Perlane with added lidocaine in USA.

2011 Belotero Balance has been approved by FDA to treat moderate to severe facial wrinkles and folds. De-listing of Q-Med AB (publ) from NASDAQ OMX Stockholm. Q-med is acquired by Galderma.

CE-approval of Restylane SubQ lidocaine.

2012 Glytone Range of Injectable Hyaluronic Acid Products of Pierre Fabre Group was acquired by Merz Aesthetics Inc.

Allergan introduces the new filler Juvederm Volbella with lidocaine.

1.4 Macrofillers: Hyaluronic Acid for Body Modelling

Giulia Beltrami

The use of liquid filler for body enhancement was first described in 1899 by Gersuny, who injected silicone into the scrotum of a patient in order to reconstruct a testicle after an orchiectomy [29, 30]. Since then, there has been a steady increase in the use of implants and filler substances to reshape body defects. In particular, many permanent liquids and gels have been injected for breast augmentation (e.g. silicone, paraffin, polyalkylimide and polyacrylamide hydrogel). However, the use of these materials has been hampered by complications, such as chronic inflammatory reactions, palpable nodule formation, granuloma formation, and migration [29, 31–33]. As a consequence of these complications, new materials on the market can face scepticism, even if they are biocompatible and non-permanent.

Hyaluronic acid specifically produced for body remodelling was introduced in 2009, in particular Macrolane, a new formulation of injectable stabilized hyaluronic acid–based gel of non-animal origin (NASHA-based gel; Q-Med AB, Uppsala, Sweden) have been developed for use in breast enhancement, volume restoration and contouring body surfaces [31, 34]. Since larger volumes are required for body enhancement than for facial augmentation, the Macrolane formulation has increased viscosity (i.e. a thicker gel). With a high resistance to deformation, hyaluronic acid gel augments body tissue simply by occupying space (in a similar manner to permanent implants).

In 2010, Bioscence (Bioscence, Germany) introduced Hyacorp for body enhancement, with exclusion of breasts. Hyacorp is a specially designed cross-linked HA gel which becomes less viscous under pressure (injecting force) and returns immediately to the original viscosity upon pressure release (injecting force). This is a characteristic of a system (advanced thixotropic technology = ATT technique) exhibiting a decrease in viscosity with an increase in the rate of shear, usually a function of time.

Breast augmentation was Macrolane major indication. Many women have undergone breast augmentation with Macrolane in Europe and Asia. It has never been approved for breast augmentation by the Food and Drug Administration [31, 34]. In January 2010 Goisis et al. wrote a contribution to Aesthetic Plastic Surgery [35]. Three major questions were examined in this paragraph. The first question is related to the duration and cost of Macrolane. Macrolane is a resorbable material, and the study of P. Heden et al. published in 2009 showed 30–50 % resorption at 12 months [31]. The echographic measurements in the study of Goisis et al. [35] showed a 60 % rate of resorption after one year. Consequently, a second treatment was usually done 9 months after the first. The necessity of a touch-up increases the cost of breast augmentation with NASHA gel, which is as expensive as a single surgical treatment with a prosthesis after three or four touch-ups. The second problem is related to the radiological evaluation of patients. Macrolane is a new material and it constitutes a diagnostic challenge for radiologists. Indeed, the appearance of NASHA gel may mimic a cyst on mammography and sonography [31]. Therefore, it is important that radiologists become familiar with the spectrum of imaging findings of Macrolane. In particular, in order to make an accurate diagnosis in these patients, it is important to send them to specialized radiological centres. The last open question is related to post-treatment adverse events. Goisis et al. had a high rate of minor complications. Goisis et al. concluded in this study that NASHA gel for breast volume augmentation was an interesting treatment, although the three open questions require more studies. P. Heden et al. answered this paper with a letter, writing that Macrolane injection did not reduce sensitivity and specificity in breast cancer screenings [36]. After the paper of Goisis et al, some other authors reported complications associated with