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.

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.

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.

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.

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 the procedure [32, 37]. In 2011, Goisis et al. wrote two papers about difficulties on breast imaging, which were described by manyauthors as the most important problem of breast augmentation by hyaluronic acid [38–40]. To reduce these problems, Goisis et al. stressed the importance to carry out the injections under ultrasound guidance. In particular, they suggested to inject a single deposit of hyaluronic acid gel. A cavity with a uniform symmetrical globular shape must be created in the space under the deep fascia of the breast, anterior to pectoralis muscle. The gel can be also placed posterior to the pectoralis muscle (submuscular plane) or inside the pectoralis muscle (intramuscular plane) in order to minimize visibility and palpability. In fact, in Goisis et al. published experience, the overall incidence of complications among patients receiving submuscular or dual-plane or intramuscular injection appeared lower than in patients receiving subglandular injection. Injection of gel into the space between the glandular tissue and the deep fascia of the breast may be related to a higher risk of displacement into the gland tissue and into the subcutaneous fat, especially if multi-pocket injection is performed without ultrasonography guidance [41]. In April 2012, after reviewing the current situation and in consultation with the regulatory authorities, Q-Med has decided to discontinue the indication for breast augmentation until consensus for best practices in breast radiology examination following Macrolane treatment has been reached. Q-Med announced that a safety reporting system has been in place since launch and no safety concerns have been identified. Despite this, Macrolane can interfere with the reading of mammograms. Since no safety concerns have been identified with the product itself, Q-Med suggested that women who have undergone breast augmentation with Macrolane do not need to take any additional actions other than the routine follow-up consultations or as directed by their doctors. As with any other breast prosthesis, it is important to inform the healthcare professional of previous Macrolane treatment before any breast assessment is carried out.

Gina Bianco

Initially launched in the US in 2000 as Radiance FN, this dermal filler was introduced in Europe in June 2004 under the name Radiesse™. Radiesse™ is a medical device developed by Bristol-Myers Squibb and BioForm Medical (since acquired by Merz Aesthetics).

Radiesse is an injectable filler material composed of synthetic calcium hydroxylapatite microspheres (30 %) suspended in an aqueous carrier gel (70 %). These uniform microspheres (25–45 m) are smooth in shape and are identical in composition to the mineral portion of human bone and teeth [42].

Radiesse injectable implant is a steam sterilized, latex-free, non-pyrogenic, semi-solid, cohesive completely biodegradable deep and sub-dermal implant. The principle component is synthetic calcium hydroxylapatite. Calcium hydroxylapatite is the primary mineral constituent of bone and teeth. The semi-solid nature of the implant is created by suspending calcium hydroxylapatite in a gel carrier that consists primarily of water and glycerine. The gel structure is formed by the addition of a small amount of sodium carboxymethyl cellulose. It does not contain any animal- or human-derived components. The gel is dissipated in vivo and replaced with soft-tissue growth, while the calcium hydroxylapatite remains at the site of injection.

Results from extensive in vitro and in vivo safety studies and in several retrospective physician reports, including toxicology assessments, standardized biocompatibility testing, and a 3-year animal study, demonstrate that injectable calcium hydroxylapatite is biocompatible, non-toxic, non-irritating and non-antigenic. Patient sensitivity testing is not required before use [43].

Calcium hydroxylapatite has been used for more than 20 years in various forms in surgery and dentistry. In the United States, injectable calcium hydroxylapatite has been used for several years for the correction of oral/maxillofacial defects, for vocal fold augmentation and as a radiographic tissue marker. In 2006, Radiesse was approved in the United States for the correction of moderate to severe facial wrinkles and folds, including the nasolabial folds, and restoration and/or correction of the signs of facial fat loss (lipoatrophy) in people with human immunodeficiency virus. In Europe, Radiesse™ is approved for plastic and reconstructive surgery, including deep-dermal and sub-dermal soft-tissue augmentation of the facial area.

When placed into soft-tissue, Radiesse provides immediate correction. Over time, the carrier gel is gradually absorbed and the calcium hydroxylapatite particles remain (Figs. 1.1, 1.2, 1.3). Local histiocytic and fibroblastic response at the site appears to result in the production of new collagen around the microspheres [44]. Preclinical canine studies (Fig. 1.4, above) have demonstrated histologically progressive integration of collagen fibres in and around the calcium hydroxylapatite microspheres up to 78 weeks after implantation (Fig. 1.4, centre and below).

Over time, calcium hydroxylapatite particles are broken down into calcium and phosphate ions via normal metabolic processes and eliminated through the body’s normal excretory processes. In one long-term animal study in the bladder neck, the particles remained intact at the site of injection throughout the entire 3-year study period [45]. Our experience with calcium hydroxylapatite use for facial soft-tissue augmentation has shown results lasting an average period of a year or more in most patients. In vivo, durability depends on factors such as injection technique, site of material placement and patient age and metabolism. The study was conducted on 357 patients and is not yet published.

Claudio Rinna, Chiara Brillante