Text: Bengt Ågerup, Ph.D., Ove Wik, Ph.D.

Illustrations: Ove Wik, Peter Wikstrand

1. Introduction

NASHA is an acronym for the Non-Animal Stabilized Hyaluronic Acid patented and produced by Q-Med AB, Uppsala, Sweden.

NASHA is used in products for facial tissue augmentation (RESTYLANE), for treatment of osteoarthritis in the knee and hip (DUROLANE), for treatment of vesicoureteral reflux (VUR) in children (DEFLUX) and for treatment of stress urinary incontinence in women (ZUIDEX).

The manufacturing of NASHA is based on hyaluronic acid (HA).

Hyaluronic acid is one of nature’s most versatile and fascinating macromolecules. Since this polysaccharide was first isolated from bovine vitreous in the mid-1930s, it has been found in all tissues in all vertebrates. Thus, hyaluronic acid is a universal component of the extra cellular space,

where the molecule has multiple properties to constitute a matrix that supports the normal function of cells and tissues. Hyaluronic acid is a uniform, unbranched linear polysaccharide with the same simple chemical structure in all species and tissues. Hyaluronic acid is also biosynthesized by some bacteria. The chemical structure of hyaluronic acid is invariable, i.e. the chemical structure is always the same, independent of the source. The identical structure of hyaluronic acid from all sources makes this polysaccharide an ideal substance for use as a biomaterial in health and medicine. Hyaluronic acid has a

• Simple chemical structure, and is

• Identical in all species and in all tissues, and is hence

• An ideal biomaterial

Biomaterials are typically macromolecules extracted from human or animal tissues or synthesized to mimic native biomolecules. The safe use of these materials must be properly documented in biocompatibility studies, as these molecules or their contaminants do differ from their native, human counterparts.

Hyaluronic acid is a unique biomaterial with the same chemical structure in all species and tissues. It merely differs in the length of the molecular chain or, most importantly, its purity. Sufficiently pure hyaluronic acid is in itself inherently biocompatible.

However, the presence of impurities, especially those of animal origin, in hyaluronic acid raw material may affect the biocompatibility, as impurities may cause severe adverse reactions in the human body. The purity of hyaluronic acid preparations is therefore of the utmost importance for the safe use of hyaluronic acid products in humans.

The various terms and their usage in the scientific literature are shown in the following table:

Hyaluronic acid has a very simple chemical structure:

a disaccharide unit containing glucuronic acid and N-acetylglucosamine. These are joined together forming a uniform, linear polysaccharide molecule as shown in the following figure. The number of repeating disaccharide units is denoted by n. These sugar units are hydrophilic - water loving. Water is attracted to hyaluronic acid, which is therefore highly soluble in water. Hyaluronic acid contains these, and only these, two sugar units in all tissues and in all species. The identical hyaluronic acid molecule can also be manufactured from a non-animal source by modern biotechnological methods. It has been proposed that protein or other exogenous sugar units except for those shown above are an integral part of hyaluronic acid. However, the unique mechanism of biosynthesis of hyaluronic acid (see Page 13) demonstrates that hyaluronic acid only contains the simple disaccharide unit without amino acids, proteins or other sugar moieties.

The completely identical chemical structure of hyaluronic acid – independent of source – is most significant from a biological point of view. Hyaluronic acid is an ideal material for use in health and medicine due to its inherent biocompatibility.

Hyaluronic acid is a uniform, linear and unbranched molecule consisting of multiple identical disaccharide units. The only variation between hyaluronic acid preparations is the length and size of individual molecules.

Name Comment Usage

Hyaluronic acid Meyer & Palmer, 60%

Na-hyaluronate Salt at neutral pH 10%

Hyaluronan Balazs et al 30%

Natrii hyaluronas Latin notion Singular

For example, the molecular size of hyaluronic acid is often lowered in synovial fluid from patients with joint disorders. In healthy tissues the molecular weight of hyaluronic acid is typically in the order of 5 to 10 million. In some tissues or species, especially in diseased tissues, the molecular weight may be lower: ~1 million. The molecular weight in hyaluronic acid products varies from 0.5 to 5 million. For comparison, the molecular weight of typical proteins is <100 000. Most polysaccharides in vertebrates have a molecular weight in the order of 10 000 and are linked to various types of proteins.

The length and molecular weight of hyaluronic acid are determined by the number of disaccharide units linked together, i.e. the degree of polymerization denoted by n in the figure above. The length of hyaluronic acid varies somewhat between different tissues and species, but there is much larger variation depending on the condition of the tissue. A hyaluronic acid molecule with a molecular weight of 10 million contains 25 000 disaccharide units linked together forming a very long linear chain consisting of repeating disaccharide units with a dimension of ~1 x 1 nm. The hyaluronic acid molecule in normal tissue with a molecular weight of 10 million is 1 nm thick and 25 μm long. In comparison the diameter of a red blood cell is 7.5 μm.

In solution the very long and thin hyaluronic acid chain molecules kink and bend and adopt a conformation of an expanded random coil. These hyaluronic acid coils are so large that even at a low concentration of about 0.1% (1 mg/ml) the hyaluronic acid molecules fill up the whole solution. At higher concentrations the hyaluronic acid coils intertwine and entangle, forming a flexible molecular network of entangled molecules.

This entangled network of hyaluronic acid molecules is able to hold large amounts of water while allowing the passage of metabolites to and from cells.

Hyaluronic acid is an essential component of the extra cellular matrix of all tissues. Especially high concentrations are found in tissues such as the umbilical cord (4 mg/g), synovial fluid (3-4 mg/ml) and vitreous (0.1-0.4 mg/g). The average concentration of hyaluronic acid is 200 mg/kg (0.02%). Thus, a human body weighing 60 kg contains about 12 g hyaluronic acid.

Flexible Molecular

Network

Random coils

Synovial fluid 3500

Vitreous 200

Oocyte cumulus 500

Cartilage 1200

Skin 200

Lung 150

Serum 0.05

Intracellular Absent

Although the highest concentrations of hyaluronic acid are found in connective tissues, most hyaluronic acid, 56% (7 g), is found in the skin.

The normal state of hyaluronic acid in tissues is as a free polymer. However, in some tissues such as the cartilage and tendons hyaluronic acid is bound to large glycoprotein structures (proteoglycans) or in other tissues to specific cell receptors (e.g. CD 44).

The metabolism – the biosynthesis and the catabolism – of hyaluronic acid is in many ways unique. The biosynthesis occurs via an enzyme complex within the cellular membrane, and the removal and degradation of hyaluronic acid is mediated by receptor binding followed by intracellular degradation. This process is very fast and efficient.

The unique cell ‘machinery’ that produces hyaluronic acid has been elucidated during the last decades. Biomolecules – both intracellular and extra cellular components – are synthesized within the cell. Vertebrate polysaccharides are generally synthesized onto a protein core that works as a primer. The enzyme complex producing hyaluronic acid is not situated within the cell but is maintained within the cell membrane. The two basic sugar units are added onto the growing hyaluronic acid chain from the cell interior, and the hyaluronic acid product is released directly into the surrounding extra cellular medium.

Many different cells have the capacity to produce hyaluronic acid, e.g. fibroblasts, synovial cells, endothelial cells, smooth muscle cells, adventitial cells and oocytes. The same synthase that produce invariant hyaluronic acid has been identified in a number of species: humans, mice, chickens, frogs, and zebra fish. These facts confirm the concept of a uniform chemical structure of hyaluronic acid within the animal kingdom.

The overall turnover rate of hyaluronic acid is very fast compared to other extra cellular components such as collagen. The half-life of hyaluronic acid in most tissues ranges from 0.5 to a few days. In skin the half-life is <24 hours. The daily turnover of hyaluronan is in the order of one-third of the total body content at a rate similar to that of albumin. In a normal human body about 3 grams of hyaluronic acid is thus catabolized each day.

snake-like motion. Cell receptors bind the free hyaluronic acid molecules, which are engulfed by the cells. Intracellular enzymes in the lysosomes subsequently degrade the hyaluronic acid to its basic constituents.

The residence time of hyaluronic acid in tissues is only slightly dependent on molecular weight. Endogenous and exogenous hyaluronic acid generally has a molecular weight ranging from 1 to 10 million. The turnover of hyaluronic acid in rabbit knee joints as a function of molecular weight is shown below. Despite the more than 10-fold difference in molecular weight of the implanted hyaluronic acid samples, there is only a 30% difference in half-life time.

Most commercial products have a molecular weight of 1 million. There are some products with a molecular weight of 5 million and a few modified products with a molecular weight of 10 million.The residence time of hyaluronic acids implanted in different tissues will be affected by the molecular weight of the hyaluronic acid in approximately the same way as the residence time in joints shown above. Inflammatory processes will degrade the hyaluronic acid almost instantaneously. For the majority of medical applications of hyaluronic acid a residence time in the order of weeks or months is necessary to accomplish the desired effect of the implanted hyaluronic acid. It is evident that hyaluronic acid must be modified in order to obtain a product with a reasonable duration. The NASHA technology described in Chapter 3, results in significantly prolonged duration using a minimum degree of modification.

Hyaluronic acid is an important component of the extra cellular space in the maintenance of the proper structure and function of tissues by:

• Creating volume

• Lubricating tissues

• Affecting cell integrity, mobility and proliferation

The physiological function of hyaluronic acid is based on the very large size and hydrodynamic volume of the hydrophilic (water-retaining) molecular network. In the extra cellular space, the hyaluronic acid network has the capacity to hold large amounts of water. Elevated levels of extra cellular hyaluronic acid accompany processes that require cell movement and tissue reorganization. That is, when cells need space for motility and separation these functions are performed in a hyaluronic acid medium. The hyaluronic acid network assists in cell differentiation, cell migration, tissue morphogenesis, embryogenesis and wound repair. Moving tissues are lubricated by hyaluronic acid. Such effects are dependent on the rheological status of the fluid. The most important property of the rheology performance is mediated through the molecular weight. The high viscosity and elasticity of hyaluronic acid solutions will create thick layers of unstirred fluid that will protect the tissues under movement.

In general, biomolecules synthesized by different species differ in chemical composition. The difference in e.g. the amino acid composition of proteins and sugar components of glycoproteins

Hyaluronic acid

Molecular Half-life time

weight (hours)

Exogenous 100 000 10

Exogenous 6 000 000 13

Endogenous 13 000 000 16

makes these molecules foreign to another species or individual. The body responds in various ways when such different molecules are encountered: immunological reactions or rejection of organs transplanted. In contrast to other biomolecules hyaluronic acid is independent of source as the chemical structure is invariant. All cells that synthesize hyaluronic acid produce the same compound. This also applies to the hyaluronic acid produced by some bacteria, which have pirated the enzymatic machinery for biosynthesis of hyaluronic acid from vertebrates. The bacteria with a protective coat of hyaluronic acid will not as easily be recognized as foreign by the defense system and the inflammatory reaction will be greatly reduced.

Hyaluronic acid may either be obtained by extraction from tissues or produced by adopting modern biotechnological methods. The extensive entanglement of hyaluronic acid with other components in tissues complicates its isolation and purification from animal sources. In practice it is inevitable that hyaluronic acid products isolated from tissues will contain impurities. With regard to the type of impurity and the amount of impurities, there are large and significant differences between different hyaluronic acid preparations. The purity of hyaluronic acid depends on the choice of raw material, method of manufacturing and molecular size of the isolated hyaluronic acid.

Tissues containing large amounts of hyaluronic acid have been utilized as raw material. Rooster combs are currently the major source for tissue-derived hyaluronic acid.

Cells capable of producing hyaluronic acid are found not only in animal tissues, but also interestingly some bacteria have also pirated the unique enzymes that synthesize hyaluronic acid. These cells can be utilized for production of hyaluronic acid by adopting modern biotechnological methods. The cells are grown in a medium containing water and nutrients. The hyaluronic acid synthesized within the cell membrane is excreted into the medium for easy access and purification. Provided that the integrity of the cells is maintained during manufacturing, the hyaluronic acid produced will contain minute and insignificant amounts of other biomolecules.

Tissues are, from many aspects, a complicated starting material for the manufacture of highly purified hyaluronic acid. Isolation of hyaluronic acid from a tissue necessitates the mincing of tissues. Therefore, the initial raw material is a complex mixture of tissue components and contaminant products. The complete isolation of hyaluronic acid from minced tissues is essentially impossible to accomplish due to the low concentration (ca. 0.5%) of hyaluronic acid. The very high molecular weight (appr. 10 million) hyaluronic acid is extensively intermingled with other biomolecules and cells, and the final product will contain significant amounts of impurities.

The development of NASHA was based on three basic considerations:

• Pure hyaluronic acid

• Modification by as mild a stabilization as possible to obtain the desired physical form and sufficient residence time in the various clinical applications.

• High clinical performance as well as safe use with virtually no side effects. This can be obtained since the hyaluronic acid is virtually unchanged and therefore similar to native hyaluronic acid.

The hyaluronic acid used in the manufacture of NASHA is biosynthesized from a non-animal source. The molecular weight of the hyaluronic acid is ~1 million. Higher molecular weights are not needed as the hyaluronic acid is stabilized. Furthermore, higher molecular weights increase the probability of higher amounts of impurities as these are bound to the entangled hyaluronic acid network.

The raw material for NASHA is manufactured by biotechnological methods in order to obtain a product of high purity. The amounts of impurities are minimized by preserving the integrity of the hyaluronic acid producing cells. Subsequent isolation of hyaluronic acid aims at reducing the amount of impurities instead of maintaining as high a molecular weight as possible. The presence of potentially harmful components such as viruses, proteins and endotoxins in general, and those of animal origin in particular, is therefore excluded.

The manufacturing of NASHA is performed under controlled conditions at Q-Med AB, Uppsala, Sweden. The manufacturing includes the stabilization of hyaluronic acid to form NASHA. The stabilized material is a continuous 3-dimensional molecular network – i.e. a gel of any shape and form. In some applications gel particles of defined sizes are produced. This unique technology, which can produce a defined polymer with a physical form that matches the intended use, is nowhere else to be found.

The stabilization is essential in order to improve the storage conditions, the shelf life and the residence time following injection from a few days to many months. To maintain the ultimate tolerance of native hyaluronic acid only slight stabilization of the hyaluronic acid network is carried out.

The minor modification needed to obtain the stabilized NASHA is presented in the following figures:

In the NASHA products, the hyaluronic acid molecules are stabilized to a minor degree. The stabilization is accomplished using a compound that does not cause any significant biological reaction. Due to the high molecular weight of the starting material (1 million) minute amounts of stabilization are needed to obtain a few permanent linkages that join all the hyaluronic acid molecules in the solution, thus forming a continuous gel. Therefore, very low amounts of stabilizer are needed.

The molecular weight of hyaluronic acid in various products varies between 1 and 10 million. In NASHA the hyaluronic acid molecules are stabilized by linking the molecules together. In hyaluronic acid solutions the molecules form an entangled molecular network where the molecules can move freely. In NASHA the stabilized molecules form a stable 3-dimensional molecular network, a so-called gel. From a scientific point of view it is not common practice to calculate the molecular weight of a gel. Nevertheless, it may be appropriate to do so in order to demonstrate the very large difference between non-stabilized hyaluronic acid and NASHA. Each NASHA gel particle contains billions of stabilized hyaluronic acid molecules. As these molecules with a molecular weight of 1 million are bound together, we find that the molecular weight of a NASHA gel particle is higher than 100 billion.

The hyaluronic acid used in the manufacture of NASHA is biosynthesized from a non-animal source. The raw material for NASHA is manufactured by biotechnological methods in order to obtain a product of high purity. The amounts of impurities are minimized by preserving the integrity of the hyaluronic acid producing cells. Subsequent isolation of hyaluronic acid aims at optimum purity instead of optimum molecular weight. The presence of potentially harmful components (proteins, viruses, etc.) of animal origin is excluded in NASHA.

The molecular weight of the hyaluronic acid is 1 million. Higher molecular weights are not needed as the hyaluronic acid in NASHA is stabilized. Moreover, manufacture of higher molecular weights increases the probability of higher amounts of impurities due to increased viscosity and increased entanglement with impurities.

The concept ‘Biocompatibility’ was originally defined as "the total absence of interaction between the material and the tissues". This definition has been modified to read: "the ability of a material to perform with an appropriate host response in a specific application" Hyaluronic acid in itself is fully biocompatible, as described above. The question of the biocompatibility of hyaluronic acid products is therefore only related to the amount and type of impurities present in the product.

Nevertheless, the biocompatibility of NASHA has been extensively tested both in vitro and in vivo. This testing has followed the guidelines in the ISO (International Organization for Standardization) 10993 standard on "Biological Evaluation of Medical Devices". These biocompatibility tests have demonstrated that NASHA:

• is neither cytotoxic nor genotoxic

• does not give rise to any acute, subacute or chronic effects

As discussed above the turnover of endogenous hyaluronic acid is very fast and efficient. In most tissues the half-life varies from half a day to a few days. Exogenous hyaluronic acid implanted into a tissue will similarly disappear within this short time. The residence time may be slightly modified by changing the molecular size or concentration of hyaluronic acid, or by the modifying the method of application. However, modification of the hyaluronic acid molecular weight will increase the residence time only slightly, as was shown above (section 2.8), by a factor <2.

Hyaluronic acid molecules within the extra cellular matrix are able to move to cells, where the molecules bind to the cellular membrane for subsequent pinocytosis. The most abundant removal is carried out by lymphatic uptake, partial depolymerization and removal to the blood stream. Blood is then effectively cleared from hyaluronic acid by uptake and hepatic degradation to carbon dioxide and water. When NASHA is implanted into a tissue a prerequisite for removal of the stabilized hyaluronic acid is the degradation in situ of the 3-dimensional hyaluronic acid gel matrix.

In healthy tissue the extra cellular capacity to degrade hyaluronic acid is very low. The most probable means of degradation is by free radicals. These are present in very low concentrations in normal tissue. However, the capacity of free radicals to break down hyaluronic acid molecules is well documented. This very slow degradation of NASHA results in the slow release of free hyaluronic acid chains, which are catabolized by the same mechanism as the endogenous hyaluronic acid described above.

The residence time of non-animal stabilized hyaluronic acid – NASHA – is dependent on the size of the gel particles due to tissue migration, the concentration of stabilized hyaluronic acid and the existence of inflammatory reactions in the area. The smaller the gel particle size, the easier it will escape from its place of residence. In contrast to such a mechanism, too large gel particles will rupture the tissue and cause reparative inflammatory reactions that will speed up the degradation. Hence a careful tissue match is essential.

The size of the gel particle will also determine its time of removal due to a favorable surface to mass (volume) relationship. Degradative agents will be produced from the outside of the gel particle (surface) whereas the degrading effect is carried out on the mass (volume) of the gel particle.

The NASHA gel can be manufactured to almost any shape and form. Depending on the clinical demand, the gels can be thick or thin, dense or loose as well as containing big or small gel particles. For the purpose of tissue augmentation, the size of the gel particles has to match the density of the tissue. For facial augmentation e.g. several products with different size of the gel particles have been developed.

The clinical uses of NASHA are not limited by its physical form, its purity or the cost of the raw material. Thus, any application is possible. Q-Med has selected its applications based on the uniqueness of the material for the indication.

For esthetic use, facial soft tissue augmentation, the gel does not just predictably augment the tissue to full esthetic satisfaction but also adds hyaluronic acid to the cellular environment. So far, more than 4 million treatments have been performed with RESTYLANE. The products in the RESTYLANE product range are intended for facial soft tissue augmentation, such as filling out wrinkles, enhancing lips or creating more pronounced chins and cheeks, and for skin rejuvenation of the face, neck, hands and décolletage.

DUROLANE is indicated for symptomatic treatment of mild to moderate knee or hip osteoarthritis.

The body’s hyaluronic acid constitutes a natural part of the synovial fluid and acts in the joints both as a lubricant of cartilage and ligaments and as a shock absorber. It is known that the synovial fluid in joints affected by osteoarthritis has a much lower viscosity and elasticity than in healthy joints. Injections of hyaluronic acid in the joint to restore the viscosity and elasticity can diminish the pain and improve the mobility of the joint.

Products based on NASHA for urological indications have also been developed, resulting in one product (DEFLUX) for the treatment of VUR (Vesicoureteral Reflux) in young children. NASHA is used to carry a dextranomer bead that is a fibroblast activator. Once the implant is in place, the NASHA-based carrier is reabsorbed. The same principle is also used in another product (ZUIDEX) to support the urethral sphincter muscle in patients suffering from stress urinary incontinence (SUI) – an inconvenience that millions of people, mainly women, are affected by. DEFLUX is intended to augment the urinary bladder wall at the orifice of the ureter to form a ventilum that prevents urine leaking back and consequent kidney infections. ZUIDEX is used for augmenting the urethra wall at the level of the weakened sphincter muscle. After injection the patient is able to contract the urethra and keep dry.

NASHA gels are continuously being used in international clinical trials for a number of indications. Many trials are carried out in accordance with FDA approved protocols for the purpose of documenting products for sale on the US market.

Several clinical studies have been performed in order to evaluate the safety and efficacy of RESTYLANE. The safety profile of RESTYLANE is excellent with only 1 in 10 000 treated patient reporting inflammatory reactions. The majority of reactions are of mild intensity and transient. Comparative trials have been carried out with FDA approved protocols for the purpose of documenting products for sale on the US market. The FDA approved RESTYLANE in December 2003.

DUROLANE has undergone full safety documentation in accordance with the EU Directive for implantable devices. Clinical trials have demonstrated the efficacy and safety of DUROLANE. One injection of DUROLANE is well tolerated and may provide significant improvements in pain for up to 6 months after treatment. Most of the available data for DUROLANE relate to OA of the knee, as viscosupplementation is most commonly used for this condition. The potential use of DUROLANE for OA in the hip have also been investigated, and in 2004 DUROLANE gained European approval for this indication. The safety profile of DUROLANE is excellent, with no reports of any emergent concerns.

Clinical experience over the last two decades has demonstrated that the endoscopic correction of primary vesicoureteral reflux and stress urinary incontinence caused by intrinsic sphincter dysfunction is both possible and effective. However, the materials in Europe as well as the US have been nondegradable or quickly degradable animal implants. The NASHA-based implants are non-animal and slowly degradable for a prolonged residence time.

Endoscopic treatment with DEFLUX has provi-ded successful outcomes worldwide for more than 8 years. DEFLUX has a well-documented safety record with more than 30 000 children treated with no reports of persistent adverse events. Long-term success with DEFLUX has also been demonstrated in several studies.

3. Friedman PM, Mafong EA, Kauvar ANB, et al: Safety data of injectable nonanimalstabilized hyaluronic acid gel for soft tissue augmentation. Dermatol Surg 2002; 28(6): 491–4

4. Akermark C, Berg P, Björkman A, et al. Non-animal stabilised hyaluronic acid in the treatment of osteoarthritis of the knee - a tolerability study. Clin Drug Invest 2002; 22: 157-66.

5. Altman RD, Akermark C, Beaulieu AD, et al. Efficacy and safety of a single intra-articular injection of non-animal stabilized hyaluronic acid (NASHA) in patients with osteoarthritis of the knee. Osteoarthritis Cartilage 2004; 12: 642-9.

6. Berg P, Olsson U. Intra-articular injection of non-animal stabilised hyaluronic acid (NASHA) for osteoarthritis of the hip: a pilot study. Clin Exp Rheumatol 2004; 22: 300-6.

7. Läckgren G, Wahlin N, Stenberg A: Endoscopic treatment of children with vesico-ureteric reflux. Acta Paediatr 1999; 88 (Suppl, 88): 62-71

8. Stenberg A and Läckgren G. A new bioimplant for the endoscopic treatment of vesicourethral reflux: experimental and short-term clinical results. J Urol 1995; 154: 800-3

9. Kirsch AJ, Perez-Brayfield M, Smith EA, et al: The modified STING procedure to correct vesicourethral reflux: improved results with submucosal implantation within the intramural ureter. J Urol 2004; 171: 2413-6

10. Stenberg AM, Larsson G, Johnson P: Urethral injection for stress urinary incontinence: long-term results with dextranomer/hyaluronic acid copolymer. Int Urogynecol J Pelvic Floor Dysfunct 2003; 14(4):335-338

11. van Kerrebroeck P, ter Meulen F, Larsson G et al. Efficacy and safety of a novel system (NASHA/Dx copolymer using the IMPLACER device) for treatment of stress urinary incontinence. Urology 2004; 64(2):276-81

12. Chapple CR, Haab F, Cervigni M, Dannecker C, Fianu-Jonasson A, Sultan AH: An open,multicentre study of NASHA/Dx Gel (Zuidex) for the treatment of stress urinary incontinence

15-10040-04. RESTYLANE, ZUIDEX, DEFLUX and DUROLANE are trademarks owned by Q-Med AB.

Seminariegatan 21 • SE-752 28 Uppsala • Sweden

Phone: +46(0)18-474 90 00 • Fax: +46(0)18-474 90 01 • e-mail: info@q-med.com • website: http://www.q-med.com/

Per Hedén1, Michael Olenius2

1Akademikliniken, Stockholm, Sweden; 2ProForma Clinic, Stockholm, Sweden.

l The increased demand for minimally invasive procedures is driving the overall growth of the cosmetic industry. The search for improved volume enhancing techniques has led to the use of a variety of solid implants and injectable materials for tissue augmentation procedures, including breast enhancement.

l Many investigated materials have significant associated drawbacks. Non-resorbable materials can accumulate permanently in the body and may cause granuloma formation or chronic foreign body reactions.1 Complication and reoperation rates as high as 50% have been reported with silicone implants, during the first three years following surgery.2 Fat transfer can provide substantial volume to deficient areas, but the costs are high and the surgery can be complex. A further criticism of fat transfer is its unpredictable efficacy.3

l A number of injectable, resorbable products based on hyaluronic acid are well established in facial esthetics.4,5

l To address the need for an injectable, biocompatible and resorbable product for body contouring and volume restoration, a new medical implant comprising hyaluronic acid-based gel of non-animal origin (NASHA™ gel) was developed by Q-Med AB, Uppsala, Sweden. Accordingly, two variations of Macrolane™ VRF received CE approval in 2007. Macrolane VRF30 is intended for use in areas where tissue cover is considered substantial (deep deposition), while VRF20 is intended for areas with thin tissue cover (more superficial deposition).

l In a pilot study of NASHA gel for breast enhancement (19 participants), mammograms and magnetic resonance imaging (MRI) were performed in 5 patients following treatment. Injected NASHA gel had increased radiolucency compared with silicone or saline implants, allowing visualization of tissue behind the gel. In addition, MRI results showed persistence of implanted NASHA gel up to 12 months postinjection, albeit with a degree of biodegradation.6