Filler Substances
Gary D. Monheit, M.D.
Associate Professor
Department of Dermatology
University of Alabama at Birmingham
Birmingham, Alabama

Soft tissue augmentation has increased in popularity as minimally invasive procedures have surged to the forefront in a cosmetically elegant and time-sensitive society. Although many filler substances have been developed for soft tissue augmentation, no perfect filler exists. Each dermal filler has its own niche based on its inherent properties. Different fillers require specific injection techniques as well as amount of correction needed to achieve optimal results. In general, each filler has similar risks as well as its own unique set of risks. It is the physician’s responsibility to know the risks and benefits of each filler substance as well as which filler or fillers is best suited for the patient’s specific contour irregularities. At times in order to obtain the best results, fillers should be layered with denser fillers injected deeper into the dermis and finer fillers in the upper dermis. Correction of contour defects over areas of high movement can be prolonged with underlying muscular paralysis by adjuvant therapy with Botox. It is important that the patient has realistic expectations of what can be achieved with fillers and other adjuvant therapy.

Injectable bovine collagen was developed in the 1970s. Today bovine collagen (Zyplast) remains the gold standard for which other filler products are compared. Permanent injectable collagen, Artecoll, was developed as a long lasting alternative to Zyplast. Recent advances in filler substances include human derived collagen (Cosmoderm and Cosmoplast), hyaluronic acid derivatives (Restylane and Hylaform), calcium hydroxylapatite microspheres (Radiance FN), and polylactic acid microspheres (Sculptra).

Bovine Collagen Derivatives: Zyderm and Zyplast (McGhan Medical Corporation)

Key Points
1. Zyderm and Zyplast were the first FDA approved injectable bovine collagen products in the United States, being approved in 1982 for correction of soft tissue deformities of the dermis. Bovine collagen is processed from the hides of isolated herds of domestic Angus/Hereford cattle fed fresh grass or grains in California, thereby negating the possibility of contamination with bovine spongiform encephalopathy virus or prion that causes mad cow disease.
Carruthers J and Carruthers A. Mad cows, prions, and wrinkles. Arch Dermatol/Vol 138, May 2002, p667-670.

2. Zyderm is a purified bovine dermal collagen that is dispersed in phosphate-buffered physiological saline containing 0.3% lidocaine. It is available in two forms, Zyderm 1 and Zyderm 2 with Zyderm 2 containing almost twice the collagen concentration as Zyderm 1. Zyderm contains 95-98% type I collagen and the remainder is type III collagen. Zyderm is best used for the correction of fine lines.
Package insert for zyderm

3. Zyplast is a collagen implant composed of purified dermal bovine collagen that is lightly crosslinked with glutaraldehyde and dispersed in a phosphate-buffered physiological saline containing 0.3% lidocaine. Zyplast is best used for augmentation of deeper rhytides or grooves.
Package insert for zyplast

4. Before administration of the bovine collagen derivatives, a test implantation is required which consists of a 0.1 cc injection of Zyderm into the volar forearm. The test site is monitored over a four week period. If erythema, induration, tenderness, or edema occurs, the patient is considered sensitive to the injection and the use of bovine collagen in contraindicated. If the results are equivocal, a second test syringe should be used on the opposite arm and monitored for four weeks.
Elson ML. The role of skin testing in the use of collagen injectable materials. J Dermatol Surg Oncol 1989;15:301-3.

5. Approximately 3.0% of those patient’s tested have a sensitivity to bovine collagen and therefore treatment is contraindicated. Approximately 1.3% of patients developed transient localized adverse reactions. If hypersensitivity occurs, it is usually within 1-2 weeks of treatment.
Watson W, Kay RL, Klein AW, et al. Injectable collagen: a clinical overview. Cutis 1983;31:543-6.

Reports of adverse events with bovine collagen:
Reactivity to bovine collagen has been noted even with a negative test implantation site. A study done by ML Elson verified that of 188 patients, 3% demonstrated hypersensitivity to the test implant. Further observation concluded that treatment with Zyderm and Zyplast collagens in patients with a negative skin test resulted in 6 hypersensitivity reactions and in these patients reactions were not observed to Zyplast treated sites but to those treated with Zyderm.
Elson ML. Clinical assessment of Zyplast Implant: a year of experience for soft tissue contour correction. J Am Acad Dermatol. 1988 Apr;1894 Pt 1):707-13.

Localized hypersensitivity reactions may occur in 3-35% or treated individuals. Symptoms include erythema, induration, discoloration, or pruritus of the treatment site. Eighty percent of these reactions occur within four weeks after administration.
Rare cases or long-term sequelae including firmness or discoloration have been reported.

Systemic hypersensitivity reactions have rarely been reported generally occurring within 48-72 hours after injection. Fever, malaise, and urticaria are common. Treatment is with systemic steroids and several months of therapy may be needed. Rare granulomatous reactions consisting of palpable nodules have been reported. Rarely the hypersensitivity response has progressed to a cystic reaction which may drain purulent material. These reactions develop weeks to months following injection and may result in scar formation. This type of reaction can occur as multiple and/or recurrent sterile abscesses which tend to be persistent and resistant to drug therapy. Incision and drainage has been a useful treatment.
Stegman SJ, Chu S, Armstrong RC: Adverse reactions to bovine collagen implant: Clinical and histologic features. J Dermtol Surg Oncol 14(Suppl):39-48, 1988
Labow TA, Silvers DN: Late reactionsat Zyderm skin test sites. Cutis35:154-158, 1985. Overhold MA, Tschen JA, Font RL: Granulomatous reaction to collagen implant, light and electron microscopic observations. Cutis 51:95-98, 1993.
Cucin RL, Barek D: Complications of injectable collagen implants .Plast Reconstr Surg 71:731, 1983.

Treatment of Hypersensitivity Reactions

Other case reports in the literature verify that despite adequate pretreatment testing, allergic reactions due to bovine collagen hypersensitivity can develop. Treatment of these reactions includes topical steroids and/or tacrolimus and oral antihistamines. If needed injected steroids or oral steroids can be used. One case report concluded that oral cyclosporine may be a safe and effective treatment for hypersensitivity reactions. As the collagen implant degrades, the hypersensitivity reaction should lessen, however Brooks reported a foreign body granuloma persisting for ten months at a second test implantation site on the forearm after her first test site two weeks earlier showed equivocal results.
Moody BR, Sengelmann RD. Topical tacrolimus in the treatment of bovine collagen hypersensitivity. Dermatol Surg. 2001 Sep;27(9):789-91.
Baumann LS, Kerdel F. The treatment of bovine collagen allergy with cyclosporine. Dermatol Surg. 1999 Mar;25(3):247-9.
Brooks N. A foreign body granuloma produced by an injectable collagen implant at a test site. J Dermatol Surg Oncol. 1982 Feb;8(2):111-4.
Barr RJ, King RD, McDonald RM, et al: Necrobiotic granulomas associated with bovine collagen test site injectio.s. J Am Acad Dermatol 6:867-869, 1982.

Due to the reactivity to injectable bovine collagen, a new injectable collagen was developed, CosmoDerm and CosmoPlast, with the goal of less antigenicity and therefore a better safety profile. A pre-test screening to rule out sensitivity is not required.
Non-bovine collagen: CosmoDerm and CosmoPlast (INAMED Corporation)
Key Points:
1. CosmoDerm and CosmoPlast, which were FDA approved in 2003, are made from a human fibroblast derivative. Both products are used similarly to Zyderm and Zyplast respectively.
2. Cosmoderm collagen implants are dispersed in phosphate-buffered physiological saline containing 0.3% lidocaine and are available in two forms: CosmoDerm 1 and Cosmoderm 2. Cosmoderm 2 contains approximately twice as much collagen as CosmoDerm1.
Package insert cosmoderm
3. CosmoPlast collagen implant is crosslinked with glutaraldehyde and dispersed in phosphate-buffered physiological saline containing 0.3% lidocaine.
Package insert CosmoPlast
4. Both CosmoDerm and CosmoPlast are human-based collagen implants. These injectable collagen products are less antigenic than their bovine counterparts and safety tests have deemed them free of any pretreatment test injections. Patients should still be counseled as to the risk and benefits of injectable human collagen which may be similar to but much less common than with bovine collagen.

Injection technique of Collagen:
1. Zyderm and CosmoDerm
a. Zyderm and CosmoDerm are injected into the superficial papillary dermis into the plane of the deformity with insertion or withdrawal of the needle. The serial puncture technique can also be employed at 1 to 3 mm intervals. Blanching should occur with injection and if this does not occur, the substance is likely being injected too deeply in the dermis. After injection, a transient or minimal amount of edema, erythema, and discomfort is expected with should quickly resolve.
b. When using Zyderm 1 and CosmoDerm 1, overcorrection to 1.5-2.0 times the initial depth of the lesion is recommended due to the loss of saline in the suspension with time.
c. A lesser degree of overcorrection of Zyderm 2 and CosmoDerm 2 is needed to achieve correction. Care should be taken around the periorbital area and vermilion which require less of a correction as the material is slow to resolve.
2. Zyplast and Cosmoplast
a. Zyplast and CosmoPlast are injected into the mid to deep dermis and should be injected so that it is more felt than seen. Either can be injected while inserting or withdrawing the needle through this plane. No blanching should occur. The area should be corrected 100% but not more.
Klein AW. Indications and implantation techniques for the various formulations of injectable collagen. J Dermatol Surg Oncol 1988;14 (Suppl. 1):27-30.
Package insert for Zyderm, Zyplast, CosmoDerm, CosmoPlast.

Longevity
Studies have shown that after injection of collagen products, the suspended collagen forms a network of fibers that over a period of time becomes colonized by host connective tissue cells taking the texture and appearance of normal tissue.
Correction achieved by collagen lasts 3-5 months with repeat maintenance injections required after this. Longevity of the products is increased if the area injected is static.
Knapp TR, Luck E, Daniels JR. Behavior of solubilized collagen as a bioimplant. J Surg Res 1977;23:96-105.

Pearls and General Information
1. Zyplast and Cosmoplast are not recommended for use in the periorbital or glabellar areas. Collagen can initiate platelet aggregation and if implanted into dermal vessels may cause vascular occlusion, infarction, or embolic phenomenon.
2. Firm massage of the injection site can reduce lumpiness.
3. Reports of connective tissue diseases occurring subsequent to collagen injections in patients with no previous history of these disorders have been written. Conflicting studies have been published regarding the association between polymyositis and dermatomyositis and injectable collagen. A casual relationship has not been established. A thorough history and physical exam should be done on each patient. Caution should be used in a patient who has a family or personal history or collagen vascular disease.
Cukier J, Beauchamp R, Spindler J, Spindler S, Lorenzo C and Trentham D: Association implants and a dermatomyositis or a polymyositis-like syndrome. Ann Internal Med 118:920-928, 1993.
Rosenberg M and Reichlin M: Is there an association between injectable collagen and polymyositis/dermatomyositis? Arth Rheum 37:747-753, 1994.

Polymethyl-methacrylate: Artefill (Artes Medical)
With the advent of Zyplast, the popularization of dermal fillers began. One disadvantage noted with Zyplast was the need for frequent reinjections to obtain maximal results. Therefore a filler with more permanency was sought. Polymethyl-methacrylate (PMMA) microspheres, found in bone cement, were purified and combined with a collagen solution acting as the carrier material for the microspheres to avoid lumpiness and aid in injection. These microspheres provide a scaffold to promote our own bodies deposition of connective tissue. Since 1994, this suspension of purified PMMA microspheres in bovine collagen has been distributed under the trade name Artecoll. Clinical trials in the United States were completed in September 2001 and in 2003, the FDA advisory panel recommended marketing approval of Artecoll which will be marketed under the trade name of Artefill in the United States. Artefill is a suspension of 20% PMMA microspheres of 30 to 42 micrometers diameter in 80% bovine collagen solution produced from calf hides. The mixture contains lidocaine.
Lemperle G, Ott H, Charrier U, Hecker J, Lemperle M. PMMA microspheres for intradermal implantation. I. Animal research. Ann Plast Surg 1991:26:57-63.
Lamperle G, Gauthier-Hazan N, Lemperle G. PMMA microspheres (Artecoll) for long-lasting correction of wrinkles: refinements and statistical results. Aesthetic Plast Surg 1998;22:356-65.
Hamilton D. A pilot study of the first patients treated in United States with Artecoll implantation for the aging face. Cosmet Dermatol 200: 147-51.

Artefill is designed for implantation into the deep reticular dermis under areas of well defined wrinkles or furrows. The viscosity of Artefill is three times higher than that of Zyplast and is more technique sensitive than injecting collagen. In addition to adverse events similar to those of bovine collagen there is a low but true risk of allergenicity to the PMMA microspheres. Allergic reaction can occur with Artefill even with a negative test site. Due to the persistence in tissue, patients may have a prolonged allergic response. Patients who form keloids and hypertrophic scars may form scarring at the site of injection due to a tissue reaction around the PMMA microspheres and therefore caution should be heeded in these patients.
Lemperle G, Romano J, Busso M. Soft Tissue Augmentationwith Artecoll: 10-Year History, Indications, Techniques, and Complications. Dermaatol Surg 2003;29:573-587.

Hyaluronic Acid: Restylane (Medicis Aesthetics, Inc) and Hylaform (Genzyme Corporation)

Hyaluronic acid is a glycosaminoglycan polymer found in the skin. It is found ubiquitously in mammalian connective tissue and decreases with aging. Its primary function is to provide volume and pliability to the skin. Hyaluronic acid is a high molecular weight polymer composed of repeating dimers of glucuronic acid and N-acetyl glucosamine on a protein backbone. Its shape is much like that of a bottle brush with each sugar residue radiating outward and densely filling the space around the protein core. A unique characteristic of hyaluronic acid is its binding capacity of water. The repeating sugar moieties can bind 1000 times their own volume of water. Hyaluronic acid is chemically, physically, and biologically identical in the tissues of all species which increases its chance of biocompatability. Its viscoelastic properties make it a desirable agent for soft tissue augmentation. Hyaluronic acid undergoes isovolemic degradation. This type of degradation allows the product to hold more water the less concentrated it becomes, maintaining its correction even in low presence of the material.
Goa KL, Benfield P. Hyaluronic acid. A review of its pharmacology and use as a surgical aid in ophthalmology and its therapeutic potential in joint disease and wound healing. Drugs 1994;47:536-66.

Restylane and Hylaform are injectable hyaluronic acid derivatives. They were developed primarily as an alternative to collagen injections for augmentation. One of the advantages to injectable hyaluronic acid derivatives versus collagen is the potential longevity of the product in tissue. Restylane and Hylaform were approved by the FDA in December 2003 for treatment of facial wrinkles. When seeking FDA approval, the safety and effectiveness of Restylane for the treatment of nasolabial folds was compared to Zyplast in a randomized, controlled study. One nasolabial fold was injected with Restylane and one with Zyplast to optimal correction. Less volume of Restylane was required to achieve optimal correction. The side effect profile after injection between both products was similar. The patients were evaluated at six months to compare longevity of the products. The FDA panel found Restylane comparable to Zyplast. Two independent scales of wrinkle assessment evaluated by a blinded investigator done at six months after injection revealed that Restylane was superior in 57% and 62% of patients while Zyplast was superior in 10% and 8% of patients. This study was published in Dermatologic Surgery where it was concluded that Restylane provided a more durable aesthetic improvement.
Narins RS, Brandt F, Leyden J, Lorenc ZP, Rubin M, Smith S. A randomized, double-blind, multicenter comparison of the efficacy and tolerability of Restylane versus Zyplast for the correction of nasolabial folds. Dermatol Surg. 2003 Jun;29(6):588-95.

Hylaform was also compared to Zyplast with respect to safety and longevity in FDA trials over a twelve week period. The FDA panel found Hylaform comparable to Zyplast. In the investigational trials, Genzyme excluded patients allergic to avian materials composing the hyaluronic acid gel from their study, and because of this, the FDA panel stipulated that assessment of avian protein allergies should be required before injection, either through a test or confirmation of history. However, this argument was refuted and hyalaform was released onto the market shortly following Restylane and does not require a pre-test injection.

The major difference between the hyalunonic acid injectables is their origin, composition and cross-linkage. Restylane, produced by bacterial fermentation, has a lower molecular weight but a higher concentration (20 mg/ml), and its viscoelastic properties have a more viscous tendency. Hylaform, produced by extraction from rooster combs, has a higher molecular weight but a lower concentration (6 mg/ml) and its viscoelastic properties have a more elastic tendency.
Duranti F, Salti G, Bovani B, Calandra M, Rosati ML. Injectable hyaluronic acid gel for soft tissue augmentation. A clinical and histological study. Dermatol Surg. 1998 Dec;24(12):1317-25.

Restylane is a gel of hyaluronic acid generated by Streptococcus species of bacteria, chemically cross-linked with BDDE, stabilized and suspended in physiologic buffer at pH = 7 and concentration of 20 mg/ml. Restylane is indicated for mid-to-deep dermal implantation for the correction of moderate to severe facial wrinkles and folds, such as nasolabial folds. There are three separate products made from the above streptococcus bacteria: Restylane, Restylane Fine Line, and Perlane. Restylane Fine Line is used for correcting thin superficial lines. Perlane can be used for shaping facial contours, such as the cheeks and chin, correcting deep folds, and for volume augmentation of the lips.

Hylaform (hylan B) is a sterile, nonpyrogenic, transparent gel implant composed of cross-linked molecules of hyaluronan generated from the hyaluronic acid of domestic rooster combs at a concentration of 6.0 mg/ml. Hylaform is indicated for correction of soft tissue contour deficiencies, such as wrinkles an acne scars. There are three products in this line: Hylaform, Hylaform Plus (used for shaping facial contours), and Hylaform Fineline (used for thin superficial lines).

Restylane and Hyalaform are injected in the mid to deep dermal plane. Before injecting, the material should be advanced to the tip of the needle by gently applying pressure to the plunger of the syringe. The needle should be advanced under the area to be filled and the substance should be injected while pulling the needle back. Serial puncture injections and/or the tunnel technique can also be used to achieve the desired affect. The wrinkle should be eliminated after the injection. Correction should be 100% with no overcorrection needed. After injection, the area should be gently massaged and molded into the contour of the surrounding tissues. If overcorrection has occurred, a firm massage can help to mold the contour to a desirable affect. If blanching occurs with injection, downward pressure and firm massage can push the filler more deeply into the tissue. Additional treatment with Restylane may be needed to maintain optimal correction. The patient should return to clinic for evaluation at least two weeks after injection. Occasionally a fairly exuberant inflammatory reaction occurs with injection which subsides within a few days. This is more commonly seen with Restylane than with Hylaform. An ice pack can be used for pain and control of inflammation after injection.

Synergestic affects of cosmetic procedures have been reported. In 2003, an article comparing the treatment of glabellar furrows with Restylane alone versus treatment with both Restylane and Botox was done. This study revealed that the median time for the return of preinjection furrow status occurred at 18 and 32 weeks in the Restylane alone and the Restylane and Botox treated groups respectively. By paralyzing the musculature underlying the glabella, the movement that caused the furrows to occur is eliminated. This musculature movement may decrease the longevity of injectable products by allowing them to shift and be pushed toward the subcutaneous tissue rendering them unable to fill out the dermal tissue.
Carruthers J, Carruthers A. A prospective, randomized, parallel group study analyzing the effect of BTX-A (Botox) and nonaminal sourced hyaluronic acid (NASHA, Restylane) in combination compared with NASHA (Restylane) alone in severe glabellar rhytides in adult female subjects: treatment of severe glabellar rhytides with a hyaluronic acid derivative compared with the derivative and BTX-A. Dermatol Surg. 2003 Aug;29(8):802-9.

Although the injectable hyaluronic acids seem as though they should be almost free of side effects this has not proven to be true. It is true that there are fewer allergies to hyaluronic acid injectables than with injectable collagen (allergy to bovine-derived collagen: 3-4% ), however side effects are occurring and the question of whether human anti-hyaluronic acid antibodies occur has been raised. In a study done by Lowe et al, of the 709 patients treated with injectable hyaluronic acid, the incidence of allergy was found to be 0.42%. Another study done by Friedman et al, of 144,000 patients who received a hyaluronic implant had an incidence of adverse events of 0.15%. There have been several reports of granulomatous foreign body reaction of the lip after hyaluronic acid injection. Delayed hypersensitivity reactions have been seen in patients and verified by challenge skin testing. Hypersensitivity is an inflammatory reaction has been observed with edema, erythema, tenderness, induration, and rarely acneform papules at the sites of injection. To date, no systemic reactions have been directly correlated to hyaluronic acid injectables. Although no systemic symptoms have been directly linked, some have advocated for a pretreatment skin test to rule out allergy before treatment with these agents can be administered.
Micheels P. Human anti-hyaluronic acid antibodies: is it possible? Dermatol Surg. 2001 Feb;27(2):185-91.
Lowe N, Maxwell CA, Lowe P, Duick M, Shah K. Hyaluronic acid skin fillers: adverse reactions to skin testing. JAAD 2001;45:930-3.
Friedman PM, Mayfong EA, Kauvar AN, Geronemus RG. Safety data of injectable nonamincal stabilized hyaluronic acid for soft tissue augmentation. Dermatol Surg. 2002 Jun;28(6):491-4.
Fernandez-Acenero MJ< Zamora E, Borbujo J. Granulomatours foreign body reaction against hyaluronic acid: resport of a case after lip augmentation. Dermatol Surg. 2003 Dec;29*12):1225-6.
Lupton JR, Alster TS. Cutaneous hypersensitivity reaction to injectable hyaluronic acid gel. Derm Surg 2000;26:135-7.
Raulin C, Greve B, Hartschuh W, Soegding K. Exudative granulomatous reaction to hyaluronic acid. Contact Dermatitis. 2000 Sep;43(3):178-9.

Calcium Hydroxylapatite (Radiance: Bioform)

Calcium Hydroxylapatite (CaHA) is an inorganic substance that mimics the structure of bone. In the United States, it is marketed as Radiance. Radiance is currently FDA approved for use in oral maxillofacial defects and for soft tissue vocal fold augmentation and as a radiographic tissue marker. CaHA is currently widely used in Europe as a soft tissue filler. Radiance is currently not approved in the United States by the FDA for cosmetic applications and can only be used as an off-label use for soft tissue augmentation.

In its soft tissue injectable form, CaHA microspheres are suspended in a carboxycellulose absorbable gel, and it is injected into the dermis or subcutaneous tissue. As the gel is absorbed, collagen deposition into and around the microspheres causes collagen formation and enhances augmentation. It is expected to last between two to five years and its break down products include calcium and phosphorous.
Sklar JA, White SM. Radiance FN: a new soft tissue filler. Dermatol Surg. 2004 May;30(5):764-8.

Poly-L-lactic Acid: Sculptra/New Fill (Dermik)
Poly-L-lactic acid (PLLA) received conditional FDA approval for treatment of HIV-related lipoatrophy under the trade name Sculptra on March 2004. However, the FDA has not yet approved Sculptra for general cosmetic use in the United States. Studies of this product are currently underway to gain FDA approval. Poly-L-lactic acid has been marketed as New-Fill in Europe since November 1999.

PLLA is a synthetic polymer which is resorbable, biocompatible, and biodegradable. It has been used for several years in multiple medical devices and is a component of vicryl suture. PLLA can be injected into the deep dermal tissue or subcutaneous tissue. The area to be filled should be undercorrected. After injection, gradual degradation takes place by hydrolysis while gradual deposition of collagen occurs. A study by Gogolewski et al was done to assess changes in tissue in rats after subcutaneous implantation of PLLA. Biopsies were taken at 1, 3, and 6 month intervals. It was found that the PLLA degraded by 6%, 32%, and 58% at 1, 3, and 6 months respectively. It was also found that the amount of collagen present in the specimens increased with each progressive biopsy.
Nayak, PL. Biodegradable polymers: opportunities and challenges. JMS Rev Macromol Chem Phys, 1999, C39(3):481-505
Gogolewski S, et al. Tissue response and in vivo degradationof selected polyhydroxyacids: polylactides (PLA), poly(3-hydroxybutyrate) (PHB), and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHB?VA). Jouranl of Biomedical Materials Researach, 1993,27(9):1135-48.

The initial apparent correction, due to implantation of the PLLA decreases over the next few days as the diluent is resorbed. The area treated with PLLA will then slowly refill as the tissue reacts to the implant. A gradual increase in the volume will continue to occur over the next few months.

The side effects of this material are similar to other injectables and include erythema, edema, and bruising at the injection site. Palpable but nonvisible subcutaneous nodules have been noted in some patients which can resolve spontaneously. These nodules may be due to over-correction. Massaging the treated area after injection may reduce the incidence of this side effect. Rare cases of sterile abscess, late granuloma formation and hypersensitivity reactions have been reported.
Moyle GJ, Lysakova L, Brown S, Sibtain N, Healy J, Priest C, Mandalia S, Barton SE. A randomized open-label study of immediate versus delayed polylactic acid injections for the cosmetic management of facial lipoatrophy in persons with HIV infection.
Lombardi T, Samson J, Plantier F, Husson C, Kuffer R. Orofacial granulomas after injectionof cosmetic fillers. Histopathologic and clinical study of 11 cases. J Oral Pathol Med. 2004 Feb;33(2):115-20.
Valantin MA, Aubron-Olivier C, Ghosn J, Laglenne E. Pauchard M, Schoen H, Bousquet R, Ktz P, Costagliola D, Katlama C. Polylactic acid implants (New-Fill) to correct facial lipoatrophy in HIV-infected patients: results of the open label study VEGA. AIDS. 2003 Nov 21;17(17):2471-7.

Biocompatibility and Durability of Ten Injectable Fillers
A study of ten injectable filler substances used for soft tissue augmentation was conducted to assess both biocompatibility and durability of each substance. Each filler was injected deep intradermally into the volar forearm (0.1 cc) and reviewed for clinical reaction and permanence. At 1, 3 ,6, and 9 months the test sites were excised, histologically examined, and graded according to foreign body reactions classification. The histologic grading system consisted of Grades I through IV, with Grade I representing slight reaction with a few inflammatory cells and Grade IV representing granuloma with encapsulated implants and clear foreign body reaction. Collagen (Zyplast) was phagocytosed at 6 months and resulted in a Grade I inflammatory reaction. Hyaluronic acid (Restylane) was completely phagocytosed at 9 months and resulted in a Grade II inflammatory reaction. PMMA microspheres (Artecoll) had encapsulated with connective tissue, macrophages, and sporadic giant cells (Grade III). The injected substance remained visible clinically throughout the study. Polylactic acid microspheres (New-Fill, Sculptra) induced a mild inflammatory response clinically and persisted 9 months in tissue. Calcium hydroxylapatite microspheres (Radiance FN) induced almost no foreign body reaction but were absorbed by the skin at 12 months where it became whitish and shining through the skin. PMS 350 (Silicone) dispersed into the surrounding tissue and resulted in an intense inflammatory response. Reviderm intra (dextran beads) injection caused swelling an erythema continuing for 10 days with edema persisting for more than 3 months. Histologically it also produced the greatest amount of granulation tissue. Dermalive (hydroxyethyl-methacrylate persisted clinically 4 months and showed the least cellular reaction of all implants. Aquamid (clear gel of polyacrylamide) is used for breast augmentation in Ukraine and China. This product remained palpable at 9 months but steadily decreased in size. The histological reaction resembled that of injected fluid silicone. Evolution (polyvinylhidroxide microspheres suspended in acrylamide gel) clinically resembled Artecoll and histologically resembled PLA.

It was noted by the authors that a late or delayed inflammatory reaction could be missed due to an inadequate duration of the study. Lemperle G, Morhenn V, and Charrier U. Human Histologya dn persistence of various injectable filler substances for soft tissue augmentation. Aesthetic Plastic Surgery. Springer-Verlay 2004. Published online: 14 Jan 2004.

As new filler products are approved by the FDA, these products will become more widely used and possibly unreported adverse side effects unveiled. Publishing these events and contacting the company is paramount as these side effects need to be reported and verified as linked or not linked to the product. Also if another physician has had a patient with a similar adverse event, possible treatment modalities can be shared.