Collagen and Other Injectable Fillers Treatment & Management
- Author: Ashok Tholpady, MD, MSc; Chief Editor: Deepak Narayan, MD, FRCS more...
Medical therapy for the specific types of injectable fillers is discussed in the sections below.
Numerous fillers are available. Each of these preparations has special properties, indications, and contraindications.
Biodegradable fillers include bovine collagen (Zyderm/Zyplast, Resoplast), human collagen (Dermalogen), autologous fibroblasts (LAVIV, AlloDerm), hyaluronic acid (Hylaform gel, Restylane), calcium hydroxylapatite (Radiesse), and poly-L-lactic acid (PLLA).[3, 4]
Nonbiodegradable fillers include silicone (off-label) and polymethylmethacrylate beads (Bellafill).
Fillers are used to fill defects within the skin and subcutaneous tissue. The depth of the defect should determine the filler chosen for the appropriate procedure. For example, collagen and hyaluronic acid are used to fill relatively superficial defects, while deeper defects may require fat or synthetic products, including implants or permanent fillers. Multiple fillers or implants may be layered to achieve maximal correction.
Superficial defects are filled with collagen or hyaluronic acid polymers.
Deeper defects are filled with fat, synthetic materials, silicone, implants, or permanent fillers.
Collagen fillers can be divided into those of bovine and human origin. Since the autologous forms are prepared from the patient's own tissues, they are not allergenic and do not run the risk of viral transmission.
Human collagen - Allogeneic (AlloDerm, Cymetra [micronized AlloDerm], CosmoPlast, Dermalogen)
Bovine collagen – Bellafill, Zyderm I and II, Zyplast
Porcine collagen - Permacol
AlloDerm and Cymetra (human collagen)
AlloDerm and Cymetra are approved by the FDA and manufactured by LifeCell Corporation, Branchburg, NJ.
AlloDerm is an acellular human dermal graft processed from tissue bank–derived skin. It has been used since 1992 on more than several thousand patients; initially, it was used for burn victims and, later, in oral surgery and soft tissue augmentation. Because AlloDerm is available in sheets 1-2 mm thick, it is not injected but implanted surgically. Scar correction is theoretically the result of the ingrowth of tissue during the remodeling phase of wound healing.
Insertion requires the use of local anesthesia by nerve block, local infiltration, or both. After rehydrating the graft in normal saline, the dermal sheet is rolled and trimmed to the appropriate length of the defect. A tunnel is then created under the scar or contour deformity and an instrument is used to pass the tissue to the opposite side, where it may be sutured into place.
A clinical trial of 12 lip augmentation procedures showed no rejection or displacement at 12 months postoperatively. Suture site infection and reactivation of herpes labialis was reported. Results from AlloDerm last for approximately 6-12 months, but persistence of grafts can reach several years. AlloDerm appears to have greater longevity than collagen fillers, though no controlled studies have been performed.
Cymetra is a micronized form of AlloDerm that is injectable. This material is rehydrated with lidocaine in the physician’s office before injection. Because it is human-derived, no skin test is required by the manufacturer. Clinical trials of 200 patients to date show no evidence of allergic reactions; however, transient bruising, redness, and swelling occurred at a rate of 2.1%. Results last in the range of 3-6 months.
CosmoDerm and CosmoPlast (human collagen)
These agents are approved by the FDA and are manufactured by INAMED Aesthetics, Santa Barbara, Calif.
CosmoDerm and CosmoPlast are both human collagen fillers that are created under laboratory conditions. They are supplied as a 35mg/mL solution of collagen and 0.3% lidocaine. CosmoDerm is for superficial lines and wrinkles; CosmoPlast is made more resistant to endogenous proteases by glutaraldehyde, and its crosslinking treatment is for deeper wrinkles. Because both of these products are of human origin, no allergy testing is recommended or required.
Dermalogen (human collagen)
Dermalogen is approved by the FDA and is manufactured by Collagenesis Corporation, Beverly, Mass.
Dermalogen is a human collagen preparation that consists predominantly of intact collagen fibers as well as other matrix proteins suspended in a neutral pH buffer. The material is harvested from cadaver skin specimens from the American Association of Tissue Banks (AATB), which is a group of accredited tissue skin banks. It is sterile and has undergone several viral and prion inactivation steps. Dermalogen is injected through a 30-gauge needle. This preparation does not contain lidocaine; therefore, some form of anesthesia is necessary. Implantation of the filling agent is followed by neovascularization and collagen synthesis by host fibroblasts. The injection site is mid dermis to deep dermis, and a 125% correction is achieved by the clinician.
To produce the stability necessary for a 1-2 year correction, 2-3 injections over 2-4 weeks are typically required. Few adverse effects are associated. No allergic reactions have been reported over the last 10,000 administered injections; thus, the previously recommended skin test has been discontinued. This product has also been discontinued by the company.
Bellafill (formerly, ArteFill) (bovine collagen)
Bellafill, under its former name, ArteFill, received FDA approval in 2006. The product's name was changed to Bellafill in 2014; in 2015, the FDA approved it for use in the treatment of acne scars.
Bellafill is composed of polymethylmethacrylate beads suspended in bovine collagen. The beads remain intact as the collagen degrades. Polymethylmethacrylate acts as a foreign body, causing a local inflammatory response, and becomes trapped in the resultant fibrous connective tissue.
Prior to injection of Bellafill, a special skin must be given. Patients should not undergo injection with Bellafill if they have a positive skin test or 2 equivocal skin tests. Patients with a higher-than-normal antibovine collagen serum immunoglobulin G level at baseline are advised not to undergo treatment with Bellafill.
Zyderm and Zyplast (bovine collagen)
These agents are approved by the FDA and are manufactured by INAMED (Santa Barbara, Calif).
The first injectable filling material to be approved by the FDA was Zyderm collagen. This bovine collagen implant has been used for approximately 20 years and the injection technique has been standardized. Each is delivered in 1-mL syringes packaged with lidocaine and a 30-gauge needle.
Three variations are available for this collagen implant. Zyderm I collagen is a 25% suspension of purified bovine dermis in saline with 0.3% lidocaine. The saline carrier is absorbed and the remaining implant persists for 3-10 months. Zyderm I is used most successfully to treat shallow distensible scars and fine rhytides.
Zyderm II has double the concentration and is a more viscid substance. The longevity of scar correction is increased and it can be used for larger filling defects.
Zyplast is a cross-linked derivative of bovine collagen, which is a heavier filling material and has greater longevity. Zyplast can be used for larger scars that require a greater and deeper filling of volume and lasts longer. It is placed deeper in the dermis and requires 100% correction at the time of implantation, rather than the 150% used for Zyderm I. Zyderm I has a longevity of 6 weeks to 3 months; Zyderm II, 4-5 months; and Zyplast may last 9 months to 1 year, especially in a relatively immobile scar.
These two filling agents are the most commonly used in implants in the United States. They are user friendly, relatively easy to inject, and can be integrated into a simple office visit for the patient requesting dermal augmentation. The filling agent is technique dependent for longer lasting results, proportional to the clinician's ability to place the collagen correctly. Adverse reactions have been noted including allergic reactions, hypersensitivity reactions with Zyderm I and II, and vascular necrosis occurring with Zyplast, particularly in the glabella and on the nose. Although these complications are rare, they have been reported and proper allergy testing must be performed for each patient.
Permacol (porcine collagen)
Permacol is a porcine-derived source of collagen. It is manufactured in an injectable form and a graft form. The matrix graft is used for human dermal tissue defects, while the injectable form is used for urinary bulking in patients with urinary incontinence.
Hyaluronic acid-based fillers are the most commonly used (Belotero, Hydrelle, Juvadérm Ultra, PREVELLE Silk, Restylane, Perlane, Reviderm). Other noncollagen fillers include polyacrylamide, fat, autologous fibroblasts, calcium hydroxyapatite, poly-L-lactic acid, and silicone.
Aquamid is a nonabsorbable filler that contains approximately 2.5% cross-linked polyacrylamide and 97.5% nonpyrogenic water. A more viscous version is marketed as Aquamid Reconstruction. The filler is packaged as a sterile, prefilled 1-mL syringe. Advese events were localized to reactions at the injection site. It is recommended that Aquamid be injected subcutaneously in a retrograde, fan-shaped manner. A minimum of 14 days should elapse before additional injections.
Belotero Balance is approved by the FDA and is manufactured by Merz Pharmaceuticals (Greensboro, NC).
Belotero Balance is a hyaluronic-based dermal filler that is derived from streptococcal cultures and cross-linked with the binding agent 1,4-butanediol diglycidyl ether. It is indicated for correction of moderate-to-severe facial wrinkles and folds via injection into the mid-to-deep dermis. Belotero Balance is obtained in a sterile 1-mL prefilled glass syringe. Clinical trials showed that 1.5 mL per nasolabial fold was the average volume needed to obtain optimal correction. Belotoro Balance can be injected using a 30-gauge needle, which is attached to the syringe. Needles are provided to assure proper needle attachment. Adverse reactions include injection site symptoms, such as swelling, induration, erythema, pain, discoloration, and rash. Nonlocal adverse events, reported in 2.5% of study subjects, include mild herpes simplex, mild headache, and moderate urticaria.
Fat injections have been available and performed for more than 100 years as live, free fat grafts. Liposuction has made the harvesting of fat a simpler procedure. For grafting, this is performed with a syringe in an atraumatic manner. The best donor sites include the thighs, buttocks, knees, and abdomen. The resultant fat is then centrifuged gently to separate the intact fat cells from supernatant serum-free lipid. Fat cells are then injected into a subcutaneous plane under larger scars with a 16- to 18-gauge needle or special cannula. Fat is used as a subcutaneous filling substance and is not indicated in dermal augmentation. Thus, it is reserved for large, atrophic defects that include skin and fat.
Hydrelle (formerly Elevess)
Hydrelle (formerly Elevess) is approved by the FDA and is manufactured by Anika Therapeutics (Bedford, Mass).
Hydrelle (previously known as Elevess) is a cross-linked hyaluronic acid and lidocaine injectable gel. The hyaluronic acid in this product is produced from Streptococcus equi. It is contraindicated in patients with a history of allergies to lidocaine, sodium metabisulfite, or gram-positive bacterial proteins. Adverse events include injection site ecchymosis and edema, as well as nodule formation, edema, contusion, and facial swelling.
Hylaform (hylan B gel)
Hylaform (hylan B gel) is approved by the FDA and is manufactured by INAMED (Santa Barbara, Calif) and Genzyme Corporations (Cambridge, Mass).
Hylaform B gel (previously known as hylan B gel) is a hyaluronic acid derivative of an avian polysaccharide from the rooster comb. It is a cross-linked derivative of natural hyaluronan polymer with little immunologic activity and no species specificity. It is an intradermal injection used to augment scars. No skin test is required, but the procedure requires a series of injections rather than a single treatment session. After 2 or 3 injections, the initial clinical trials resulted in 80% of patients satisfied with their correction at 12 weeks. Longevity is 9 months to 1 year, after which reinjection is necessary. Adverse reactions have been minimal, including erythema, ecchymosis, and acneiform dermatitis, with no reported allergic reactions.
Azficel-T (formerly Isolagen)
Azficel-T (LAVIV) was approved by the FDA in June 2011 and is manufactured by Fibrocell Science, Inc.
Azficel-T is prepared by harvesting autologous skin, purifying the host fibroblasts, and packaging it in a suspension for intradermal injection. A piece of skin derived from a punch biopsy from behind the ear is sent to the company. From this, the fibroblast population of cells is isolated and grown. These cells are the ones responsible for collagen synthesis in vivo. After 6 weeks, a vial of cells (~18 million fibroblasts/1.2 mL) is sent back to the physician for injection. Implantation of the material must take place before the vial expires, otherwise it is unusable. Therapy consists of a series of 3 intradermal injection sessions administered 3-6 weeks apart. The dose is 0.1 mL ID per linear centimeter into the nasolabial fold wrinkles. Only physicians who complete a Fibrocell-approved training program will be able to administer it.
This is a biological that works over time to provide gradual and natural results.
The FDA approval was based largely on 2 identical phase 3 multicenter, randomized, double-blind, placebo-controlled studies involving 421 patients who underwent 3 treatment sessions approximately 5 weeks apart.
On the basis of investigators' and patients' assessments, a significantly greater proportion of patients demonstrated a positive response to treatment with azficel-T than with placebo. The treatment improved the appearance of nasolabial fold wrinkles for the 6 months of patient follow-up after the last treatment. The company said studies are ongoing, looking at how long beyond 6 months after the last treatment the effect may last.
Because the product is autologous, little risk exists of allergic response. In clinical trials, the most common adverse events were mild-to-moderate injection-site reactions that usually resolved within 1 week. Once harvested and processed, a long-term supply of fibroblasts is then available for the patient. The cells can be cryogenically stored for use years later. A theoretical benefit may also exist in using cells that were isolated from the patient at a much younger age.
Juvadérm Ultra is approved by the FDA and is manufactured by Allergan.
Some formulations of Juvaderm contain lidocaine. Juvadérm is a gel containing cross-linked hyaluronic acid produced from Streptococcus equi bacteria. Its indications are for correction of moderate-to-severe facial wrinkles and folds.
A multicenter, randomized controlled study with 87 subjects demonstrated that at 24 weeks post injection, treatment effects were maintained in 96% of nasolabial folds injected. Subsequent treatment required a decrease in volume of Juvéderm Ultra.
The most common adverse events were swelling, redness, discoloration, and bruising as reported by postmarket safety surveillance of Juvéderm injectable gel in countries outside the United States.
PREVELLE Silk is approved by the FDA and is manufactured by Genzyme Biosurgery in Ridgefield, NJ.
PREVELLE Silk is a hyaluronic acid dermal filler derived from bacteria that contains 0.3% lidocaine designed to decrease pain at the time of injection.
A prospective, randomized controlled trial comparing PREVELLE Silk with the same filler without lidocaine showed greater than 50% pain relief at every postinjection time point compared with the same filler without lidocaine. The largest difference in pain between the groups was seen at the time of injection.
Radiesse is approved by the FDA and is manufactured by BioForm Medical, San Mateo, Calif.
Radiesse (formerly known as Radiance) is an aqueous gel that contains microspheres of calcium hydroxyapatite. This formulation has been used to correct bony defects and has been used off-label as a cosmetic filler. Hydroxyapatite has a much slower rate of resorption by the body and, so, has the potential to give a semipermanent result when used as a filler. Calcium hydroxyapatite does not elicit an inflammatory reaction, so no allergy testing is necessary. The formulation does not contain lidocaine; therefore, some form of anesthesia is required.
Restylane and Perlane
These agents are approved by the FDA and are manufactured by Medicis, Scottsdale, Ariz.
Both of these products are similar to Hylaform in that they are composed of hyaluronic acid. Instead of being produced from animal sources, however, they are both derived from bacteria that produce hyaluronic acid. Restylane is used for superficial wrinkles, while Perlane, which is much less susceptible to breakdown in the body, is for deeper wrinkles. Both products do not pose an allergy risk and are thought to be broken down at a slower rate than the collagen products. Results can last as long as 1 year. In 2012, the FDA approved a form of Restylane, called Restylane-L, that contains 0.3% lidocaine.
Reviderm Intra is not approved by the FDA and is manufactured by Rofil Medical International, The Netherlands.
Reviderm Intra is a bacterial hyaluronic acid–based product that contains suspended 40-60 micron dextran beads. The dextran beads are thought to elicit an inflammatory response that is followed by fibroblast mediated collagen production. This product is intended for intradermal injection and correction of superficial and deep wrinkles.
Sculptra is approved by the FDA and is manufactured by Dermik Aesthetics, a division of Sanofi-Aventis, Bridgewater, NJ.
Sculptra is a novel injectable filler that is composed of poly-L-lactic acid. This material has been used for years to make suture materials and is known to be highly biocompatible. It has been approved for treatment of HIV facial lipoatrophy. It is supplied as a freeze-dried material that can be reconstituted in sterile water at room temperature. Multiple treatments over several weeks are required for the best results; however, results can last up to 2 years.
Silikon 1000 and ADATO Sil-OI-Silicone Oil
Silikon 1000 is approved by the FDA for certain ophthalmologic applications but not cosmetic surgery; it is manufactured by Dow Corning, Midland, Mich. ADATO Sil-OI-Silicone Oil is approved by the FDA as an intraocular fluid; it is manufactured by Bausch & Lomb, Tampa, Fla.
Medical grade silicone was originally used in the 1960s for correction of wrinkles and soft tissue defects. Its popularity led untrained practitioners to use industrial grade silicone, which resulted in many severe, well-publicized complications. In the hands of a trained practitioner, its use can yield cosmetically superior results. At present, it is not approved for cosmetic filler applications but is used for off-label indications.
Other synthetic fillers
There are several other fillers that are not approved by the FDA but are approved in other countries. Bioplastique is a silicone filler approved in Europe. Several polyacrylamide fillers are approved in Europe, Asia, South America, or Canada and include Beautical, Bio-Alcamid, Outline, Evolution, Formacryl, Argiform, Bioformacryl, Amazing Gel, DermaLive/DermaDeep, Metacril, and ArteSense. Other fillers available internationally include Laresse Dermal Filler (carboxymethylcellulose/polyethylene), Atléan BTCP (tricalcium phosphate), Bioinblue (polyvinyl alcohol), and Matridex (DEAE Sephadex).
Other procedures include surgical methods of replacing or implanting material into the dermis for scar elevation.
Dermal grafting is an old technique for the treatment of larger depressed scars. The dermis is harvested, defatted, placed in saline, and then divided into sections to fit the size of the defect. A simple access incision is made to create a pocket within and under the scar in which the dermal implants are placed. Because this represents a graft, little absorption occurs and the results may be long-lasting.
Similarly, synthetic grafts such as Gore-Tex and SoftForm can also be used to fill scars. These are synthetic products that are surgically placed within and under the dermis for augmentation. Gore-Tex is a polytetrafluoroethylene product that has been used extensively in cardiovascular, urologic, and reconstructive surgery. For skin augmentation, it must be placed in the superficial subcutaneous tissue. It is a technique-sensitive operation with adverse reactions including infection, foreign body extrusion, and movement of the implant from the placement site. The product is best for atrophic scars, full-thickness skin defects, and deep melolabial furrows. The implant is permanent and movement or extrusion requires replacement and surgical revision.
The use of either injectable or surgically placed implants for the correction of acne scars depends on the surgeon's and patient's desires. Many patients are satisfied with the simple but repeatable procedure of Zyderm collagen, while others insist upon a single procedure. Both of these choices are available with the advent of new injectable and implantable skin-filling substances.
To reduce potential bruising, patients should discontinue any medications that inhibit platelet aggregation approximately 2 weeks prior to collagen or any filler augmentation.
To provide adequate pain management, topical anesthetics may be applied and allowed to stand for 30 minutes. Nerve blocks to anesthetize the proposed treatment area can also be applied to alleviate the pain associated with filler injection. Injectable collagens are prepackaged with lidocaine within the syringe, thus, obviating the need for local anesthesia. Some dermal fillers are also manufactured with lidocaine.
The technique of filler injection is operator-dependent; however, 2 methods commonly used by physicians include serial puncture and linear threading.
Serial puncture involves injecting small amounts of collagen several times in a row to fill a fold. This method provides greater precision but at the expense of multiple entry sites.
In linear threading, an injection is used only once and fills the fold with collagen in a linear fashion. Although this technique allows for a better outline of the wrinkle, the inability to see while injecting the collagen carries a greater risk of vascular accidents.
Cooling the area after the procedure reduces inflammation around the injection site. The patient may resume daily activities soon thereafter.
Complications include bruising, purpura, lumpiness, delayed mediated hypersensitivity reaction with granuloma formation, vascular infarction with tissue necrosis, and cystic ulceration.
Outcome and Prognosis
Collagen is an excellent temporary skin filler that yields a natural cosmetic result. After 1 or 2 treatments, the patient's defect should be stable and the correction should last 6-9 months.
See the photos below.
Future and Controversies
Some questions remain concerning prion activity among the bovine herds and possible "mad cow disease" infection from collagen injections. However, this is hypothetical and care has been taken to isolate the Zyderm bovine herd from other cattle to prevent such an occurrence.
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