Collagen and Other Injectable Fillers Treatment & Management

Medical therapy for the specific types of injectable fillers is discussed in the sections below.

Fillers

Numerous fillers are available. Each of these preparations has special properties, indications, and contraindications.

• Biodegradable - Zyderm/Zyplast, Resoplast, Dermalogen, Autologen, Isolagen, AlloDerm, human placental collagen, recombinant human collagen (future), Hylaform gel, Restylane
• Nonbiodegradable - Silicone (illegal in US), Artecoll, Gore-Tex, SoftForm, Endoplast-50, Profill

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 - Collagen, hyaluronic acid polymers
• Deeper defects - Fat, synthetic materials, silicone, implants, or permanent fillers

Dermal collagen

Collagen fillers can be divided into those of bovine and human origin. The bovine products are used most widely. Human collagen can be divided into allogeneic and autologous forms. Since the autologous forms are prepared from the patient's own tissues, they are not allergenic and do not transmit exogenous infectious agents.

• Bovine collagen - Zyderm I and II, Zyplast, Resoplast, Artecoll, Endoplast-50, ArteFill
• Human collagen

  • Allogeneic - CosmoPlast, Dermalogen, AlloDerm, Fascian, Cymetra (which is micronized AlloDerm)
  • Autologous collagen - Autologen
• Human placental collagen/recombinant human collagen
• Porcine - Evolence, Permacol

AlloDerm and Cymetra

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.

Artecoll

Artecoll is not approved by the FDA and is manufactured by Rofil Medical International, The Netherlands.

Artecoll is a synthetic mixture of polymethyl methacrylate (PMMA) microspheres suspended in bovine collagen, saline, and 0.3% lidocaine. The mixture is injected deeply in the dermis and subcutaneous tissue. Following injection, the collagen is gradually degraded with permanent deposition of PMMA spheres. Artecoll is injected subdermally and overcorrection is not necessary. Broad experience in Europe has found this product reliable and long lasting, and its use in acne scars is well documented. It is presently not available in the United States, and many concerns have been raised about the safety of injection of PMMA because of the risk of ulceration and inflammatory reactions to the product.

ArteFill

ArteFill received FDA approval in 2006.

ArteFill is composed of polymethylmethacrylate beads suspended in bovine collagen. The beads remain intact as the collagen degrades. Polymethacrylate acts as a foreign body causing a local inflammatory response and becomes trapped in the resultant fibrous connective tissue.^[1]

Autologen

Autologen does not require FDA approval and is manufactured by Collagenesis Corporation, Beverly, Mass.

Autologen is an injectable dermal implant harvested from autologous collagen. It provides 2 theoretical advantages for implant material. First, it is autologous, which means that allergic and tissue reactions should not occur; second, it contains intact dermal collagen fibers that may exhibit greater resistance to enzymatic degradation. The skin material is provided from skin specimens obtained from plastic and reconstructive surgery procedures in which skin is removed and discarded. The removed skin is processed into a collagen suspension with concentrations from 25-100 mg/mL and injected through a syringe (27-30 gauge).

Results from controlled evaluations in 30 patients demonstrated that 3 layered Autologen treatments provided greater than 75% correction for more than 1 year. Autologen is no longer available in the United States.

CosmoDerm and CosmoPlast

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

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.

Endoplast-50

Endoplast-50 is not approved by the FDA and is manufactured by Laboratories Filorgra.

Endoplast-50 consists of elastin peptides solubilized in bovine collagen. This mixture is thought to stimulate the resident host fibroblasts into producing collagen and, thus, producing a long-term benefit. Results are thought to last as long as 1 year.

Evolence

Evolence is derived from the collagen of porcine tendons. After polymerization, the collagen is cross-linked with ribose moieties to slow its degradation in vivo. Porcine skin is similar to human skin; thus, it is less antigenic than bovine collagen. In fact, no allergic reactions have been reported in clinical trials.

Fibrel

Fibrel is approved by the FDA.

Fibrel has been an effective method of elevating scars using 3 agents; porcine gelatin, amino caproic acid, and 1% lidocaine. The mixture is placed within distensible scars and provides correction for more than 1 year. In select patients, scar elevation has persisted for up to 5 years.

Adverse effects include a prolonged inflammatory reaction in select patients, which is probably related to an idiosyncratic sensitivity response to the products. It has been used extensively in patients who are allergic to Zyderm and has been a reliable filling agent for acne scars.

Permacol

Permacol is another porcine-derived source of collagen. It is manufactured in injectable form and 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.

Zyderm and Zyplast 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.

Fat

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, and for grafting, this is performed with a syringe in an atraumatic manner. The best donor sites include the thighs, buttocks, knees, and abdomen, and 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.

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 and provides 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.^[2]

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.

Radiesse

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.

Reviderm Intra

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

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.^[3] 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.^[4] 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

Silikon 1000 is approved by the FDA for certain ophthalmologic applications but not cosmetic surgery; it is manufactured by Dow Corning, Midland, Mich.

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 procedures include surgical methods of replacing or implanting material into the dermis for scar elevation.

Dermal grafting

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 stab 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.

Synthetic grafts

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 augmentation.^[5]

To provide adequate pain management, topical anesthetics may be applied and allowed to stand for 30 minutes. Injectable collagens are prepackaged with lidocaine within the syringe, thus, obviating the need for local anesthesia.^[5]

The technique of collagen 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.^[5]

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.

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.

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.