COSMETIC DERMATOLOGY
`
`0733;8635/95 $0.00 + .20
`
`Michael H. Gold, MD
`
`Cosmetic dermatologic surgeons continue to
`search for the one ideal product that would benefit
`all patients who require soft tissue augmentation
`to correct facial lines, wrinkles, and depressed cu—
`taneous scars. Numerous products are currently
`available for use in the United States or are under
`
`going clinical investigation. These are listed in Ta—
`ble 1. Table 2 reviews properties required for an
`“ideal” soft
`tissue augmentation product. The
`major criteria for such a compound include one
`that is easily obtained and produced; easily im—
`planted in skilled hands; nontoxic, noncarcino—
`genic, and nonteratogenic; produces no allergic or
`hypersensitivity reactions; and persists in the site
`injected and over the long term, that is, is a perma~
`nent product. Thus far,
`this ideal substance still
`alludes researchers, and therefore, physicians must
`be knowledgeable of which products are available
`and their potential uses. It is no longer acceptable
`to offer patients only one therapeutic option in
`treating these cutaneous defects; the skilled derma—
`tologic surgeon will possess knowledge and know—
`how on several of the products available to offer
`patients the most information and best care.
`Fibrel was the second product line approved by
`the US Food and Drug Administration following
`Collagen Injectable Material (CIM) for use in soft
`tissue augmentation. Fibrel
`received Food and
`Drug Administration approval for the treatment
`of depressed cutaneous scars in 1989 and for facial
`lines and wrinkles in 1991. By mid-1994, Fibrel
`was available for use in five countries and a total
`
`Dr. Gold performs clinical research for Mentor Corpor
`ration. He does receive financial support
`for
`these
`projects. He has no other financial interests in the come
`pany.
`
`of more than 35,000 injections have been per-
`formed. This article reviews the history of Fibrel,
`the proper uses, and future trends.
`Fibrel has a history that spans some 50 years. In
`1944, Bailey and Ingraham' described the use of
`”fibrin foam,” a pooled plasma derivative that
`they used as a hemostatic agent in surgical proce—
`dures. Spangler,” in 1957, reported on the use of
`fibrin foam in the treatment of depressed cutane—
`ous facial Scars; good results were found in 23
`patients. By 1975, Spangler20 had treated over 7000
`patients with fibrin foam and noted 80% with good
`to excellent results. Gottlieb‘”7 helped standardize
`the fibrin foam, and his pioneering work with the
`material became known as the “GAP” repair for
`soft
`tissue augmentation. The mixture included
`gelatin powder (G), epsilon-aminocaproic acid (A),
`and the patient’s plasma (P). A 1987 study re
`ported 44 treated depressed scars with more than
`50% improvement in 75% of the treated group.“7
`Fibrel emerged as a lyophilized form of CAP (ly—
`
`Table 1. DERMAL FILLERS FOR SOFT TISSUE
`AUGMENTATION
`
`Collagen injectable material
`Zyderm I,
`II
`Zyplast
`Fibrel
`Microlipoinjection of fat
`Autologous collagen
`Materials under study
`Koken atelocollagen implant
`Gore—Tex fibers
`Bioplastique
`Human collagen
`Botulinum toxin
`
`
`
`From the Division of Dermatology, Department of Medicine, Vanderbilt University School of Medicine, Nashville,
`Tennessee
`
`DERMATOLOGIC CLINICS
`
`VOLUME 13 - NUMBER 2 - APRII. 1995
`
`ETHICON EXHIBIT 1025
`
`ETHICON EXHIBIT 1025
`
`

`

`Table 2. IDEAL DERMAL FILLER
`
`Easily obtainable
`Easily implanted
`Reasonable cost to physician and patient
`
`Noncarcinogenic
`Nonteratogenic
`No allergy or hypersensitivity
`Resists mechanical strains
`Consistency like normal
`Persists long term
`Persists in same location
`
`ophilized gelatin powder) and is now readily
`available for use in soft tissue augmentation.
`
`MECHANISM OF ACTION
`
`To fully understand the mechanism of action of
`Fibrel, a review of normal wound healing path—
`ways is warranted. When tissue injury occurs, a
`variety of clotting factors are released at the injury
`site. Fibrinogen is one of these factors. The fibrin-
`ogen is converted into fibrin in a reaction catalyzed
`by thrombin, with the resultant formation of a
`fibrin clot. This clot is reabsorbed during a fibri—
`nolysis process that results in tissue loss for the
`affected area. A fibroblastic proliferation follows,
`leading to the development of new collagen and
`
`
`
`Figure 1. Schematic drawing illustrating the wound heal-
`ing cascade following a tissue injury.
`
`scar W
`
`Figure 2. Schematic drawing illustrating the response to
`Fibrel in the treatment of a depressed cutaneous scar or
`line or wrinkle.
`
`the possible formation of a skin depression, that
`is, a scar.2 This is schematically shown in Figure 1.
`Figure 2 demonstrates the proposed mechanism
`of action for Fibrel
`in combating the normal
`wound healing pathways and correcting the skin
`depression. Through the injection process of the
`Fibre] implant within the skin, tissue injury will
`occur. The tissue injury results in the release of
`a variety of clotting factors. The Fibrel
`implant
`physically elevates the skin defect; it is hypothe—
`sized that the gelatin matrix acts to trap the clot—
`ting factors and fibrinogen. The matrix is infil—
`trated by fibroblasts and serves as a template for
`the formation of new collagen.13 The patient’s
`plasma is used as an additional source of fibrino—
`gen, thrombin, and other clotting factors.Z Epsilon
`aminocaproic acid is an available product with
`properties known to inhibit fibrinolytic activity.5
`This helps stabilize the fibrin clot. Further, new
`collagen synthesis is aided by blocking the fibrino—
`lytic systems.2 Thus, Fibrel not only corrects the
`cutaneous depression but promotes new collagen
`synthesis at the site of tissue injury.
`Several investigations have studied Fibrel histo—
`logically in guinea pigs. In 1974, Chavpel and asso—
`ciates (unpublished data)1 reviewed their findings
`that the Fibrel implant formed a sponge—like ma—
`trix at the injection site. An inflammatory response
`was found at the site, and at 90 days only newly
`formed connective tissue was identified. In 1980,
`Ulreich (unpublished data) noted that following
`
`

`

`100
`
`80
`
`60
`
`g
`3
`"3
`'0
`
`9 “
`
`CD
`3’
`.9
`
`(1)
`E 40
`CD
`.5
`
`.c
`£0
`o\°
`
`20
`
`0
`
`Control
`
`3months 6months 9months
`
`Figure 4. Result of tissue biopsies. Elastic tissue produc-
`tion over time—histologic evaluation in human volunteers.
`
`THE FlBREL KIT
`
`Fibrel is supplied by Mentor Corporation, Go-
`leta, CA. It comes as a sterile kit that has a long
`shelf life and contains all of the materials required
`for reconstitution and treatment (Fig. 6). The Fibrel
`mixture of lyophilized gelatin powder and earninor
`caproic acid is contained in one of the syringes
`provided. The kit also contains needles and syrin—
`ges
`for phlebotomy,
`for mixing, and for
`injection itself.
`The first‘step in preparing the implant
`remove blood from the patient. The blood is
`placed in a centrifuge to obtain the necessary
`plasma. In the extra syringe provided, 0.5 mL of a
`9% sodium chloride solution is mixed with 0.5 mL
`
`injection in guinea pigs, a spongy matrix
`Fibrel
`formed that was infiltrated by host inflammatory
`cells by 14 days. These inflammatory cells con—
`sisted of granulocytes, macrophages, and fibro—
`blasts. Also at 14 days, newly formed collagen was
`identified within the implant. This was further
`confirmed by immunofluorescent analysis. Within
`90 days, the implant is invaded by blood vessels
`and other connective tissue—producing cells.
`This author has studied the response of Fibrel
`histologically over time in healthy human volun-
`teers.3 Skin biopsies performed over various time
`periods were consistent with the proposed mecha—
`nisms of action for Fibrel. The amount of collagen
`found at
`implant sites increased from baseline
`through 6 months before beginning to show a re—
`duction at 9 months. Using a O to 4 scale, where 0
`represents no collagen at the implant site and 4 is
`the maximum collagen present, there was an aver—
`age of 1.34/4 or 32% collagen at baseline in the
`volunteer subjects. At 3 months there was an aver—
`age increase of 34.2% over baseline in collagen
`production; and an average increase of 36.9% at 6
`months over baseline. This supported the premise
`that Fibrel increases the amount of collagen syn—
`thesis over time. At 9 months resorption of colla—
`gen had begun; however,
`there was still an in-
`crease of collagen production of 25.8% over
`baseline (Fig. 3).
`The study also demonstrated no change in elas—
`tic tissue over time (Fig. 4). Elastic tissue provides
`tensile strength to connective tissue; this may ex—
`plain why resorption proceeds over time. Figure 5
`demonstrates
`the inflammatory response over
`time. Inflammatory cells are vital parts of the
`wound—healing pathways. At baseline, there was
`an average of 1.8/4 or 8% inflammatory cells at
`the implant sites. This increased to 35.6% at 3
`months; 80.9% at 6 months; and 74.4% by 9 months
`over the baseline values.
`
`100
`
`100
`
`80
`
`60
`
`
`
`
`
`%showinginflammatoryresponseproduction O
`
`
`
`2O
`
`Control
`
`3 months 6 months
`
`tissue biopsies.
`Figure 5. Result of
`response over time—histologic evaluation in human vol—
`unteers.
`
`I I | C
`
`ontrol
`
`Smonths 6months 9months
`
`fl
`
`
`
`
`
`"/0showingcollagenproduction
`
`Figure 3. Result of tissue biopsies. Collagen production
`over time—histologic evaluation in human volunteers.
`
`

`

`
`
`Figure 6. The Fibrel kit.
`
`of fresh plasma. This syringe is then connected to
`the gelatin matrix and e—aminocaproic acid sy—
`ringe, and using the special adapter provided, the
`two mixtures are brought together (Fig. 7). The
`mixture is passed back and forth through the
`adapter until a uniform suspension is achieved.
`This routinely requires 10 to 12 passes.8 The two
`syringes are disconnected, and one of the needles
`provided in the kit is applied for delivery of the
`final product to the patient.
`
`SKIN TEST PROCEDURE
`
`is necessary to perform a skin test prior to
`Fibrel injection. A 0.5—mL Fibrel suspension in a
`121000 saline solution is used as the Fibrel skin test
`
`(Fig. 8). The skin test is placed intradermally. Skin
`tests should always be placed in the same areas.
`This author places the test in the volar aspect of
`the right forearm. The test should be evaluated by
`a trained observer at 48 hours and again at 4
`weeks to determine both immediate and delayed
`hypersensitivity reactions. A positive skin test re-
`sult is defined as erythema or induration that per—
`sists for more than 5 hours or appears more than
`24 hours after implantation. A positive reaction
`in 1.9% of
`the patients evaluated for
`treatment?! 10 After 4 weeks, the patient may re-
`
`This author performs two intradermal skin tests
`on all individuals who present for soft tissue aug—
`mentation. The first test is performed on the right
`volar forearm, and 2 weeks later a second test is
`performed on the left volar forearm. If both test
`results remain negative 4 weeks later, the injection
`of Fibrel can be performed. The rationale rivals
`that for CIM, in that it is hoped that by using two
`
`skin tests more delayed reactions will be identi‘
`fied, reducing the incidence of allergic reactions.21
`
`INDICATIONS AND
`CONTRAINDICATIONS
`
`Fibrel is indicated for the treatment of depressed
`cutaneous lines, wrinkles, and scars. It is a dermal
`implant material approved by the US Food and
`Drug Administration. Cutaneous scars that can be
`elevated by stretching the scar edges are the likeli—
`est defects to respond.13 Fibrotic and ice-pick scars
`also may respond; special techniques (described in
`the following section), however, are necessary.13
`Facial lines, creases, grooves, and furrows also re—
`spond well
`to the Fibrel
`implant. Because the
`injection process causes an associated inflamma—
`tory response, injection into fine periorbital lines
`is not recommended.13
`
`During the initial consultation, it is imperative
`to review wound healing properties and the resul—
`tant cutaneous reaction with the patient: possible
`erythema, induration, and swelling that may last
`up to 5 days postinjection. This will allow the
`patient to schedule the treatment at an appropriate
`time. Collagen synthesis will occur over time, and
`the patient must understand that several weeks
`are required for the treatment
`to be completed
`under the skin surface. In the Future Uses section,
`attempts to minimize these morbidities are re—
`viewed.
`
`is contraindicated in patients who have
`Fibrel
`extremely loose skin, those with a history of keloid
`formation, or those with known sensitivity to gela-
`tin or aminocaproic acid.13 Pregnant or lactating
`women should also not receive Fibrel. It is to be
`
`in patients
`if at all,
`used with extreme caution,
`with history of a bleeding disorder or those on
`anticoagulant therapy.2 Fibrel has not been associ—
`ated with the development of autoimmune disor-
`ders; caution, however, is advised if a patient has
`a history of an autoimmune disease.
`
`INJECTION TECHNIQUES
`
`There are several recommended techniques used
`for injection of Fibrel. Again, the Future Uses sec—
`
`'1?
`
`Figure 7. The mixing or reconstitution phase. A special
`adapter provided allows for passage of materials and
`mixing (horizontal plasma transfer is shown). Gloves
`should be worn at all times.
`
`

`

`
`
`Figure 8. A, The Fibrel skin test. B, Placement of the Fibrel skin test injection in the volar forearm.
`
`tion describes newer injection techniques to make
`Fibrel more user friendly. Each scar or wrinkle to
`be treated needs to be identified and even outlined
`
`using a surgical marking pen. This allows the pa—
`tient to express their desires for treatment and the
`clinician to show which areas may be successfully
`corrected.
`
`Distensible scars can be treated using either the
`25- or 27—gauge needle provided with the Fibrel
`
`kit. Some prefer using a 30—gauge needle. A direct
`multiple puncture or fanning technique (Fig. 9),
`similar to that used with CIM, can be used for
`distensible scars. The needle is inserted into the
`
`skin at a 35—degree angle, and after intradermal
`injection, a blanched or peau d'orange appearance
`occurs on the skin surface. Overcorrection, up to
`150%, is required to allow for reabsorption of the
`fluids in the mixture. In the direct multiple punc~
`
`1 Custom needle
`is inserted at an
`angle
`
`2 Needle is
`threaded
`forward
`unbinding the
`fibrotlc scar
`tissue creating
`_a tunnel
`
`3 Needle is
`withdrawn lrarn
`the tunnel while
`Fibrel' Is injected
`
`a pocket
`
`1 Custom needle
`is inserted at an
`angle
`
`2 Needle is
`manipulated
`tram side to
`side, creating
`
`3 Needle is
`withdrawn lror'n
`pocket while
`Fibrel' is injected
`
`Figure 9. A, Multiple puncture technique for injection of Fibrel. B, Fanning technique for injection of Fibrel.
`
`

`

`tion technique,2 the needle is placed at the edge of
`the scar and advanced into the middle of the scar
`
`for injection of material. In the fanning technique,13
`the needle is advanced from the scar’s edge in a
`circumferential pattern through the scar, creating
`a pocket prior to injection of material. For best
`results, Fibrel should be injected into the upper
`half of the dermis.
`
`Fibrotic or ice-pick scars require special atten-
`tion?” 13 A special ZO—gauge “undermining" needle
`is included in the Fibrel kit and allows the dermal
`
`pocket to be created by loosening strands of bound
`connective tissue scar (Fig. 10). Most
`injections
`with this technique require pretreatment with 1%
`lidocaine in a field or ring block. Once undermin—
`ing is completed, injection of Fibrel is enhanced.
`Again, overcorrection is recommended.
`Treatment of lines and wrinkles can be per—
`formed using either a linear or a zigzag method.2
`The linear technique is similar to that described
`for distensible scars. The needle is advanced
`
`through the area, in the upper half of the dermis,
`and the Fibrel injected as the needle is withdrawn.
`Again, a blanched or peau d’orange effect is rec-
`ommended (Fig. 11).
`In the zigzag method de-
`scribed by Gottlieb (unpublished data, 1985), the
`needle is advanced beneath the wrinkle and zig—
`zagged across the central axis of the area being
`is injected as the needle is with—
`
`
`
`
`Figure 10. A, The undermining needle. B, The advantage
`of the undermining needle in breaking up scar tissue.
`it
`is useful in fibrotic 0r ice-pick scars.
`
`
`
`Figure 11. Serial puncture techniques (linear) for treat—
`ment of lines and wrinkles.
`
`easily
`are
`sites
`drawn. Fibrel posttreatment
`molded for best treatment results (Figs. 12 and 13).
`
`RESULTS OF TREATMENT
`
`Three major manuscripts have demonstrated the
`efficacy of Fibrel.‘°‘12 Since then, several mono—
`graphs have supported the data described.8 14 in
`1987,10 a multicenter study published its findings
`in the use of Fibrel in the treatment of depressed
`cutaneous scars. Twenty—two centers participated,
`reporting findings in 321 patients. After skin test—
`ing, 288 patients were treated with the Fibrel im-
`plant and evaluated by the physicians, patients,
`and by photogrametric
`analyses. The
`study
`showed that approximately half of the patients
`showed improvement of greater than 65% at
`1
`year.
`The second major study11 furthered the work of
`the original investigators. It was noted that at the
`end of 1 year, the scars treated that showed moder—
`ate, marked, or complete resolution were 65%,
`63.3%, and 85.8% according to physician, patient,
`and photogrametric analyses. One hundred eleven
`patients were studied through the second year.
`Successful correction was found in 64.4%, 58.9%,
`and 78.9% by physician, patient, and photograme—
`tric evaluations. A 5—year study” followed 83 pa-
`tients after one or two total injections. Reported
`results of correction were 55.1% by physician eval~
`uation and 50.0% by patient evaluation. It was
`thus concluded that Fibrel
`is effective in main—
`
`taining greater than 50% correction of cutaneous
`scars for up to 5 years.
`Scientific studies with regard to Fibrel’s use in
`cutaneous lines and wrinkles are not readily avail—
`able in the medical literature. There needs to be
`documentation for these treatments in the litera-
`
`ture. It is also extremely important to have a sense
`of how the original manuscripts can be translated
`and incorporated into one’s clinical practice. When
`informing patients of the possible results, it is pru—
`dent to use all of the available literature regarding
`the longevity of Fibrel. Most patients treated prop-
`
`

`

`
`
`Figure 12. Treatment of cutaneous scars. A, Before treatment (scars injected with ring-block anesthesia). B, Immediately
`posttreatment 0, Six months posttreatment.
`
`erly with Fibre] should receive approximately 6 to
`9 months’ correction for lines and wrinkles (similar
`to CIM“) and up to 1 year correction for scars. If
`patients respond longer, then they have responded
`well
`to treatment. Honesty is important and it
`is inappropriate to promise results that may be
`impossible to deliver.
`
`ADVERSE REACTIONS
`
`The majority of adverse reactions associated
`with Fibre] are of a local variety and are directly
`attributable to the injection process. These include
`pain, swelling, and induration at
`the treatment
`site. Because Fibre] causes an inflammatory re—
`sponse, many do not consider these true allergic
`reactions, but part of the normal Fibre] response.
`Nodule formation, persisting for up to ] to 2 weeks,
`has been described, as well as acne exacerbation
`and herpes simplex virus activation at the injection
`site.18 Rare adverse reactions also have been de—
`
`including a prolonged inflammatory re—
`scribed,
`sponse“ and emboli with cutaneous necrosis}7
`Fibre] has successfully been injected into pa—
`tients who have had previous allergic responses to
`CIM. Thus, there appears to be no cross—reactivity
`between the autoantibodies to collagen in those
`allergic to CIM and any potential allergic reactions
`to Fibre].l3
`
`FUTURE USES
`
`In an attempt to make Fibre] more user friendly,
`various techniques are employed by this author
`
`to minimize the morbidities associated with the
`
`injection of Fibre].4 First, as already indicated, all
`patients undergo two skin tests to minimize the
`potential of delayed allergic—type hypersensitivity
`reactions. Second, to minimize the pain associated
`with the injection,
`the areas to be treated are
`”iced” prior to the injection.
`Third, variations in the reconstitution steps have
`also been found to be useful in minimizing mor-
`bidity. Fibre] without plasma is used by many
`investigators at the time of this writing. Lidocaine,
`1%, with or without sodium bicarbonate may be
`added. Formulations used are shown in Table 3. It
`
`is thought that this helps minimize the associated
`cutaneous inflammatory response and still allows
`the reaction to proceed intradermally. The plasma
`supplies an additional source of fibrinogen and
`other clotting factors;
`these may or may not be
`required.5
`Fourth, patients rarely require ring—block anes—
`thesia with ]% lidocaine prior to injection, and
`finally, all injections can be successfully completed
`using a 30—gauge needle. The future role of the
`"undermining” needle is also in question. A large
`
`Table 3. NEWER FORMULATIONS FOR THE USE OF
`A MORE USER-FRIENDLY FIBREL
`
`Gelatin matrix and e—aminocaproic acid syringe to be
`mixed with
`0.5 mL
`0.25 mL
`0.25 mL
`
`Sodium chloride
`Lidocaine
`Sodium bicarbonate
`
`0.9%
`1%
`8.4%
`
`

`

`
`
`Figure 13. Treatment of lines or wrinkles. A, Before treatment. 5', Immediately posttreatment. C, Six months posttreatment.
`
`multicenter study is planned in the near future
`to further document a more user—friendly Fibrel
`
`References
`
`is a useful product for the treatment of
`depressed cutaneous scars, facial lines, and wrin-
`kles. There have been documented increases in
`
`collagen production and inflammatory response
`over time. Adverse reactions seem to be minimal.
`
`If a more user—friendly product can be used#no
`plasma, minimal inflammatory response, 30—gauge
`needle Fibrel should be considered in all patients
`for soft tissue augmentation.
`
`I"
`
`. Bailey OT, Ingraham FD: Chemical, clinical and im—
`munological studies on the products of human
`plasma fractionation. J Clin Invest 235917596, 1944
`Cohen 18: Fibrel. Semin Dermatol 6:228—237, 1987
`Gold MH: The Fibrel mechanism of action studywA
`preliminary report. I Dermatol Surg Oncol, in press
`Gold MH: Reducing the morbidites associated with
`Fibrel injections. In Program and Abstract of the In—
`ternational Society of Dermatologic Surgery, 1992
`. Gold MH: PlasmaiLess Fibrel. In Program and Abe
`stracts of the Hawaii Dermatologic Seminar, 1994
`Gottlieb SK: CAP repair technique. Poster exhibit.
`Annual meeting of the American Academy of Der—
`matology, Dallas, TX, December 1977
`Gottlieb SK: Soft tissue augmentation: The search for
`implantation materials and techniques. Clin Derma~
`tol 521287134, 1987
`
`

`

`Instruction Guide: Fibrel Technique Workshop.
`MEDED program for Serono Corporation, July 1988
`Melton JL, Ilanke CW: Soft tissue augmentation; new
`techniques and recent controversies. In Roenigk RK,
`Roenigk IIII (eds): Surgical Dermatology. Chicago,
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`Millikan L, Rosen T, Monheit G: Treatment of de—
`pressed cutaneous scars with gelatin matrix implant:
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`1162, 1987
`Millikan L: Long term safety and efficacy with Fibre]
`in the treatment of cutaneous scars. J Dermatol Surg
`Oncol 15:837—844, 1989
`Millikan 1., Banks K, Purkart G, et al: A five—year
`safety and efficacy evaluation with Fibrel in the core
`rection of cutaneous scars following one or two treat-
`ments. J Dermatol Surg Oncol 17:223—229, 1991
`Monheit GD: Soft tissue augmentation. In Wheeland
`RG (ed): Cutaneous Surgery. Philadelphia, WB Saun—
`ders, 1994, pp 4464162
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`ration, 1980
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`ration, 1991
`Rosen T: Fibrel#A new implant material. I Am Acad
`Dermatol 16:155~162, 1987
`Spangler AS: New treatment for pitted scars. Arch
`Dermatol 76:7087711, 1957
`Spangler AS: Treatment of depressed scars with Fi—
`brin foam—Seventeen years of experience. I Dermae
`to] Surg 1:6i69, 1975
`Stegman S], Tromovitch TA: Filling agents. In Stegman
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`gery. Chicago, Year Book Medical, 1990, pp 14&160
`
`Address reprint requests to
`
`Gold Skin Care Center
`102 Woodmont Boulevard, Suite 320
`
`