An Investigation of Changes in Physical Properties of
`Injectable Calcium Hydroxylapatite in a Carrier Gel When
`Mixed with Lidocaine and with Lidocaine/Epinephrine
`y
`MARIANO BUSSO, MD,
`
`AND ROBERT VOIGTS, MS
`
`INTRODUCTION As physicians incorporate calcium hydroxylapatite (CaHA) into their aesthetic treat-
`ment regimens, the question has arisen of whether the addition of anesthetic agents to prefilled CaHA
`syringes might provide sufficient anesthetic prophylaxis to warrant reduction in conventional anesthetic
`pretreatment procedures.
`
`STUDY DESIGN Investigators sought to determine changes in the physical properties of CaHA induced
`by the addition of lidocaine and lidocaine with epinephrine into the prefilled CaHA syringe. The CaHA
`and gel carrier (CHM) were mixed with varying amounts of lidocaine and lidocaine with epinephrine to
`measure the number of passes back and forth for optimal homogeneity of lidocaine and CaHA in sy-
`ringes, changes in viscosity, extrusion force, needle jam rates, elasticity, and pH.
`
`RESULTS Ten mixing passes appeared sufficient for homogeneity. Viscosities and extrusion forces of
`CHM/lidocaine blends decrease with increasing amount of lidocaine. Needle jams do not increase. The
`pH and elasticity of the CHM/lidocaine blend are essentially equivalent to those of CHM alone. Epi-
`nephrine added to lidocaine did not alter the results enough to reach statistical significance.
`
`CONCLUSIONS Addition of lidocaine to original CHM can be safely added without harmful changes in
`physical properties of the original soft tissue filler. Further studies are required to explore whether the
`addition of lidocaine to CHM alters patient discomfort, durability, and efficacy.
`
`Dr. Busso has been an investigator for Radiesse and Artefill clinical trials; he is a member of the BioForm
`Medical Education Faculty. He is also on the advisory boards for Dermik and Allergan. Robert Voigts is an
`employee of BioForm Medical.
`
`R adiesse (BioForm Medical Inc., San Mateo,
`
`CA) is a soft tissue filler consisting of calcium
`hydroxylapatite (CaHA) microspheres, 25 to 45 mm
`in diameter, and a sodium carboxymethyl cellulose
`(CMC) carrier gel. Collectively, these two elements
`constitute the CaHA media, referred to herein as
`CHM. The filler is usually injected through a 25- to
`27-gauge needle, 0.5 to 1.5 inches in length. Over a
`period of several weeks, the CMC is replaced by
`fibroblasts and extracellular matrix, leaving the
`CaHA microspheres in place to provide mechanical
`support.1 Even though individual CaHA micro-
`spheres are radioopaque, moderate injection
`amounts do not disrupt most radiographic analysis.2
`
`CHM is currently approved for treatment of severe
`facial folds and wrinkles, such as nasolabial folds,
`
`and for treatment of human immunodeficiency
`virus–associated facial lipoatrophy. Durability is
`estimated ranging from 10 to 18 months.3–6
`Additional uses of the product in the correction of
`marionette lines, oral commissures, prejowl sulcus,
`acne scarring, cheeks augmentations, infraorbital
`rim, and temporal hollows have been reported.5,7–13
`
`Late in 2007, Busso and Applebaum14 published a
`report of their experiences in combining CHM with
`lidocaine for off-label use of the soft tissue filler in
`treatment of the hand. In the report, Busso and
`Applebaum briefly explained how mixing the two
`compounds together appeared to considerably lessen
`discomfort in patients receiving a bolus of the mix-
`ture for hand rejuvenation and augmentation. Busso
`and Applebaum observed that 0.15 mL of 2% lido-
`
` University of Miami, Coral Gables, Florida; yBioForm Medical, Franksville, Wisconsin
`& 2008 by the American Society for Dermatologic Surgery, Inc.  Published by Wiley Periodicals, Inc. 
`ISSN: 1076-0512  Dermatol Surg 2008;34:S16–S24  DOI: 10.1111/j.1524-4725.2008.34238.x
`
`S 1 6
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`B U S S O A N D V O I G T S
`
`caine per 1.3-mL syringe of CHM was the minimum
`amount of anesthetic that appeared to yield adequate
`anesthesia without excessive loss of physical proper-
`ties. A number of other physicians are adopting the
`technique of Busso and Applebaum technique for
`mixing CHM with standard 2% lidocaine-HCl
`solutions, mixing between 0.05 and 0.40 mL of
`lidocaine with a 1.3-mL syringe of CHM.15 Mixing
`0.23 mL of 2% lidocaine solution with 1.3 mL of
`CHM yields 0.3% lidocaine concentration. This
`concentration is equivalent to that found in other soft
`tissue fillers, such as Zyderm and CosmoPlast.16,17
`
`Not only do the individual volumes of lidocaine
`differ in this off-label application of CHM by phy-
`sicians, but the mixing techniques are physician-
`specific as well. Some physicians draw the lidocaine
`directly into the syringe of CHM; others mix
`lidocaine and CHM with a nose-to-nose Luer-lok
`connector. Some physicians barely mix the lidocaine
`with CHM, while others mix to produce a homog-
`enous media. The effects of these mixing techniques
`on the performance of CHM are unclear.
`
`To characterize the effects of various lidocaine vol-
`umes and mixing techniques on CHM, the physical
`properties of CHM blended with 2% lidocaine-HCl
`solutions were measured. The results detailed below
`should help physicians better understand the prop-
`erties of CHM mixed with lidocaine solutions.
`
`Study Purpose and Design
`
`This study sought to characterize the physical prop-
`erties of CHM combined with plain 2% lidocaine-
`HCl solutions and combined with 2% lidocaine-HCl
`solutions and 10 mg epinephrineFunder various
`mixing conditions. Researchers studied a range of
`lidocaine concentrations, described below, to com-
`pare the dynamic viscosity, extrusion force, and
`needle jamming rate of the mixtures compared to
`those of commercially available CHM. Investigators
`also evaluated the dynamic viscosity of the mixtures
`at the front, middle, and back of each mixed syringe
`of lidocaine and CHM, as a measure of mixing
`
`efficiency. In addition, they compared the results of
`CHM mixed with lidocaine to those of CHM mixed
`with lidocaine and epinephrine.
`
`Materials/Equipment
`
`CHM (Radiesse, BioForm Medical Inc) was com-
`mercially available material. The nominal fill volume
`per syringe was 1.3 mL as shown by product label-
`ing. Testing was completed using from 3 to 12
`different commercially available lots of CHM for
`each test condition.
`
`The 2% lidocaine solution was composed of anhy-
`drous lidocaine-HCl (20 mg/mL), NaCl (6 mg/mL),
`and methylparaben (1 mg/mL; Hospira, Lake Forest,
`IL). The 2% lidocaine solution with epinephrine was
`composed of anhydrous lidocaine-HCl (20 mg/mL),
`epinephrine (10 mg/mL), NaCl (6 mg/mL), sodium
`metabisulfite (0.5 mg/mL), citric acid (0.2 mg/mL),
`and methylparaben (1 mg/mL; Hospira).
`
`A rheometer (Haake RS-600, Thermo-Fisher, New-
`ington, NH) measured dynamic viscosity of the me-
`dia. Extrusion force was measured by a materials
`tester (R5K Plus, Lloyd Instruments, Fareham,
`Hampshire, UK). Media pH was measured using a
`pH meter with a probe (Model 720A and SureFlow
`probe, respectively, Orion Instruments, Baton
`Rouge, LA). The female-to-female Luer-lok connec-
`tors used to connect the mixing and media syringes
`were Ark-Plas Part No. AP18FLXFEP (Flippin, AR).
`
`Procedures
`
`During the course of the study and at each test
`condition, researchers examined a 1.3-mL syringe
`of CHM, mixed with one of four volumes of 2%
`lidocaine or 2% lidocaine plus epinephrine solution:
` 0.05 mL (0.07% final lidocaine-HCl);
` 0.10 mL (0.14% final lidocaine-HCl);
` 0.15 mL (0.21% final lidocaine-HCl);
` 0.23 mL (0.30% final lidocaine-HCl).
`
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`P H Y S I C A L P R O P E R T I E S O F I N J E C TA B L E C A L C I U M H Y D R O X Y L A PAT I T E
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`Nine rheology replicates, 12 extrusion force repli-
`cates, and at least three pH replicates were con-
`ducted per test condition. Rheology was evaluated
`with a 20-mm titanium rotor, with a gap of 2.0 mm
`and tau (t) of 5 N, over a frequency sweep of 0.1 to
`10 Hz evaluated at 0.6 and 5.0 Hz. Extrusion force
`was evaluated through 27-gauge, 0.5-inch B-D nee-
`dles, with an extension rate of 2 inches per minute.
`Media pH was obtained by completely coating the
`glass bulb of the pH probe with media, spreading
`or smoothing the media with a plastic spatula as
`necessary.
`
`To evaluate the extent of mixing under different
`conditions, rheology and pH were tested for media
`from the front (hub), middle, or back (plunger) of
`the syringe barrel. Approximately 0.4 mL of media
`from the front, middle, or back of two syringes was
`combined for each measurement.
`
`Results
`
`Investigators evaluated seven test conditions in the
`study: 1) number of passes between syringes suffi-
`cient for blending lidocaine and CHM; 2) changes in
`viscosity with differing concentrations of lidocaine;
`3) extrusion forces of lidocaine and CHM, compared
`to CHM alone; 4) incidence of needle jamming in
`lidocaine/CHM blend; 5) pH of lidocaine/CHM
`compared to CHM alone; 6) viscosity and elasticity
`of CHM and lidocaine compared to CHM and
`lidocaine with epinephrine; and 7) extrusion force
`of CHM and lidocaine compared to CHM and
`lidocaine with epinephrine.
`
`1. Number of Passes between Syringes
`Sufficient for Blending Lidocaine and CHM
`
`Figure 2 shows the percentage difference from the
`mean for the dynamic viscosity at 0.6 Hz under
`various mixing conditions. With ‘‘adequate mixing’’
`defined as a percentage difference less than 10% for
`media across all regions of the syringe, 10 mixing
`passes provided adequate mixing for all lidocaine
`volumes tested. Five mixing passes provided adequate
`
`Figure 1. CHM mixed with lidocaine, using a female-to-fe-
`male Luer-lok connector. (Photo courtesy of Mariano Busso,
`MD; used by permission of Blackwell Publishing Inc.)
`
`Because the graduations on the tuberculin syringe
`are more accurate than those on a standard 1.3-mL
`syringe, the lidocaine solution was withdrawn from
`a 50-mL vial with a 1.0-mL tuberculin syringe
`(Becton Dickinson [B-D], Franklin Lakes, NJ) fitted
`with a 0.5-inch, 27-gauge B-D needle. The lidocaine
`solution was then injected from the tuberculin sy-
`ringe into the nose of a BioForm 1.3 mL syringe
`(mixing syringe). The push rod of the mixing syringe
`was depressed to remove all excess air and then the
`mixing syringe with lidocaine was firmly connected
`to a syringe of CHM using a female-to-female
`Luer-lok connector (Figure 1).
`
`Lidocaine and CHM were mixed by alternately
`depressing the plungers on the mixing and media
`syringes for 2, 5, or 10 mixing strokes. Each mixing
`stroke was composed of one complete compression
`of the CHM syringe push rod, followed by one
`complete compression of the mixing syringe push
`rod. Push rods were compressed firmly and quickly,
`at approximately two compressions per second.
`Following mixing, the mixing syringe and Luer-lok
`connector were removed and discarded, and the
`lidocaine/CHM mixture was recapped with the
`original media syringe cap. The CHM and lidocaine
`blends were tested between 15 minutes and 2 hours
`after mixing with lidocaine.
`
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`B U S S O A N D V O I G T S
`
`mixing for 0.05 mL of lidocaine solution, but not for
`the other volumes. Two mixing passes did not provide
`adequate mixing for any volume tested, with the net
`front-to-back spread ranging from 39% at 0.05 mL of
`lidocaine, up to 52% at 0.23 mL of lidocaine.
`
`The magnitude of the front-to-back difference in
`viscosity increased with increasing volume of lido-
`caine, suggesting that larger volumes of lidocaine
`required more mixing than small volumes, but also
`reflecting a greater magnitude of change in physical
`properties with increasing concentration of lido-
`caine. Profiles of the extrusion force versus syringe
`extension also demonstrated that 10 mixing strokes
`were adequate to homogeneously mix the CHM and
`lidocaine solution (Figure 3).
`
`Following 10 mixing strokes, the extrusion force was
`uniform from the front to the back of the syringe,
`even at the maximum tested volume of lidocaine. In
`contrast, the front extrusion force was much lower
`than the back extrusion force for syringes blended
`with 2 or 5 mixing strokes, and the front of the
`syringe exhibited numerous jagged troughs, indicat-
`ing the presence of air bubbles in the syringe.
`
`2. Changes in Viscosity with Differing
`Concentrations of Lidocaine
`
`Viscosities of CHM/lidocaine blends decreased with
`increasing lidocaine HCl. As shown in Figure 4, the
`dynamic viscosity of CHM/lidocaine blends was in-
`versely proportional to the volume of lidocaine-HCl
`solution (R2 = 0.99). Even at 0.23 mL of lidocaine
`HCl, the CMC gel was cohesive enough to suspend
`the particles for the 24-hour testing period (Figure 4).
`
`3. Extrusion Forces of Lidocaine and CHM
`Blend, Compared to CHM Alone
`
`The extrusion forces of CHM/lidocaine blends were
`lower than those of CHM alone (Figure 5). The
`extrusion force through a 27-gauge, 0.5-inch B-D
`needle was nearly constant around 5.3 pounds of
`force (lbf) for CHM blended with 0.05, 0.10, or
`0.15 mL lidocaine-HCl, down from 6.0 lbf for CHM
`
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`Figure 2. Percentage differences in distribution of four sep-
`arate volumes of lidocaine with CHM, under three mixing
`conditions.
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`P H Y S I C A L P R O P E R T I E S O F I N J E C TA B L E C A L C I U M H Y D R O X Y L A PAT I T E
`
`Figure 4. Dynamic viscosity of CHM blended with various
`volumes of 2% lidocaine-HCl.
`
`conditions, for a total of 204 extrusions. Only two
`needle jams were observed among these extrusions,
`for an estimated jam rate of 0.98%. This jam rate is
`comparable to the jam rate observed for CHM.18
`
`5. Elasticity and pH of Lidocaine/CHM
`Compared to CHM Alone
`Elasticity is a qualitative term, while G0, G, and tan
`(d) are quantitative measures of how vigorously a
`material bounces back to its initial position follow-
`ing a stress or strain. The elasticity of CHM and
`lidocaine blends decreased with increasing concen-
`tration of lidocaine mixes (Figure 6). The tan delta
`(d) values (the tangent of the ratio of loss modulus
`[G] over the storage modulus [G0]) provides a
`
`Figure 5. Extrusion force, CHM blended with various vol-
`umes of 2% lidocaine-HCl.
`
`Figure 3. Force versus extension of CaHA with 0.23 mL lido-
`caine (0.3%).
`
`alone. Extrusion force decreased to 4.7 lbf for
`1.3 mL CHM with 0.23 mL 2% lidocaine solution.
`
`4. Incidence of Needle Jamming in Lidocaine/
`CHM Blend
`
`Blending CHM with lidocaine did not increase the
`incidence of needle jamming. Twelve extrusions were
`performed for each of the seventeen experimental
`
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`B U S S O A N D V O I G T S
`
`Figure 6. Tan (d), CHM blended with various volumes of
`2% lidocaine-HCl.
`
`Figure 8. Extrusion force of CHM and lidocaine compared to
`CHM and lidocaine with epinephrine.
`
`quantitative tool to evaluate the relative elasticity of
`the media. CHM and lidocaine blends were less
`elastic than CHM alone. The pH of all CHM and
`lidocaine blends was between 6.6 and 7.2 for all
`samples.
`
`6. Dynamic Viscosity of CHM Compared to CHM
`and Lidocaine with or without Epinephrine
`
`Dynamic viscosity measures the way a fluid responds
`to stresses and strains. Dynamic viscosity decreased
`with the increasing volume of lidocaine solution
`added to 1.3 mL CHM (Figure 7). There was a trend
`toward higher viscosity for lidocaine with epineph-
`rine versus lidocaine only. However, statistical
`
`Figure 7. Dynamic viscosity, CHM blended with various
`volumes of 2% lidocaine-HCl.
`
`significance in viscosity differences (po.05) was
`only seen with the 0.15- and 0.23-mL additions to
`lidocaine/epinephrine solution volumes.
`
`7. Extrusion Force of CHM and Lidocaine Com-
`pared to CHM and Lidocaine with Epinephrine
`
`Extrusion force decreased with the increase in vol-
`ume of lidocaine solution added to 1.3 mL CHM
`(Figure 8). Although the extrusion force was found
`to be slightly lower with the addition of lidocaine
`with epinephrine, the difference was not statistically
`significant. At all volumes of lidocaine, the extrusion
`force was essentially equivalent for CHM blended
`with lidocaine and CHM blended with lidocaine/
`epinephrine, suggesting that epinephrine had no
`effect on extrusion force.
`
`Discussion
`
`Mixing lidocaine with CHM does not compromise
`the physical properties of the original soft tissue
`filler. The viscosity of the gel in CHM and lidocaine
`blends is sufficient to keep the CaHA particles in
`suspension and prevent needle jams after dilution
`with 2% lidocaine solutions. The pH values of CHM
`and lidocaine blends are functionally equivalent to
`those of CHM alone. In addition, blending CHM
`with lidocaine reduces viscosity and extrusion force,
`and for physicians who wish to add epinephrine to
`
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`the lidocaine used in the CaHA/lidocaine mix, there
`is no substantial change in viscosity properties in the
`epinephrine/lidocaine combination compared to li-
`docaine alone. We proved that 10 mixing strokes
`of the CaHA and carrier gel with various amounts
`of lidocaine are necessary for homogeneity.
`
`CaHA has been approved essentially for ‘‘bulking’’
`applications. A bulking filler is characterized by
`minimum lateral implant leakage. In this study, the
`changes in rheology, viscosity, extrusion, and pH
`suggest that CaHA/CMC has even broader applica-
`tions. Anatomic areas like temples, preauricular
`space, and dorsum of the hand benefit from having
`‘‘malleability’’ or ‘‘spreadability’’ of the product with
`the addition of lidocaine and reduction of viscosity.
`By altering the viscosity, the physician can more
`easily inject the product in layers, criss-crossing the
`junction of the dermal/subdermal plane or a bolus
`followed by a blending massage.
`
`The combination of lidocaine and CaHA intuitively
`suggests, as do anecdotal reports, that patient dis-
`comfort levels will likely be reduced during injection
`of the product. One example of the decrease in pa-
`tient discomfort is the treatment of the hand with a
`bolus of CaHA. With the addition of lidocaine (and
`perhaps epinephrine) to the CaHA, physicians have
`increased flexibility in their treatment techniques
`and sites of injection, and the benefits of decreased
`patient discomfort.
`
`From a physiologic properties perspective, the find-
`ings of the study provide scientific data to physicians
`who are engaging in off-label mixing of lidocaine
`and/or lidocaine and epinephrine with CHM. The
`pH stays within physiologically safe ranges, the vis-
`cosity and extrusion forces decrease, and CHM and
`the anesthetic agent(s) are adequately mixed with 10
`back-and-forth passes of anesthetic into CHM. The
`benefits to physicians who choose to mix lidocaine
`with CHM may include: reduction of confounding
`edema secondary to pretreatment infiltration with
`lidocaine, increased ease in molding, increased
`comfort to the patient, reduced need for nerve
`
`blocks, and decreased treatment times. Altogether,
`these benefits allow larger volumes to be injected in
`one treatment session, such as those necessary for
`full facial recontouring.
`
`Answers to several other questions about the mixing
`process were beyond the scope of the study and re-
`main unknown. The study did not address the an-
`esthetic efficacy of lidocaine following prolonged
`contact with CHM. Since CMC is a known time-
`release agent for lidocaine-HCl19 and CaHA is a
`well-known controlled release agent for many
`drugs,20–23 a significant time delay between mixing
`media with lidocaine and injection could have un-
`desirable effects on anesthetic efficacy. Conse-
`quently, physicians may have to rely on their best
`clinical judgments and anecdotal evidence as they
`consider the addition of lidocaine to the prefilled
`syringe of CHM. In addition, the mixing of a sterile
`product with lidocaine increases the risk of microbial
`contamination and any storage of opened CHM is
`not recommended.
`
`The question could be raised about whether these
`results represent merely a 10% to 15% dilution
`factor or whether there are other chemical changes in
`lidocaine/vehicle interactions, for example, whether
`other bonds be disrupted by the addition of lido-
`caine. CaHA and CMC are both known to adsorb
`drugs without chemically altering them; there is no
`reason to anticipate that they would behave differ-
`ently toward lidocaine. Further studies are needed to
`confirm the hypothesis of no chemical alterations.
`
`This study also does not address the effect of lido-
`caine on in vivo duration of the clinical benefits of
`CHM. Physicians have reported that they see no
`significant decrease in durability for media diluted
`with lidocaine. However, the test condition of a
`0.23-mL lidocaine dose (0.3% concentration of li-
`docaine) represents a 15% dilution of CMC and
`microspheres, by volumeFa larger lidocaine volume
`than the 0.10-mL lidocaine dose described in the
`original study by Busso and Applebaum. Without
`answers to possible dilution of anesthetic properties
`
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`B U S S O A N D V O I G T S
`
`and shortening or extending durability of the soft
`tissue filler, the manufacturers of CHM rely on the
`judgment of the treating physician to include the
`mixing of CHM with lidocaine solutions into their
`practice. Controlled animal or clinical trials would
`be required to prove that dilution of CHM with li-
`docaine does not adversely affect product durability.
`The benefits of using CHM with lidocaine with the
`lower viscosity, lower extrusion force, greater ease of
`molding, and increased patient comfort may be
`attractive to healthcare providers who use CHM
`in their daily practice.
`
`Acknowledgments
`The authors express their ap-
`preciation to several members of the research and
`development division of BioForm Medical, especially
`Dale DeVore, PhD, for initial counsel and subse-
`quent comments on manuscript drafts; Michelle
`Johnson, for assistance with extrusion testing; and
`Xanthi Merlo, for design and execution of testing. In
`addition, David J. Howell, PhD, San Francisco, CA,
`contributed to the writing of the manuscript.
`
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`23. Mizushima Y, Ikoma T, Tanaka J, et al. Injectable porous
`hydroxyapatite microparticles as a new carrier for protein and
`lipophilic drugs. J Controll Release 2006;110:260–5.
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`5. Goldberg DJ. Calcium hydroxyapatite. In: Goldberg DJ, ed. Fillers
`in Cosmetic Dermatology. Abingdon, England: Informa UK Ltd;
`2006. p. 81–109.
`
`6. Jansen DA, Graivier MH. Evaluation of a calcium hydroxylapa-
`tite-based implant (Radiesse) for facial soft tissue augmentation.
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`
`Address correspondence and reprint requests to: Mariano
`Busso, MD, 3003 Aviation Boulevard, Suite 2-C, Coconut
`Grove, FL 33133, or e-mail: DrBusso@aol.com
`
`3 4 : S 1 : J U N E 2 0 0 8
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`P H Y S I C A L P R O P E R T I E S O F I N J E C TA B L E C A L C I U M H Y D R O X Y L A PAT I T E
`
`COMMENTARY
`
`The authors are to be commended for an excellent study. In the practice of medicine, many times products
`are adulterated based on anecdotal information passed from physician to physician. Without appropriate
`studies, we as clinicians have no way of knowing if these adulterations may have a negative impact on the
`product. This article exhaustively examines and puts to rest any concerns about harmful changes to the
`physical properties of injectable calcium hydroxylapatite (CaHA) when mixed with lidocaine.
`
`It remains to be seen if this combination has any negative effect on the efficacy or duration of effect of
`injectable CaHA. There is no question the addition of lidocaine makes the injection of this material
`markedly more comfortable, as well as allowing more aggressive massage of the treated area. In addition,
`it allows the clinician to avoid a nerve block, thereby speeding up the procedure and sparing the patient
`the edema and profound anesthesia associated with the block.
`
`Hopefully further studies will appear documenting the efficacy of this mixture. Until then, many clini-
`cians, including myself, will continue to use this mixture based on our observation that its efficacy and
`duration seem unaffected by the addition of lidocaine.
`
`MARK G RUBIN, MD
`Beverly Hills, CA
`
`S 2 4
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`D E R M AT O L O G I C S U R G E RY
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