calcium hydroxylapatite to treat the face · 2018-10-17 · thickens and loosens. many different...

Calcium Hydroxylapatite to Treatthe Face

Gabriela Casabona and Mauricio Shigueru Sato

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328

Basic Concepts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328Calcium Hydroxylapatite . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328Histology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328Biostimulation and Degradation Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329Duration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329

History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333

Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333Fat Pads . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333Bone Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335Cosmetic Units and Plan of Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337

Classifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341

Indications and Contraindication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342On-Label Use on the Face (Approved by CE and FDA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342Off-Label Use on the Face . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343

Use and Doses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343Dilution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343

Side Effects and Their Managements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343Delayed Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344

Take Home Message . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346

AbstractFace rejuvenation is a wide concept andinvolves not only, but mostly, volume resto-ration of mainly fat and bone. With aging,subdermal fat and dermis thickness diminishat the extremities, and in the face, the dermis

G. Casabona (*)Clinica Vida – Cosmetic, Laser and Mohs Surgery Center,São Paulo, SP, Brazile-mail: [email protected]

M. S. SatoMohs Surgeon at Hospital das Clinicas, Curitiba, Parana,Brazile-mail: [email protected]

# Springer International Publishing AG, part of Springer Nature 2019M. C. A. Issa, B. Tamura (eds.), Botulinum Toxins, Fillers and Related Substances, Clinical Approaches andProcedures in Cosmetic Dermatology 4, https://doi.org/10.1007/978-3-319-16802-9_25

327

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mailto:[email protected]

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https://doi.org/10.1007/978-3-319-16802-9_25

thickens and loosens. Many different fillerscan be used to restore facial volume, andeach of them has advantages and disadvan-tages. In this chapter, we describe the use ofcalcium hydroxylapatite (CaHa) as a secureand effective product to be used to not onlyrestore volume but also stimulateneocollagenesis.

KeywordsCalcium hydroxylapatite · Fillers · Volumerestoration · Biostimulation · Neocollagenesis

Introduction

Face rejuvenation is a wide concept and involvesnot only but mostly volume restoration ofmainly fat and bone (Fitzgerald and Rubin2014). Although subdermal fat disappears andthe thickness of the dermis diminishes at theextremities with aging, in the face, the dermisthickens and loosens (Pellacani and Seidenari1999). Calcium hydroxylapatite (CaHA) is amineral constituent of bone and has been usedin various medical applications for more than adecade. Like hyaluronic acid (HA), CaHA isnon-immunogenic. CaHA gel is more palpablethan HA derivatives, especially if injected toosuperficially. To prevent bumps and lumps,injection is preferably performed subdermallyor deeper according to the anatomic area. Toavoid side effects, anatomy knowledge is cru-cial, and understanding anatomy of the agingprocess is even more important (RadiesseDatasheet 2006; Hirsch and Stier 2008;Casabona and Michalany 2014; Murray et al.2005).

Basic Concepts

Calcium Hydroxylapatite

Calcium hydroxylapatite (CaHA) is a mineralconstituent of bone and has been used in variousmedical applications for more than a decade. Theonly FDA and CE approved is RadiesseR

manufactured by Merz Pharmaceuticals GmbH,Frankfurt, Germany. Like hyaluronic acid (HA),this naturally occurring substance isnon-immunogenic. It is composed by a suspen-sion of 30% calcium hydroxylapatite micro-spheres (25–45 μm) in a 70% gel consisting of1.3% sodium carboxymethyl cellulose, 6.4%glycerin, and 36.6% sterile water for injection.CaHa contains a prefilled syringe with 1.5 cc ofmaterial. It should be stored at room temperature(15–32 �C) and expires 2 years from the date ofmanufacture (Radiesse Datasheet 2006; Murrayet al. 2005).

The size of the particles and the particle surfaceare particularly important since it is described thatparticles smaller than 15 μm can be phagocytedand migrate to lymph nodes, and irregular sur-faces are better recognized by the macrophage tobe phagocyted (Hirsch and Stier 2008; Murrayet al. 2005). No skin testing is required beforeuse, as a CaHa implant is immunologically inert.A CaHA gel is more palpable than HA deriva-tives, especially if injected too superficially. Toprevent bumps and lumps, injection is preferablyperformed subdermally. The product is radi-opaque, so if the patient was injected with alarge amount of the product, such as the patientsinjected for lipoatrophy correction, it could beseen in an X-ray, computed tomography(CT) scan or magnetic resonance imaging (MRI)(Fig. 1).

Histology

Histologically, CaHa stimulates almost no foreign-body reaction, but depending on the patient, it canoccur. No granuloma reaction was shown after6 months of biopsies (Casabona and Michalany2014; Berlin et al. 2008; Marmur et al. 2004)(Fig. 2a, b). At 1 month after injection, fibrin andscant cellular tissue surround the microspheres,which appear smooth and uniform, without evi-dence of inflammation. (Fig. 3a) At 3 months, afine outer capsule consisting of fibrin, fibroblasts,and macrophages surrounds the microspheres(Fig. 3b). The microspheres become deformed,appearing irregular, and start to be adsorbed after

328 G. Casabona and M. S. Sato

9 months, likely because of enzymatic breakdownof the calcium hydroxylapatite (Fig. 3c); however,electronmicroscopy shows calcium particles extra-cellularly and microspheres within macrophages(Lemperle et al. 2003) (Fig. 4).

Biostimulation and DegradationProcess

As mentioned above, the particles undergo anenzymatic breakdown, and macrophages aroundit start to phagocyte ions phosphate and calcium,following the same metabolic pathway as bonedebris resulting from orthopedic surgery or com-mon bone fractures (Drobeck et al. 1984) (Fig. 5).As a result of chemotaxis of macrophages, aninflammatory cascade starts bringing fibroblasts,as in a healing process, leading to collagen andelastin production (Murray et al. 2005).

Fibroblasts are found in all connective tissues,and CaHA microspheres are thought to elicit theiractivation and subsequent collagen productionregardless of the level of injection. Macrophagesare 25–30 μm and can ingest up to 25% of theirvolume per hour. Particle size is important inphagocytosis, but size is not the sole determinantof effective phagocytosis. In the case where the

particle volume is greater than the volume of amacrophage, macrophage aggregation is requiredand foreign-body giant cells are formed, but itdoes not mean that it will lead to a granulomatousreaction (Lee and Kim 2015).

Animal studies have shown that this new col-lagen growth occurs as early as 4 weeks post-injection and continues for at least 12 months(Loghem et al. 2015a). Most of the collagenformed is type III collagen, and a fibrotic tissuecan be seen in all surrounding areas. Then colla-gen type I gradually replaces type III(Yutskovskaya et al. 2014). In a study publishedin 2014, biopsies were taken amonth after injection,and it showed a significant collagen and elastinformation (Fig. 6) (Casabona and Michalany 2014;Drobeck et al. 1984; Loghem et al. 2015a;Yutskovskaya et al. 2014).

Duration

The effects of Radiesse have been reported to lastfrom 2 to 7 years, (Marmur et al. 2004; Narins andBowman 2005), although the clinical effects candisappear as early as 6–9 months (Broder andCohen 2006). Other articles showed duration of12–24 months but suggest that in order to have a

Fig. 1 Imaging of CT scan pre and post CaHa

Calcium Hydroxylapatite to Treat the Face 329

Fig. 2 (a) Follow up of 6 months biopsies of CaHa show-ing no granuloma reaction but some foreign body giantcells around the implant. (b) Follow up of 6 months

biopsies of CaHa showing no granuloma reaction butsome foreign body giant cells around the implant


Fig. 3 (a–c) CaHa injection site. (a) Biopsy a month after, (b) Biopsy after 3 months after, (c) Biopsy 9 months after(Stained H&E)

Fig. 4 Electron Microscopy showing CaHa surface and degradation process along 18 months


better idea of the final amount, the session shouldbe divided in two, 1 month apart (Jansen andGraivier 2006). Efficacy has been demonstrated,with 87% patient satisfaction within an 18-month

follow-up period (Jacovella et al. 2006). In ourexperience of more than 1,000 injected patients,we recommend to tell the patients that CaHaimplant may last around 9–18 months.

Phase 1 – Gel and particles and macrophages around implant

Phase 2 - Maacrophagescreatesan inflammatory cascade and fibroblast proliferation -Neocollagenesis

Phase 3 – Spheres start to Desintegrade and macrophage Fagocite CaHa and dissolves Into ions calcium and phosphate

Fig. 5 Scheme of bioestimulation and degradation process of CaHa and cells envolved

Fig. 6 Biopsy a month after CaHa injection site (d–f) versus an non injected site (g–i) stained with H&E, Masson T andVerhoeff showing a significant collagen and elastin stimulation on the injected site


History

Prior to its use in the dermatology field, CaHa hasbeen used in dentistry and reconstructive surgerywith a well-established safety record. In 2003CaHa [Radiesse®] (Merz Pharmaceuticals GmbH,Frankfurt, Germany) received FDA approval forsoft-tissue augmentation, vocal cord augmentation,and correction of maxillofacial defects. The effi-cacy and favorable safety profile of CaHA in thesesoft-tissue indications led to the adoption of itsoff-label use in facial rejuvenation (Pavicic 2013).

In Europe CaHa received a ConformitéEuropéenne (CE) certification mark (medicaldevice class 3) for plastic and reconstructive sur-gery, including deep dermal and subdermal soft-tissue augmentation of the facial area in 2003. Itmay be injected into the deep dermis, the subcu-taneous tissue, or supraperiosteally depending onthe area of the face being treated. The Europeanlabel includes, but is not limited to, the nasolabialfolds, marionette lines, cheek hollows, cheek-bone, jawline, oral commissures, chin, temple,bridge of the nose, and hands. In 2006, Radiessereceived FDA approval for the correction ofmoderate-to-severe facial wrinkles and folds,

such as nasolabial folds, and/or the restorationand correction of the signs of HIV-associatedfacial lipodystrophy (Loghem et al. 2015b; Funtand Pavicic 2013a) (Fig. 7).

Anatomy

In order to use CaHa to inject the face, anatomyknowledge is crucial, and understanding anatomyof the aging process is even more important. Theconcept of fat and bone loss was described byLambros in 2006 (Lambros 2006). Rohrich in2007 (Rohrich and Pessa 2007) described theimportance of the fat pads loss in the aging pro-cess, as did Shaw in 2011 with bone loss andskeleton changes. Merz Pharmaceuticals devel-oped scales of aging (Merz Aesthetics Scale)according to the anatomic areas of the face asdemonstrated in Figs. 8, 9, and 10.

Fat Pads

There are the superficial and deep fat compart-ments and its fusions. Each one ages differently.

Fig. 7 Areas with CE andFDA approved indications


Fig. 8 Merz aesthetis scale for upper face (Brow/crow feet/inferior eyelid)

Fig. 9 Merz aesthetis scale for mid face (mid cheek/nasolabial fold)


The knowledge of compartmentalization of theface gave us a new perspective on volume lossassessment and its restoration (Rohrich and Pessa2007). Fitzgerald in 2014 (Fitzgerald and Rubin2014) well described an excellent correlation offat pads and volume restoration (Figs. 11 and 12).

Bone Structure

The aging process has also been shown to affectthe facial bones. Multiple studies suggest that thebony aging of the orbit and midface is a processprimarily of contraction and morphologic change.

Fig. 10 Merz aesthetis scale for lower face

Superior orbital fat

Inferior orbital fat

Lateral orbital fat

Medial cheek fat

Middle cheek fatNasolabial fat

Lateral temporal-cheek fat

Buccal extension of the buccal fat

Fig. 11 Superficial fatpads compartments


The lack of bone support to facial fat pads leads toaging appearance such as below (Fig. 13):Orbit The orbit aperture, not only in inferior

margin but also the superior margin ofthe orbital rim, increase with age. Thatcombined with the loss of glabellar pro-jection generates a lack of support for themid-brow and glabella and also theorbital malar region which leads tomedial brow ptosis, inferior eye bags,and also worsening of crow’s-feetwrinkles.

Maxilla Also there is an increase aperture inpiriform aperture (nose) and a loss ofmaxillar bone projection which gener-ates a lack of support to the tip of thenose, medial fat pad, and nasojugalgroove leading to a droopy tip of thenose, inverted superior lip, inferior eyebags, and worsening of the nasojugalgroove.

Jawline There is also bone aging in the mandibu-lar area. There is an increase of mandibleangle and a decrease ofmandibular length

Sub-orbicularis oculi fat (lateral part)Sub-orbicularis oculi fat (medial part)Deep medial cheek fat (medial part)Deep medial cheek fat (lateral part)Buccal extension of the buccal fat

Ristow’s space

Fig. 12 Deep fat padscompartments

Fig. 13 Bone loss andrelation to fat pads andaging appearance


and height which generate a lack of sup-port to the neck (skin and platysma), chin,and perioral area. That leads to anincrease of prejowl sulcus, sagging neck,and an inverted inferior lip (Shaw et al.2011).

Cosmetic Units and Plan of Application

Upper Third of the Face• Forehead:

Structures of concern:Facial nerve, supraorbital/supratrochlear

nerve, and arteries (Fig. 14).

-Injection plane: Subgaleal/supraperiostealplane.

-Injection techniques: Linear threading,microdrops.

-Cannula size: 25G cannula, 1.000 (25 mm)or 1.500 (38 mm) – cannula technique is advisedstarting from the temporal crest 0.5 mm abovethe brow (Fig. 15).• Temples:The temporal fossa is divided in four quad-rants. If the temporal concavity is too deep,the two-plane correction is preferred: onedeep and another one more superficial to the

smooth transition of the temple area and fore-head (Fig. 15).

-Structures of concern: Venous network,superficial temporal artery.

-Injection plane protocols:1.Deep injection:Needle (23G). Subtemporal

muscle injection protocol; one or more bolusesare injected in the submuscular/supraperiostealplane, with the needle tip gently touching theperiosteum. The safest point of injection lies1 cm above the orbital zygoma junction and1 cm behind the lateral orbital rim. Inject lowvolume of bolus (0.1–0.3 mL per bolus).

: Cannula (22G). Below the superficial tem-poral fascia through an entrance 1 cm behindthe hairline and another 0.5 cm above the browjust on the temporal fusion line

2. Superficial injection: Subdermal injec-tion protocol with a blunt cannula 25G, but ina more superficial plane such as subdermal• Brow:

-Structures of concern: Venous plexus, supra-orbital artery and nerve, and intraorbital area.

-Injection protocol: A cannula is advised toavoid intravascular injection. If a needle isused, use a 23G and inject with (1) low volumeand (2) low pressure; (3) always perform bloodreflux test for at least 8 s each site – the dermal/subdermal plane of the area from the peak to

Fig. 15 Plan of application of CaHa with 25 G cannula forVolume restoration of lateral forehead, upper quadrants oftemporal fossa. Deep correction (purple and grey linescannula injection. The same plan can be used for superficialinjection but the cannula goes to a more superficial plane.)(Yellow dot needle injection)

Fig. 14 Upper areas of concern: red circle are location ofmain artery branches and yellow line points to the mostcommon area where the temporal and frontal branches offacial nerve sits


the lateral end of the brow; more mediallyfrom the peak, direct arterial connections tothe intraorbital area are present (supraorbitalartery, supratrochlear artery). Also avoid deepinjection to prevent intra-arterial injection.Advocate no more than 0.1 mL of total volumeto the brow in a single injection sitting.

Middle Third of the Face• Middle cheek:

Structures of concern:

• Infraorbital rim: Stay well below theinfraorbital rim when using needles.

• Infraorbital foramen: Avoid injection near theinfraorbital foramen/nerve when using needles.

• Midface fat compartments: If a needle is used,always choose a 23G or bigger. Always per-form a blood reflux test for at least 8 s if usingneedle injection to avoid the risk of intravas-cular injection. The product should be placedsupraperiosteally, below the region of thesuborbicularis oculi fat (SOOF) and medialcheek fat compartments to project these fatcompartments.

Injection procedure: First find the cheek apex.There are many ways to find it. The most used isthe one described by Hinderer in 1984 (Hindererand de Rio Lagarreta 1984). Then from there youassess and decide which areas need volumerestoration. Always start in the malar eminenceand go to lateral areas then to the middle cheek(Fig. 16).

Injection plane: Supraperiosteal (zygomaticbone and malar/maxilla) or subdermal (lateralzygoma).

Injection techniques:Needle 23G bolus or mini-bolus (0.1–0.3 ml

per site).Cannula: 25G, 1.000 (25 mm) or 1.500 (38 mm)

fanning or microdrops.Clinical results: Fig. 17.

• Nasolabial folds:


• Angularis artery: Too much product in the areaof the alar triangle may compress the arteryangularis and could cause necrosis. There isan anastomosis between the ophthalmic artery(angular artery branch) and the facial artery.

Fig. 16 Application planfor mid (yellow, entrancepoint; green, planapplication) and perioralregion (blue) on the face(cannula 25G, right side/needle 23G, left side)


• Musculus orbicularis oris: Perimuscular injec-tion anywhere on the face can lead to productcompaction/nodularity or even displacement(migration) of product by mimic activity ofthe affected muscle.

• Infraorbital foramen.

Injection Procedure:Cannula: From the same entrance we do the

middle cheek, we go toward the piriform fossaand the base of the nose deep to the muscular layerand start injecting a mini-bolus and filling with afanning technique.

Needle: Use the microdrops technique creatingbridges below the nasojugal groove toward thesupralabial area.

Injection site: Injections should be given in thesubdermal layer or supraperioteal whenaddressing the piriform fossa (Bass et al. 2010;Smith et al. 2007).

Needle or cannula: 23G needle, 25G cannula,1.000 (25 mm) or 1.500 (38 mm).

Average volumes: May depend on the degree ofcorrection needed (Bass et al. 2010; Smith et al.2007).• Submalar cheek hollows:


• Parotid gland: Found in the subcutaneous tis-sue of the face. The gland extends irregularlyfrom the zygomatic arch to the angle of themandible injection procedure.

• The facial nerve and its branches pass through

the parotid gland injection procedure.

Injection plane: Subdermal and/or subcutane-ous plane.

Injection techniques: Linear threading, fan-ning, microdrops, and cross-hatching.

Needle size or cannula: 23G needle, 25G can-nula, 1.000 (25 mm) or 1.500 (38 mm).

Average volumes: 0.5–1.5 ml per side.

Lower Third of the Face• Marionette lines:


• Orbicularis oris muscle: When injecting intothe muscle, there is a higher risk of nodularitypost-injection.

• Facial artery: Just lateral to the oral commis-sure, running lateral and inferior. Commoncause of increased bruising in the area.

Injection Procedure:

Fig. 17 (a, b) Pre and6 months after CaHainjection – Cannula 25G,Dilution 1.5 CaHa: 0.5 mlLidocaine 2% withepinephrin


Injection site: Injections should be given beloworbicularis oris or in a subdermal layer to avoidintramuscular injection in this area or injectioninto the mouth.

Injection techniques: Linear threading, micro-drops, and fanning.

Needle /cannula: 23G needle, 0.500 (13 mm),25G cannula, 1.000 (25 mm) or 1.500 (38 mm).

Average volumes: Maximum of 0.7–0.8 ml permarionette line.• Mental crease:


• Buccal sulcus: Susceptible to product accumu-lation if injection is placed too deeply superiorto the alveolar process. In this case, the productmay take the path of least resistance.

• Orbicularis oris muscle: If you inject in themuscle, there is a higher risk of nodularitypost-injection.

• Mental foramen: Pressure on the incisive andmental nerves may affect the sensitivity of themandible and anterior teeth.


Injection site: Supraperiosteal or deep dermallayer

Injection techniques: Linear threading, fan-ning, microdrop, and parallel line

Needle or cannula: 23G needle, 0.500 (13 mm),25G cannula, 1.000 (25 mm) or 1.500 (38 mm)

Average volumes: 0.2–0.4 ml total or0.1–0.2 ml per side• Prejowl sulcus:


• Orbicularis oris muscle: If the muscle isinjected, there is a higher risk of nodularitypost-injection.

• Facial artery: Just lateral to the oral commis-sure, running lateral and inferior; commoncause of increased bruising in the area.


Injection site: Subdermal/supraperiosteallayer

Injection techniques: Linear threading and fan-ning, bolus

Needle/cannula: 23G needle, 0.500 (13 mm),25G cannula, 1.000 (25 mm) or 1.500 (38 mm)

Average volumes: Maximum of 0.4 ml per PJS• Chin:


• Mental foramen and nerves: Properly map themental foramen, and avoid placing aliquotsnear this area. Keep the augmentation on theanterior side of the mandibular rim, and avoidvolume placement above the mental crease, asthis could manifest as a gingival sulcus noduleon the mucosal aspect.


Injection site: Supraperiosteal plane

Injection techniques: Bolus and/or threading

Needle size: 23G needle, 0.500 (13 mm)

Average volumes: Up to 1.5 ml• Mandibular angle and jawline:


• Arteria facialis: Just lateral to the oralcommissure, running lateral and inferior.Common cause of increased bruising inthe area.

• Facial nerve: Do not inject too deep to avoidhitting the nerve.

• Mental foramen and nerves: Properly map themental foramen, and avoid placing aliquotsnear this area.

• Masseter muscle.


Injection site: At the supraperiosteal (needle)or at the subdermal layer (cannula).


Injection technique: Bolus, linear threadingand fanning.

Needle size: 23G needle, 0.500 (13 mm), 25Gcannula, 1.000 (25 mm) or 1.500 (38 mm).

Average volumes: Linear threading – maydepend on the degree of correction needed.

Bolus: An average volume of 1.0–3.0 mlis normally used for jawline/mandibularcontouring

Clinical results: Figs. 18a, b, 19a, b, and 20a, b.

Classifications

In order to plan treatments with the patients, firstthe aging process of each area should be assessed.Carruthers and colleagues (Carruthers 2008;Carruthers et al. 2008a, b) published in 2008 agrade scale of aging divided by cosmetic areas.Grading the severity of each area, it is possible toestimate the amount of product needed in order toobtain realistic and satisfactory results. That could

Fig. 18 (a, b) Before and30 day after CaHa injectionof mid face and lower face



be done in one or more sessions as planned withthe patient always respecting the 1:1 correctionregarding the endpoint (Marmur et al. 2004).

Indications and Contraindication

On-Label Use on the Face (Approved byCE and FDA)

The European label includes, but is not limited to,the nasolabial folds, marionette lines, cheek hol-lows, cheekbone, jawline, oral commissures, chin,temple, bridge of the nose, and hands. In 2006,Radiesse received an FDA approval for the cor-rection of moderate-to-severe facial wrinkles andfolds, such as nasolabial folds, and/or the restora-tion and correction of the signs of HIV-associatedfacial lipodystrophy (Loghem et al. 2015b; Funtand Pavicic 2013a) (Fig. 7).

Off-Label Use on the Face

In the last 4 years, the use of CaHa spread, andmore off-label indications have been describedsuch as nose reshaping; dark circles; forehead,brow, and temporal area augmentations; andacne scars. Stupak et al. (Dayan et al. 2007;Stupak et al. 2007) published their experienceusing CaHA in the nasal dorsum and radix with

results persisting over 1 year. They have usedCaHA for post-rhinoplasty deformities of the dor-sum, supratip, sidewall, and ala. Becker (Hum-phrey et al. 2009; Becker 2008) reports correctingsaddle nose and retracted columella deformities.These authors find that CaHa for nose injection isvery useful, although we do not recommend itbecause most of the blindness cases were afternose and glabella injections and CaHa does nothave an enzyme like hyaluronidase that we coulduse in case of an intravascular injection.

Bernardini and colleagues in 2014 (Bernardiniet al. 2014) published a paper in which they show63 patients successfully treated for hollow eyesand dark circles with the idea of using the whitecolor to disguise the purplish color of thenasojugal area and also correct the hollownessand to enhance collagen formation which gives abetter appearance to the inferior eyelid skin.Although it seems a safe procedure, still it requiresa very experienced hand to do this procedure inorder to avoid complications such as the accumu-lation of the product and yellowish area that canappear if injected too superficially. The studyshowed 17% of complications such as this lastone but improved in 6 months at the most(Bernardini et al. 2014).

The brow, forehead, and temporal areas arevery much related when it comes to eye frameappearance. This author has been using CaHa forvolume restoration on these three areas in the last



4 years with minor complications and great satis-faction of the patients. The best indications forthese areas are the ones with great volume lossin three areas but not a very hollow temporal area(for which hyaluronic acid is better because of itsgreater projection capacity).

Contraindications

Generally, CaHa should not be used in patientswith bleeding disorders, severe allergiesmanifested by a history of anaphylaxis, a historyof hypersensitivity to the components of CaHa,and active skin inflammation or infection in ornear the treatment area. Other contraindicationsare areas in which many adverse events weredescribed such as:

-The glabellar lines and nose due to intravas-cular injection that cannot be reverted

-Lips, perioral, and periorbital lines due tomovement of the orbicularis muscle that can pro-mote an accumulation of the product and late-onset nodule

-Over a permanent filler as has been describedin the literature that any filler injected over apermanent one can stimulate a biofilm

Use and Doses

Dilution

CaHa can be used to restore volume or just tostimulate neocollagenesis.

Volume restoration: These authors recom-mend that the CaHa that comes in a 1.5 ml syringebe mixed with lidocaine 2% with epinephrine(Lido2%wE) for the use in the face. It can bemixed either with 0.25 ml or 0.5 ml of Lido2%wE. First one is for the areas we are seeking moreprojection, and the second one is for the use inareas with thinner skin. Because the gel componentoffers a 1:1 implant-to-tissue defect correction, noovercorrection is required (Marmur et al. 2004).

Biostimulation: We recommend CaHa to bemixed with 1 ml or 1.5 ml of Lido2%wE for theuse in a subdermal plane.

Technique

NeedleThe recommendation of the manufacturer is to usea 27G needle. A paper published in 2015 showedthat in order to have a positive blood reflux testprior to injection, a 23G needle should be used. Sowe recommend the use of a 23 G needle especiallyon areas in the center of the face that have higherrisks of intravascular injections that can lead toblindness (Casabona 2015).

CannulaCaHa should be used with a cannula of at least25G or larger.

Side Effects and Their Managements

All filler substances have an associated risk forboth early and delayed adverse eventsj Table 1.

CaHa implant has demonstrated safety, with noevidence of systemic adverse effects or immuno-logic responses and has a 5% incidence of hema-toma and ecchymosis. Complications, includingecchymosis and hematoma, are temporary. One ofthe most common side effects described in theliterature is nodule formation, and normally it isdue to superficial injection of the product inhyperkinetic areas, such as lips, and can lead toaccumulation of the product when the gel starts tobe reabsorbed in 3 months (Jansen and Graivier2006). The majority of all adverse events reportedare due to improper technique and not to theinjected material. Early complications resolve

Table 1 Early and delayed adverse events

Early complications/adverse events

Delayed complications/adverse events

Bruising Nodules

Tenderness Granulomas

Swelling Migration

Erythema Infection

Asymmetry Immunologic reactions

Lumpiness

Infection

Allergic reaction

Vascular accident


within 5–7 days. Delayed complications/adverseevents (>2 weeks to years following injection) aremanaged as described below.

Delayed Adverse Events

NodulesThe word nodule is a general term used todescribe the shape of a palpable induration. Pos-sible causes are an undesirable accumulation offiller product, a hematoma overlying a seroma, orthe formation of granulomatous tissue. Nodulesmay occur when the filler is unevenly spreadunder the skin, or too much is injected per site.They may be associated with inflammation, swell-ing, and infection. Generally, a nodule usuallyappears within a few hours or days of treatment.In clinical studies of CaHa, nodules reported onthe lips were due to a filler buildup as aresult of perioral muscle activity. CaHa is notrecommended for treating the lips or the zonearound the eyes, as repetitive muscle activity inthese areas may lead to filler-based nodules.Whenused for lip augmentation, nodules that occur canbe surgically excised (Jacovella et al. 2006).

Results of a large-scale clinical trial with 1,000patients and a total duration of 4 years (Tzikas2008; Sadick et al. 2007): Nodules occurred rarelyand were mostly restricted to the lips. CaHa is notrecommended for the lips. All nodules could besuccessfully treated using massage after injectionof saline solution, needle puncture in case of earlyonset, or excision (Fig. 21a, b). In the case ofnodules accompanied by an inflammation pro-cess, in our experience, the combination of10 mg/ml intralesional steroid (Kenalog40 mg/ml) with hyaluronidase and massage canresolve it. For persistent nodules, series of threeinjections of 5-FU, triamcinolone and lidocaine,or 5-FU and lidocaine may be considered (Funtand Pavicic 2013b). The risk of nodule formationwith CaHa can be reduced by avoiding areas notapproved for CaHa (e.g., the lips) and choosingthe correct injection plane (not too superficial, notintramuscularly). Evenly distribute the filler bythoroughly massaging the treated area (Voigtset al. 2010).

GranulomasA granuloma is an unwanted tissue responsewith proliferation of connective tissue and

Fig. 21 (a, b) Nodule (product accumulated) 15 day post injection CaHa fronto-temporal area (yellow arrow); and15 day after treatment with injection of saline and massage


immunoreactive cells. It may appear 2–3 monthsafter treatment. A granuloma can only be distin-guished from a simple accumulation of the fillerby removing it and examining it under a micro-scope. It can be diagnosed by the presence of fillerparticles surrounded by immune cells and fibroustissue. Since 2004, there have been only fivereported and confirmed cases of granuloma inover five million syringes shipped (0.0005%). In2009, a retrospective meta-analysis of studies dat-ing from 1985 to 2005 showed lower granulomarates with CaHA than with HAs or poly-L-lacticacids: 0.001%: CaHA; 0.04–0.4%: HAs; 0.2–1%:PLLAs.

A comparison of estimated granuloma ratesfrom the literature, presented at IMCAS 2012 bygranuloma expert Professor Gottfried Lemperle,showed that CaHa had the lowest granuloma rate(Voigts et al. 2010) (Table 2).

Standard treatment is with either oral orintralesional steroids (Sclafani and Fagien 2009).

Intralesional steroids require judicious use, asthey have been associated with localized atrophy,erythema, and pigment changes, as well as sys-temic vascular events. Adding 5-fluorouracil tothe intralesional steroid has also been advocatedfor granuloma treatment (Voigts et al. 2010).

If these treatments fail, surgical excision canbe attempted as a last resort. In two of the largeststudies performed with CaHa (Radiesse®) so far,neither granuloma formation nor severe infec-tions were observed over a total study period of39 months (Tzikas 2008) or 52 months (Sadicket al. 2007), respectively; observed adverseevents were minor and mostly restricted toinjection-related events. As of November 2014,over five million syringes have been shippedworldwide, and only in 5 CaHa (Radiesse®)cases has granuloma formation been reportedby the company.

Skin Color ChangeThat adverse event normally occurs from 1 to3 months after injection, and it is due to a verysuperficial placement of the material. SinceCaHa is white, it gives a yellowish look tothe skin. It is very easy to diagnose because

it looks like a xanthelasma. In our experience,it can be easily treated with two monthly ses-sions of ablative fractional laser using lowdensity but high energy and deep penetrationof the laser.

Take Home Message

• Before injecting CaHa, the patient should bescreened and given a written informed consent.

• The use of an anesthetic agent (e.g., lidocaine)is highly recommended.

• CaHa needs to be placed into the deep or sub-dermal tissue layer.

• Recommended injection techniques for the useof CaHa include linear threading, parallel lines,fanning, microdrops, and cross-hatching.

• CaHa indications include medial cheeks/lateralcheeks, submalar cheek hollows, nasolabialfolds, marionette lines, mental crease, mandib-ular angle and jawline, prejowl sulcus, chin,hands, frontal concavity, temporal concavity,and brow lift.

• As with all filler substances, the use of CaHamay be associated with a risk of adverseevents; however, the majority of reportedadverse events are due to technique and aretemporary.

• Proper injection technique, choice of injectionsite, and choice of filler and dilution can limitthe risk of adverse events.

• CaHa has been extensively studied, and allstudies confirmed the high safety profile.

• In two of the largest studies performed withCaHa so far, neither granuloma formation norsevere infections were observed.

• The use of CaHa is contraindicated in the gla-bellar lines and in the nose.

• The use of CaHa is not recommended onthe lips.

Table 2 Estimated granuloma rates after filler injection

RadiesseR

1:5.000Kollagen1:2500

HA 1:2500 Artefill1:2500

Artecoll1:1000

SculptraR

1:1000Acrylamide1:1000

Dermalive1:80


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