Before exploring the use ofthird generation dermal fillers atthe facial aeshetic dentalinterface, let us look back at theearly dermal fillers, as well asexamining some of the keybrand names available on themarket today. We will look attheir individual derivation(bovine/human), their gelparticle size, degree of cross-linking and percentage of cross-linking within that degree ofcross-linking.

However, let us first look backa little at the early dermal fillers,their FDA approval, and indeedthe relevance of FDA approval ornon-approval, as well as off-labeluse (including any legalramifications of off-label use)before critically analysing the useof dermal fillers within anyaesthetic practice.

Bovine-derived collagenZyplast 1 was the first FDA-approved dermal filler; this wasnearly 30 years ago, back in1981. Zyderm 1 had thepotential to cause an allergicreaction as a result of its bovinecollagen, plus its effects didn’tlast very long (less than twomonths) and it gavedisappointing results for deepfolds and scars. As a result, two

years later Zyderm 2 andZyplast were FDA-approved andintroduced into the market.Zyplast gave significantlyimproved results for deeperfolds. These dermal fillers werethen the sole FDA-approvedfillers for over a decade (Murray,2005).

Bovine-derived collagen fillersCollagen is the major structuralcomponent of the skin, and assuch it seemed a naturaldeduction that the dermiscould be replenished withbovine-derived collagen.Indeed, bovine collagen is stillused today.

According to Lowe et al(2005), there is a risk of allergyfrom bovine-derived collagenfillers. Numerous reports alsodescribe skin necrosis, especiallywith the use of Zyplast in theglabellar region (Hanke et al,1991). Two negative skin testsare required prior to treatment,and although two negative testsmake the likelihood of anallergic reaction low, it does noteliminate the risk fully. There is adelay of up to six weeks fromfirst testing the product on thepatient’s skin to actually havingdermal filler treatment, and

today’s discerning facial aestheticpatient will most likely beunwilling to wait this durationfor treatment.

Eliminating the bovine element As a result of the risk of allergyto bovine-derived collagenfillers, companies weremotivated to develop human-derived collagen dermal fillers.Since these agents do notcontain any bovine element, noallergy test is required.

In March 2003, the FDAapproved three bio-engineeredhuman collagen dermal fillers:CosmoDerm 1, CosmoDerm 2and CosmoPlast. Theseresulted in reduced patientdowntime and, similar to thebovine-derived collagenproducts, the CosmoDermfamily contained lidocaine.The incorporation of lidocaineinto dermal filler productreduces pain during treatment,but also reduces oedema andeccymosis by inhibiting theactivation of esosinophils, thusreducing the risk of bruising.

The porcine-derived rangeThe next type of filler toconsider in brief is that of theporcine-derived (pig tendons)

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The history and journey of dermal fillers

With nearly 100 dermal filler brands on the market today, Danielle Meagher delves into their history and clincial uses to help readers gauge which is the best choice for different treatments

FACIAL AESTHETICS

Dr Danielle Meaghergraduated in dentistry fromTrinity College Dublin; she alsoholds an Honours degree inAeronautical Engineering fromUMIST, Manchester. Danielle isCEO, principal dentist anddirector of facial aesthetics atDermaDental, Ireland’s firstcombined facial aesthetics anddental clinic. Daniellecompleted all of her training infacial aesthetics at HarleyStreet in London, alongsideother dentists, doctors andplastic surgeons.

family of dermal fillers. Thecommon brand is Evolence,which has been used outsidethe United States since 2004.Porcine collagen resembleshuman collagen so closely thatthe risk of allergy is remoteand no skin testing is requiredprior to treatment.

Note that Evolence is notcross-linked withglutaraldeyde, unlike Zydermand CosmoPlast. Instead,Evolence is cross-linked with anatural sugar, D-ribose. It isrecommended that Evolence isinjected into mid-to-deepdermis, and results last longerthan either human- or bovine-derived collagen fillers –reportedly up to six months(US Food and DrugAdministrationm 2008).

Introducing hyaluronic acidNext in the history of dermalfillers, and indeed possibly themost important advancement,was the introduction ofhyaluronic acid-based dermalfillers.

Hyaluronic acid (HA) isfound naturally in the body; itis the most prominentglycosaminoglycan in the skin.Hyaluronic acid is ahydrophilic substance, and assuch binds to water wheninjected into the skin. Inaddition to volumising,softening and hydrating theskin, HA plays a role in cellgrowth, repair and adhesion.

In February 2003, the FDAapproved Restylane, a cross-linked non-animal sourcehyaluronic acid (NASHA).Restylane was found to belonger-lasting, have minimaladverse reactions, be easy touse, did not requirerefrigeration, and was cost-effective. In addition, veryimportantly, it did not requireskin testing, so there was nodelay in having treatment.

However, these FDA-approved hyaluronic aciddermal fillers did not containlidocaine, and so were morepainful on injection than theprevious bovine or humanpredecessors. Also initially, dueto the heparin effect of HA,there was a greater incidence ofbruising than we had seenpreviously with collagen fillers.

Despite these shortcomings,hyaluronic acid has fastemerged as the market leaderof dermal fillers due to thepredictable superior cosmeticresults they achieve.

In 2006, the FDA approvedJuvéderm, another HA-baseddermal filler. In the USA onlytwo types of Juvéderm dermalfillers are FDA-approved(Monheit, 2007). BothJuvéderm Ultra and JuvédermUltra Plus have similarindications to Restylane andPerlane, and do not requirerefrigeration or skin allergytesting. Allergan has nowlaunched a Juvéderm productthat contains lidocaine, so itwould seem the onlyshortcoming in the HA familyof dermal fillers has now beeneliminated.

Although unwanted side-effects are rare with use of HAdermal fillers, correction ispossible with the use ofcommercially availablehyaluronidase. Hyaluronidasebreaks down unwanted HAdermal fillers. Hyaluronidasepreparations are clear,concentrated liquids that arestored in a refrigerated vial;they are reconstituted withsaline or lidocaine (with orwithout adrenaline). Prior totreatment with hyaluronidase,a skin test can be performed.Once the refrigerated vial isreconstituted withsaline/lidocaine, the mixture inthe vial is gently swirled.Before use it is advisable to do a test area. By injecting 0.06-0.1ml of reconstituted solution into the superficialdermis at the anticubital fossa,the area can be monitored for apositive hypersensitivereaction, which typicallyconsists of a weal appearingwithin five minutes withassociated itching, the effectslasting up to half an hour.

In 2003, Q-Med’s Restylaneand Perlane received FDAapproval for treatment ofnasolabial folds. This NASHA-based dermal filler is producedby fermentation in a bacterialculture of equine streptococci.Restylane contains 100,000particles per ml; these particlesare highly cross-linked.Restylane has been used in the

correction of nasolabial folds,tear troughs, glabellar frownlines and marionette lines, aswell as for lip and cheekaugmentation. It can also beused to correct nasaldeformities, as an alternative torhinoplasty surgery.

Perlane is a NASHA-baseddermal filler manufactured byQ-med; the only difference isthat is contains larger particles,and as such is suitable for thecorrection of deeper folds andcan also be used for cheekenhancement. Also in the Q-med range is RestylaneSubQ, which gives excellentcheek enhancement outcomes.Restylane Lipp, as the namesuggests, is an excellent choicefor lip enhancement treatment.

NASHA adverse effectsThe adverse effects ofNASHA-based hyaluronic aciddermal fillers such asRestylane and Perlane (bothQ-MED) and all productsincluded in each respectivebrand are minimal, but doexist.

If injected too superficially,a bluish Tyndall effect can beseen (Carruthers et al, 2006);this represents visiblehyaluronic acid seen throughthe translucent epidermis(Rayleigh effect). However, anick with a small 30 gaugeneedle is usually sufficient toallow the expression of thissuperficially-placed dermalfiller. There is, of course, thepossibility of more bruisingand pain compared to collagenfillers (due to the lack oflidocaine in NASHA-deriveddermal fillers).

On occasion, palpablenodules have been reportedunder the skin. To minimisethe risk of such nodules, alinear threading technique isbest used.

Peter and Menne (2006)also reported various cases ofretinal branch artery occlusionfollowing injection ofhyaluronic acid: ‘The potentialfor retrograde embolisation ofsubstances from the face in theretinal vascular territory exists,as there are multipleanastomoses between thevascular supply of the face and orbit.’

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Botulinum toxinIdeally, dermal filler is used inthe lower one-third of the faceand/or malar region; the upperthird of the face benefits fromtreatment with Botulinum toxinA. On occasion and in order toachieve optimum relaxation ofglabellar frown lines,Botoulinum toxin A treatmentis followed two weeks later bysome dermal filler into theglabellar region. This protocolis only for stubborn glabellarfrown lines; Botulinum toxin Anormally yields excellent resultsin this area.

Additional types of fillerThere are, in fact, many dermaltypes of filler on the markettoday. Many are FDA-approved.Some are FDA-approved forcertain uses only. Some are notFDA-approved at all.

Examples of other brands offiller include Hyalaform,Captique, Teosyal, Puragen,and Prevelle Silk. Artefill wasFDA-approved for use in theUSA in 2007. Radiesse wasFDA-approved at the end of2006 for the correction of facialwrinkles and folds, and for thecorrection of HIV-associatedfacial atrophy. Radiesse iscomposed of 30% calciumhydroxlapatite and 70% carriergel. Treatment of the lips hasresulted in cyst formation andas such it is wise to avoidtreating the lips with Radiesse(Alam, 2008).

The next significantintroduction to the dermal fillermarked was Scuptra (Poly-L-lactic acid). Sculptra differsfrom all other agents in severalways, in that the effects are notimmediate and more than onetreatment is required. Sculptrais not a true dermal filler, andworks differently bystimulating fibroblasts toproduce more collagen,therefore increasing facialvolume (Butterwick, 2007).Sculptra is a biodegradeable,biocompatible andimmunogically inert peptide sothe risk of allergy is minimal,however post-treatment dermalnodules have been reported.In the USA Sculptra is FDA-approved for the treatment ofHIV-associated lipoatrophy,although it is commonly used

to treat advanced nasolabialfolds. This off-label use iscommon, much in the sameway that Botulinum toxin Ahas been used off-label to treatglabellar frown lines.

Sculptra relies onneocollagenesis to stimulate thedermis. Results are not seen forfour to six weeks and up tothree treatments will benecessary (every four to sixweeks).

Dermal nodules have beenreported, but the risk of suchnodules can be reduced withvigorous post-treatmentmassage, as well as byreconstitution of the productwith 6ml or greater of sterilewater.

Best for your patientsWith such regular and rapidadvancements in the area ofdermal fillers, one can beforgiven for becoming easilyconfused regarding the bestchoice for patients.

An ideal dermal fillerproduct will need to satisfymany requirements, such asbiocompatibility, non-reactivity,and reversibility/minimallyinvasive delivery, while alsoallowing for pain-free delivery.

In addition, patients will nolonger tolerate a six-week leadtime in between skin testingand treatment. Yet they requiredermal filler products that lasta minimum of six months.Patients also require ‘nodowntime’ dermal fillertreatments.

Cost-effective products withgood predictable aestheticresults (every treatment) arealso favoured by the patient,and indeed the aestheticpractitioner.

Incorporating lidocaine The final ‘icing on the cake’,according to manypractitioners, is theincorporation of lidocaine intothe HA dermal filler product.As a Trinity graduate indentistry, whether or not thedermal filler product containslidocaine is of absolutely noconsequence to me. In fact,even if the brand containslidocaine, I will always usesome dental block initially.

FACIAL AESTHETICS

In 2008 Allergan launched adermal filler product thatcontains lidocaine: JuvédermUltra. This suits many non-dental practitioners, becauseoften the administration of‘dental block’ seems somewhatelusive to achieve. So the ideaof having a dermal fillercontaining lidocaine wouldsuggest there is no need fordental block. I would disagreewith this; I believe the benefit ofincorporation of lidocaine isthat it reduces oedema andeccymosis by inhibiting theactivation of eosinophils, thusreducing the risk of bruising.After the initial couple ofinjections of Juvéderm Ultrathere will be a good degree ofanaesthesia achieved, but as akeen practitioner of ‘pain-free’facial aesthetics I always usesome local dental block beforeever proceeding with any lipinjections. Excellent dentalblock, in my mind, is still thekey to pain-free facial aesthetics.

The fillers of choiceIt is my opinion that the familyof NASHA dermal fillers are thefillers of choice. They satisfy allthe safety and aestheticrequirements of both thediscerning facial aestheticpractitioner and, indeed, thediscerning facial aestheticpatient.

The benefits of using dermalfillers within a facial aestheticpractice are well documented.According to Maio (2004): ‘Thisminimal approach offers afaster, less painful, and lesscostly alternative orcomplement to surgicalfacelifts.’

This area of biodegradabledermal fillers is a rapidlygrowing field, wrote Maio(2004): ‘According to theAmerican Association of PlasticSurgeons, more than 356,000surgical rhinoplasties and128,000 face-lifts wereperformed in 2003, representingan increase of 1% and 9%respectively, over thoseperformed the year before.However, during the sameperiod the real growth incosmetic procedures was indermal injections treatments,which increased by 30%.’

The traditional face-lift isnot yet obsolete. But withmany patients opting forminimally invasive procedures(no down time/none of therisk that is associated withgeneral anaesthetic) involvingthe use of Botulinum toxin Aand, indeed, dermal fillers, theneed for a face-lift can bepostponed almost indefinitelywith regular visits to a facialaesthetic clinic.

Many surgeons also findthat following face-lift surgerythere may be some final‘tweaking’ required, and it iseasier to make any finaladjustments with dermal filler.In addition, dermal filler canbe used to fill tear troughs.

Malar augmentation usingdermal filler can be carried outto define the cheek bones; aHA product such as RestylaneSub Q is an excellent choicefor this area. Also, whilerhinoplasty is usuallyconsidered the treatment ofchoices to reshape noses,dermal fillers are proving to bean excellent option whencorrecting small defects orconcave nose bumps. HAdermal fillers can also beinjected into the base of thenose to ensure a more delicatedownturn, or indeed to reducethe drooping effect that occurswith age. It is also possible toincrease a nostril flare by usingHA products with a smallerparticle size.

According to Maoi (2004),it is possible ‘for a moreextensive nose reshaping,filling the anterior nasal spineand the columella basis withcollagen opens the nasolabialangle’ [90-110º]. This is inaddition to the benefit ofcombined treatment withBotulinum toxin A, where byinjecting the depressor of theseptum excessive nose tipdrooping can be corrected.

While the abovesuggestions may simply be‘food for thought’ for thenovice injector, there is nodenying that on a daily basisthere are more and morenasolabial folds, oralcommissures, marionette linesand lips being treated with oneor more dermal filler products.

Other usesWithin the dental arena, thebenefits of dermal filler in thecorrection of both cleft lip(Schweiger et al, 2008) andmandibular prognathia mustnot go unmentioned (Reytan etal, 2007).

Also, an Irish Dentist article(Meagher, 2008) presented acase study of a young caucasianfemale with an asymmetricupper lip. This lip wassuccessfully treated with ahyaluronic acid dermal fillerproduct.

The type of dermal filler tobe used should be at thediscretion of the individualpractitioner, within reason.There are about 100 differenttypes of dermal fillers on themarket today.

The author favours NASHA-based dermal fillers, such asRestylane (Q-Med). Juvédermand Hydrofill are excellentoptions for the novice injector,but with skill growth andexperience the Q-Med productrange is a firm favourite ofmany facial aestheticpractitioners.

Finally, as always, informedconsent is paramount to usingdermal filler products in anyaesthetic practice. According toDendy et al (2005): ‘Obtaininginformed consent is a crucialcomponent in minimising legalcomplications. This consentrepresents a vital part ofpatients’ education and canserve as a legal documentdemonstrating the patients’understanding of the risksassociated with the procedure.’

Finally, one must be awareof the legal ramifications of off-label filler use (Goldberg,2006). Many clinicians use avariety of drugs in an off-labelmanner. Botulinum toxin A isan obvious example.

Some dermal filler productsare used off-label from theirFDA approval. An example ofoff-label use would beSculptra. According toGoldbery (2006), Poly-L lacticacid is FDA cleared for use inHIV lipoatrophy. However, thisagent is more commonly usedfor off-label, non-FDA clearedfacial volume enhancement innon-HIV patients.

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The use of dermal fillers inany aesthetic practice is a keypart of the clinician’s armouryto combat the natural ageingprocess that we are all subjectto. With the Baby Boomersnow in their 50s and 60s,there is an increased demandfor anti-ageing treatments inorder to offset or even delaythe loss of youth. Thisdemand is particularly inresponse to the forcesresponsible for facial ageing,which include: sun damage,gravity, soft tissue maturation,reduced collagen and elastin,and changes due toenvironmental factors

The journey and history ofthe facial aesthetic dermalfiller, and indeed the clinicalbenefits, have beenhighlighted in this paper.After critically analysing theuse of dermal fillers in anaesthetic practice withcontemporary evidence, theauthor considers that thebenefits of use of dermal

fillers within any aestheticpractice are undisputed. Thisis not just in regard to truecosmetic enhancement, butalso in the area of cleft orasymmetric lip, non-surgicalrhinoplasty, and correction ofprognathic mandibles.

ReferencesAlam et al (2008) Injectable

fillers. Dermatol Surg 34Suppl 1: S115-48

Butterwick (2006)Understanding injectablePoly-L-lactic acid. PlastReconstr Surg 118(3 Suppl):46S-54S

Caruthers et al (2006)Management of injectedhyaluronic acid inducedTyndall effects. Lasers SurgMed 38(3): 202-4

Goldberg (2006) Legal ramifications of off-label filleruse. Dermatologic Therapy 19:189-193

Hanke et al (1991) Abscess formation and local necrosisafter treatment with Zydermor Zyplast collagen implant. JAm Acad Dermatol 25: 319-326

Lowe et al (2005) Adverse reactions to dermal fillers:review. Dermatol Surg 31(11Pt 2): 1616-25

Maio (2004) The minimalapproach: an innovation infacial cosmetic procedures.Aesth Plast Surg 28: 295-300

Meagher (2008) Treating lipasymmetry with filler. IrishDentist 11(8): 35-38

Monheit et al (2007) Juvéderm:a hyaluronic acid dermal filler.J Drugs Dermatol 6(11):1091-5

Murray et al (2005).The evolution of soft tissue fillersin clinical practice. DermatolClin 23(2): 343-63

Peter S, Mennel S (2006)Retinal branch arteryocclusion following injection of hyaluronic acid(Restylane). Clinical andExperimental Ophthalmology34: 363-364

Reytan et al (2007) Aestheticcorrection of the upper lipin a patient with mandibular prognathiawith a novel long-lastingcollagen filler: a casereport. Dermatol Surg 33:1274-1276

Schweiger et al (2008)Successful treatment withinjected hyaluronic acid ina patient with lip asymmetry after surgicalcorrection of cleft lip.Dermatol Surg 34: 717-719

US Department of Healthand Human Services(2008) US Food and DrugAdministration. DeviceApproval

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