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<strong>Review</strong> <strong>of</strong> <strong>Long</strong>-<strong>Lasting</strong><br />

<strong>Dermal</strong> <strong>Fillers</strong><br />

Volume 2 • Number 1 • 2006<br />

Supplement to the<br />

Aesthetic Buyers Guide<br />

Jean Carruthers, MD, FRCS(C),<br />

FRC(Ophth), Editor<br />

A Continuing Medical Education Program<br />

Published by Medical Insight, Inc.


CME CONTENT<br />

<strong>Review</strong> <strong>of</strong> <strong>Long</strong>-<strong>Lasting</strong> <strong>Dermal</strong> <strong>Fillers</strong><br />

Target Audience<br />

This publication is intended for plastic surgeons, dermatologists,<br />

and other allied health pr<strong>of</strong>essionals.<br />

Learning Objectives<br />

After reviewing this CME publication, the physician<br />

will be able to:<br />

• Identify the mechanism <strong>of</strong> action for CaHA, LIS,<br />

PLA & PMMA dermal fillers (volumizer vs. stimulator).<br />

• Identify the difference between dislocation and migration<br />

<strong>of</strong> filler material.<br />

• Identify the characteristics <strong>of</strong> bovine collagen.<br />

• Identify the outcomes for various injection planes.<br />

• Define granulomas and their primary treatment option.<br />

Obtaining Credit<br />

To receive CME credit for the completion <strong>of</strong> this activity, mail or fax<br />

the completed Registration, Post Test, and Evaluation Forms located<br />

at the back <strong>of</strong> this publication to: Ciné-Med, Inc., CME Department,<br />

127 Main Street North, Woodbury, CT 06798, Fax: 203-263-4839. A<br />

certificate will be sent via regular mail.<br />

Accreditation<br />

Ciné-Med, Inc. is accredited by the Accreditation Council for<br />

Continuing Medical Education (ACCME) to provide continuing<br />

medical education for physicians.<br />

Ciné-Med, Inc. designates this educational activity for a maximum <strong>of</strong><br />

1 AMA PRA Category 1 credit(s) . Physician should only claim credit<br />

commensurate with the extent <strong>of</strong> their participation in the activity.<br />

The accreditation period for this material is:<br />

February 2006 – February 2008.<br />

Commercial Support<br />

This activity is supported by an educational grant from<br />

Medical Insight, Inc.<br />

Disclosure<br />

It is the policy <strong>of</strong> Ciné-Med to insure balance, independence, objectivity,<br />

and scientific rigor in all its educational programs. Faculty, course directors,<br />

and planners participating in an accredited program are required<br />

to disclose to the program audience any real or apparent conflict(s) <strong>of</strong><br />

interest. This pertains to relevant financial relationships within the<br />

past 12 months with a commercial interest and the opportunity to affect<br />

program content relevant to products or services <strong>of</strong> that commercial<br />

interest. The intent <strong>of</strong> this policy is to allow for a determination to be<br />

made as to whether that relationship may constitute a conflict <strong>of</strong> interest<br />

that must be resolved. Information that a faculty member, course<br />

director, or planner (including spouse/partner) has no relevant financial<br />

relationships will be provided to the learners.<br />

Faculty Disclosures<br />

The following contributors have indicated they do not have any<br />

relevant financial relationships to disclose:<br />

Jack Friedland, MD<br />

Pierre Nicolau, MD<br />

Kevin Smith, MD<br />

The following contributors have indicated they do have relevant<br />

financial relationships to disclose:<br />

Alastair Carruthers, MD<br />

Allergan, Inc. - Consultant, Honoraria, Investigator.<br />

Artes Medical, Inc. - Advisory Board, Warrant Holder.<br />

Bi<strong>of</strong>orm Medical, Inc. - Consultant, Investigator.<br />

Medicis, Inc. - Consultant, Honoraria, Investigator.<br />

Q-Med, Inc. - Investigator.<br />

Jean Carruthers, MD<br />

Allergan, Inc. - Consultant, Honoraria, Investigator.<br />

Artes Medical, Inc. - Advisory Board, Warrant Holder.<br />

Bi<strong>of</strong>orm Medical, Inc. - Consultant, Investigator.<br />

Medicis, Inc. - Consultant, Honoraria, Investigator.<br />

Q-Med, Inc. - Investigator.<br />

Steven Cohen, MD<br />

Artes Medical, Inc. - Stock Holder.<br />

Also engaged in <strong>of</strong>f-label use <strong>of</strong> fillers on additional sites outside<br />

<strong>of</strong> nasolabial folds.<br />

Miles Graivier, MD<br />

Artes Medical, Inc. - Advisory Board.<br />

Bi<strong>of</strong>orm Medical, Inc. - Medical Advisory Board.<br />

Dermik Laboratories, Inc. - Medical Advisory Board.<br />

Also engaged in use <strong>of</strong> semi-permanent and permanent fillers<br />

for s<strong>of</strong>t tissue contouring.<br />

John Joseph, MD<br />

Allergan, Inc. Advisory Board, Trainer.<br />

Artes Medical, Inc. - Advisory Board, Stock & Warrant Holder.<br />

Dermik Laboratories, Inc. - Injection Trainer, Advisory Board.<br />

Q-Med, Inc. - Advisory Board.<br />

Also engaged in <strong>of</strong>f-label use <strong>of</strong> Sculptra and Botox.<br />

Nicholas Lowe, MD<br />

Medicis, Inc. - Consultant, Research Grants.<br />

San<strong>of</strong>i Aventis - Consultant, Research Grants.<br />

Rhoda Narins, MD<br />

Artes Medical, Inc. - Advisory Board, Warrant Holder<br />

ColBar - Investigator, Stock Options.<br />

Dermik Laboratories, Inc. - Investigator.<br />

Medicis, Inc. - Medical Board, Investigator.<br />

Also engaged in <strong>of</strong>f-label use <strong>of</strong> Sculptra, Radiesse and Silicone.<br />

Mark Rubin, MD<br />

Artes Medical, Inc. - Advisory Board.<br />

Inamed, Inc. - Research Grant.<br />

Medicis, Inc. - Medical Advisory Board, Research Grant.<br />

www.cine-med.com


Table <strong>of</strong> Contents<br />

Editorial Advisory Board . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4-5<br />

Introduction by Jean D. Carruthers, MD, Editor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6<br />

The History <strong>of</strong> Cosmetic <strong>Dermal</strong> <strong>Fillers</strong> . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6<br />

<strong>Long</strong>-<strong>Lasting</strong> Filler Comparison Chart. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11<br />

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12-13<br />

Clinical Roundtable . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14<br />

The Ideal <strong>Dermal</strong> Filler . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14<br />

Mechanism <strong>of</strong> Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14<br />

<strong>Long</strong>evity <strong>of</strong> PMMA <strong>Fillers</strong> . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15<br />

Characteristics <strong>of</strong> Bovine Collagen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16<br />

Allergenicity <strong>of</strong> Bovine Collagen Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16<br />

Dislocation vs. Migration <strong>of</strong> <strong>Fillers</strong> . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16<br />

Injection Techniques. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17<br />

Outcomes <strong>of</strong> Injections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19<br />

Corrective Measures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19<br />

Granulomas. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20<br />

Recommended Treatment for Granulomas. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21<br />

The Future <strong>of</strong> Permanent <strong>Fillers</strong>. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22<br />

CME Test. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24<br />

CME Registration Form . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25<br />

CME Evaluation Form . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26<br />

Publisher Information<br />

Medical Insight, Inc. ®<br />

120 Vantis, Suite 470<br />

Aliso Viejo, California 92656<br />

www.miinews.com<br />

Publishers <strong>of</strong> the Aesthetic Buyers Guide <br />

Telephone: (949) 830-5409<br />

Facsimile: (949) 830-8944<br />

Subscriptions: info@miinews.com<br />

Advertising Inquiries: sales@miinews.com<br />

Michael Moretti<br />

Publisher<br />

mmoretti@miinews.com<br />

Correction <strong>of</strong> errors: Medical Insight, Inc. assumes no liability for the information contained in this publication. Every effort has been taken<br />

to ensure the accuracy <strong>of</strong> this information by contacting sources believed to be reliable. Errors, when discovered, will be promptly corrected.<br />

Copyright: This publication is protected by U.S. Copyright Law; © 2006 Medical Insight, Inc. Unauthorized reproduction is strictly<br />

forbidden by law.<br />

Aesthetic Buyers Guide is a trademark <strong>of</strong> Medical Insight, Inc.<br />

www.miinews.com<br />

<strong>Review</strong> <strong>of</strong> <strong>Long</strong>-<strong>Lasting</strong> <strong>Dermal</strong> <strong>Fillers</strong><br />

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Editorial Advisory Board<br />

Jean D. Carruthers, MD,<br />

FRCS (C), FRC (Ophthalmology)<br />

Clinical Pr<strong>of</strong>essor,<br />

Department <strong>of</strong> Ophthalmology<br />

University <strong>of</strong> British Columbia<br />

MODERATOR<br />

Jean D. Carruthers, MD, is a clinical pr<strong>of</strong>essor in the Department <strong>of</strong> Ophthalmology at the University <strong>of</strong> British Columbia in<br />

Vancouver, where she specializes in aesthetic facial ophthalmology. Dr. Carruthers is a diplomat <strong>of</strong> the American Board <strong>of</strong> Cosmetic Surgery and<br />

fellow <strong>of</strong> the American Society <strong>of</strong> Ophthalmic Plastic and Reconstructive Surgery. She has been invited to give more than 100 presentations<br />

worldwide on topics in cosmetic surgery. Her clinical expertise comprises cosmetic and therapeutic use <strong>of</strong> botulinum A exotoxin, aesthetic fillers,<br />

aesthetic face lift, cosmetic laser-assisted upper and lower eyelid blepharoplasty, and a variety <strong>of</strong> resurfacing procedures and other s<strong>of</strong>t tissue<br />

enhancement techniques. Dr. Carruthers is currently President <strong>of</strong> the Cosmetic Surgery Foundation for Education, Research and Patient Safety<br />

and past President <strong>of</strong> the Canadian Laser Aesthetic Surgery Society. This year she is President <strong>of</strong> the Foundation <strong>of</strong> the American Academy <strong>of</strong><br />

Cosmetic Surgery and Secretary <strong>of</strong> the same Academy.<br />

Alastair Carruthers MD, FRCPC<br />

Clinical Pr<strong>of</strong>essor, Division <strong>of</strong> Dermatology<br />

University <strong>of</strong> British Columbia<br />

Dr. Alastair Carruthers is a cosmetic dermatologic<br />

surgeon who operates his own clinical practice in<br />

Vancouver, BC. He is also a clinical pr<strong>of</strong>essor <strong>of</strong> dermatology<br />

with the Faculty <strong>of</strong> Medicine at the<br />

University <strong>of</strong> British Columbia (UBC). Dr. Carruthers received his medical<br />

degree from Brasenose College, Oxford in 1969, did his dermatology<br />

residency at St. John's Hospital for diseases <strong>of</strong> the skin in London and<br />

completed his graduate studies in dermatologic surgery at the<br />

University <strong>of</strong> California, San Francisco in 1977. During his 20 years <strong>of</strong><br />

practice, Dr. Carruthers has made several major contributions to the<br />

field <strong>of</strong> dermatology. Foremost among these was the use <strong>of</strong> the BOTOX ®<br />

procedure in cosmetic applications, a discovery he made with his wife,<br />

Dr. Jean Carruthers, in 1987. Since this time, they have been at the<br />

forefront <strong>of</strong> BOTOX ® research, development and education, publishing<br />

numerous articles with their data. Dr. Carruthers is a member <strong>of</strong> several<br />

national and international associations, including the American<br />

Dermatology Association and the Canadian Dermatology Association,<br />

where he served as president from 1998 to 1999.<br />

Steven R. Cohen, MD<br />

Clinical Pr<strong>of</strong>essor,<br />

Plastic Surgery Training Program<br />

University <strong>of</strong> California, San Diego<br />

Dr. Cohen has served as the Chief <strong>of</strong> Crani<strong>of</strong>acial<br />

Surgery and Surgical Director <strong>of</strong> the Crani<strong>of</strong>acial<br />

Center at Children's Hospital <strong>of</strong> San Diego since<br />

1999. He founded FACESplus with Dr. Ralph E. Holmes, former<br />

Chairman <strong>of</strong> Plastic Surgery at the University <strong>of</strong> California, San<br />

Diego. In 1990, Dr. Cohen was recruited to direct the Crani<strong>of</strong>acial<br />

Program at the University <strong>of</strong> Michigan in Ann Arbor, where he built<br />

the infrastructure that is present to this day. He serves as a clinical<br />

pr<strong>of</strong>essor in the Plastic Surgical Training program at the University<br />

<strong>of</strong> California, San Diego. Dr. Cohen has written over 150 articles for<br />

medical literature and served on the editorial boards <strong>of</strong> Plastic<br />

Reconstructive Surgery and Annals <strong>of</strong> Plastic Surgery. He was formerly<br />

on the executive boards <strong>of</strong> the American Society <strong>of</strong> Crani<strong>of</strong>acial<br />

Surgery, the American Society <strong>of</strong> Maxill<strong>of</strong>acial Surgeons and the<br />

American Cleft Palate-Crani<strong>of</strong>acial Association.<br />

Jack A. Friedland, MD, FACS<br />

Associate Pr<strong>of</strong>essor <strong>of</strong> Plastic Surgery<br />

Mayo Medical School<br />

Phoenix, AZ<br />

After completing his undergraduate education at<br />

the University <strong>of</strong> Wisconsin, Dr. Friedland graduated<br />

from Northwestern University Medical<br />

School in 1965 where he was elected to Alpha Omega Alpha, Honor<br />

Medical Society. He completed a straight surgical internship and general<br />

surgery residency at New York University-Bellevue Medical<br />

Center, followed by the completion <strong>of</strong> a plastic surgery residency at the<br />

Institute <strong>of</strong> Reconstructive Plastic Surgery in New York City. Since<br />

1996, Dr. Friedland has practiced at Mayo Medical School in Phoenix,<br />

Arizona as Associate Pr<strong>of</strong>essor <strong>of</strong> Plastic Surgery. He has performed as<br />

Examiner for the American Board <strong>of</strong> Plastic Surgery and is a member<br />

<strong>of</strong> the American Association <strong>of</strong> Plastic Surgeons, American Burn<br />

Association, American Society <strong>of</strong> Plastic and Reconstructive Surgeons<br />

and is past President and current member <strong>of</strong> the Board <strong>of</strong> Trustees on<br />

the American Society for Aesthetic Plastic Surgery.<br />

Miles H. Graivier, MD, FACS<br />

Private Practice<br />

North Atlanta Plastic Surgery<br />

Roswell, GA<br />

Dr. Miles Graivier earned his medical degree<br />

from the University <strong>of</strong> Texas at Houston, graduating<br />

with high honors. After finishing a five year<br />

residency in General Surgery at Emory University, Dr. Graivier then<br />

completed a two year fellowship in Plastic and Reconstructive<br />

Surgery at the University <strong>of</strong> California at Los Angeles (UCLA). Dr.<br />

Graivier is Board Certified in Plastic & Reconstructive Surgery and<br />

is a member <strong>of</strong> the American Society <strong>of</strong> Plastic & Reconstructive<br />

Surgeons and the Georgia Society <strong>of</strong> Plastic & Reconstructive<br />

Surgeons. He is a Fellow <strong>of</strong> the American College <strong>of</strong> Surgeons and<br />

now works in private practice at the North Atlanta Plastic Surgery<br />

Center in Roswell, Georgia.<br />

4 <strong>Review</strong> <strong>of</strong> <strong>Long</strong>-<strong>Lasting</strong> <strong>Dermal</strong> <strong>Fillers</strong> www.miinews.com


Editorial Advisory Board<br />

John H. Joseph, MD<br />

Facial Plastic & Reconstructive Surgery<br />

Beverly Hills, CA<br />

Assistant Clinical Pr<strong>of</strong>essor<br />

UCLA School <strong>of</strong> Medicine<br />

Dr. John H. Joseph is a Facial Plastic Surgeon in<br />

private practice in Beverly Hills and is an Assistant Clinical<br />

Pr<strong>of</strong>essor at UCLA. He specializes in aesthetic facial plastic surgery<br />

but is also involved in congenital and traumatic facial reconstructive<br />

cases. Dr. Joseph received his undergraduate degree in Biology from<br />

the University <strong>of</strong> Illinois. His medical school training and General<br />

Surgery Internship were obtained from the University <strong>of</strong> Illinois in<br />

Chicago. He attended the top ranked residency in Head and Neck<br />

surgery at the University <strong>of</strong> Iowa. He completed a one year fellowship<br />

with Dr. Frank Kamer in Facial Plastic and Reconstructive Surgery,<br />

and continued to assist in that <strong>of</strong>fice until starting his own practice<br />

in Beverly Hills. Dr. Joseph is Board Certified by the American<br />

Academy <strong>of</strong> Facial Plastic and Reconstructive Surgery and by the<br />

American Board <strong>of</strong> Otolaryngology.<br />

Nicholas J. Lowe, MD, FRCP, FACP<br />

Consultant Dermatologist, Cranley Clinic<br />

for Dermatology, London, England<br />

Clinical Pr<strong>of</strong>essor <strong>of</strong> Dermatology,<br />

UCLA School <strong>of</strong> Medicine, Los Angeles<br />

Dr. Lowe graduated from the University <strong>of</strong><br />

Liverpool Medical School in England in 1968 and subsequently<br />

completed his internship in Liverpool Teaching Hospitals. He<br />

entered the Royal Navy as a Surgeon Lieutenant on a short service<br />

commission and completed an Internal Medicine residency at the<br />

Royal Navy Hospital in Hampshire and in London, England. In 1989<br />

he founded and is the Medical Director <strong>of</strong> Southern California<br />

Dermatology, Psoriasis and Laser Center and Clinical Research<br />

Specialists, Inc., in Santa Monica, California. Dr. Lowe remains at<br />

the UCLA School <strong>of</strong> Medicine as Clinical Pr<strong>of</strong>essor <strong>of</strong> Dermatology<br />

and is Senior Lecturer and honorary consultant at UCL, London. In<br />

1994, Dr. Lowe founded the Cranley Clinic for Dermatology in<br />

London, England, which houses clinical and research facilities.<br />

Rhoda S. Narins, MD<br />

Director,<br />

Dermatology Surgery and Laser Center<br />

Clinical Pr<strong>of</strong>essor <strong>of</strong> Dermatology,<br />

NYU Medical School<br />

Immediate Past-President ASDS<br />

Dr. Rhoda S. Narins, one <strong>of</strong> the nation's top dermatologic surgeons,<br />

was selected by her peers as one <strong>of</strong> only 12 dermatologists in the<br />

United States listed in "Best Doctors in America" under Aesthetic<br />

Surgery. She is currently President <strong>of</strong> the American Society <strong>of</strong><br />

Dermatologic Surgery and Clinical Pr<strong>of</strong>essor <strong>of</strong> Dermatology at New<br />

York University Medical School where she teaches advanced dermatologic<br />

surgery and is Chief <strong>of</strong> the Liposuction Surgery Unit. Dr.<br />

Narins has lectured extensively world wide on dermatologic surgery<br />

including liposuction, fat transfer, collagen and other fillers, chemical<br />

peels, Ultra-Pulse CO 2 & other lasers, sclerotherapy, BOTOX ® ,<br />

and skin care. She is board certified by the American Board <strong>of</strong><br />

Dermatology and Chief Emeritus <strong>of</strong> Dermatology at white Plains<br />

Hospital Medical Center.<br />

Pierre J. Nicolau, MD<br />

Board Certified Plastic Surgeon,<br />

Private Practice, Paris, France<br />

Former Registrar and Senior Registrar (L.T.)<br />

Leeds General Infirmary, LEEDS, U.K.<br />

Dr. Nicolau studied at the University <strong>of</strong> Montpellier<br />

—The oldest active medical school in the world—where he specialized<br />

in plastic surgery. In 1976, there were very few surgical services specializing<br />

in aesthetic and reconstructive plastic surgery. In most <strong>of</strong> the<br />

university hospitals, this specialty was taught in maxill<strong>of</strong>acial, cervic<strong>of</strong>acial<br />

or orthopedic departments. As a result, he traveled to England to<br />

perfect his surgical techniques, where reconstructive surgery was more<br />

developed due to the treatment <strong>of</strong> WWII injuries, particularly severe<br />

burns. After returning to France in 1983, he performed hospital-based<br />

procedures in reconstructive surgery focusing on burn victims, skin<br />

and breast cancers and body contouring for weight loss patients, in<br />

addition to opening his private practice. Dr. Nicolau has priviliges at<br />

l'Assistance Publique - Hôpitaux de Paris as Chirurgien Attaché and is<br />

on the staff at l'Hôpital Rothschild, l'Hôpital Saint Antoine. In<br />

Colombes, he is also on staff at l'Hôpital Louis Mourier, a leading center<br />

for the surgical treatment <strong>of</strong> obesity.<br />

Mark G. Rubin, MD<br />

Assistant Clinical Pr<strong>of</strong>essor <strong>of</strong> Dermatology<br />

University <strong>of</strong> California, San Diego<br />

Lasky Clinic<br />

Beverly Hills, CA<br />

After obtaining his MD from Jefferson Medical<br />

College in Philadelphia, PA, Dr. Rubin completed his medical residency<br />

in dermatology at the Henry Ford Hospital in Detroit, MI, and his internal<br />

medicine internship at Alton Ochsner Hospital in New Orleans, LA.<br />

Dr. Rubin has been lecturing on cosmetic dermatology and skin rejuvenation<br />

for over 13 years and has personally trained over 700 doctors<br />

from ten countries in his techniques for skin rejuvenation. In addition,<br />

he teaches and arranges Cosmetic Peel Workshops for physicians<br />

around the nation. Author <strong>of</strong> numerous medical journal articles, Dr.<br />

Rubin is Board Certified in Dermatology and is an associate Pr<strong>of</strong>essor<br />

<strong>of</strong> Dermatology at UCSD. He is a Diplomat <strong>of</strong> the American Board <strong>of</strong><br />

Dermatology and National Board <strong>of</strong> Medical Examiners, as well as a<br />

member <strong>of</strong> the American Academy <strong>of</strong> Dermatology and the American<br />

Society <strong>of</strong> Dermatologic Surgery among others.<br />

Kevin C. Smith, MD, FRCPC, FACP<br />

Dermatologist, Private Practice<br />

Niagara Falls, Ontario, Canada<br />

Dr. Kevin Smith graduated from the University <strong>of</strong><br />

Alberta in Edmonton, Candada in 1983. He became<br />

a Diplomat <strong>of</strong> the United States National Board <strong>of</strong><br />

Medical Examiners in 1984 and the American Board<br />

<strong>of</strong> Dermatology in 1988. In 1989 Dr. Smith achieved Fellowship at the<br />

Royal College <strong>of</strong> Physicians (Canada) in Dermatology. He is now in private<br />

practice for Dermatology at the Niagra Falls Dermatology and<br />

Skin Care Centre in Niagra Falls, Ontario. Concurrently, Dr. Smith<br />

serves as Courtesy Staff for the Department <strong>of</strong> Internal Medicine at<br />

Greater Niagara General Hospital in Niagara Falls, Ontario, Canada.<br />

www.miinews.com<br />

<strong>Review</strong> <strong>of</strong> <strong>Long</strong>-<strong>Lasting</strong> <strong>Dermal</strong> <strong>Fillers</strong><br />

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The History <strong>of</strong> Cosmetic <strong>Dermal</strong> <strong>Fillers</strong><br />

By Jean Carruthers, MD, FRCS<br />

To correct contour deficiencies <strong>of</strong> the face, a variety<br />

<strong>of</strong> injectable s<strong>of</strong>t tissue augmentation agents have<br />

emerged. The first was bovine collagen, introduced<br />

approximately 30 years ago 1 and marketed as<br />

Zyderm ® I and II (Inamed, Santa Barbara, Calif.)<br />

for superficial lines and later as Zyplast ® (Inamed),<br />

a glutaraldehyde cross-linked counterpart, for<br />

deeper lines and folds. 2 Both products require a<br />

skin test for allergy before use and have a long<br />

safety record. To reduce the allergenic limitations<br />

<strong>of</strong> bovine collagen, human collagen fillers were<br />

later developed and marketed as CosmoDerm I<br />

and II (Inamed) and CosmoPlast (Inamed). All<br />

five products typically last three to five months in<br />

tissue 3 and all contain lidocaine to minimize pain<br />

during treatment.<br />

Hyaluronic acid (HA) fillers such as Restylane ®<br />

(Q-Med AB, Uppsala, Sweden) and Hylaform ®<br />

(Inamed) have the advantage <strong>of</strong> reduced risk <strong>of</strong><br />

allergic reactions because HA is chemically the<br />

same for all species. 4-6 A transparent gel, Restylane<br />

is produced from streptococci by bi<strong>of</strong>ermentation 5<br />

and typically remains in tissue for six to 12<br />

months after implantation. 3 Hylaform is derived<br />

from rooster combs 6,7 and remains in tissue for six<br />

to nine months. 3 Both products are used for<br />

nasolabial folds and lips 3 and neither contains lidocaine<br />

to reduce pain during treatment. Safety data<br />

for non-animal stabilized HA gel for s<strong>of</strong>t tissue<br />

augmentation has been documented. 8 Neither<br />

Restylane nor Hylaform require an allergy skin<br />

test before use.<br />

With all s<strong>of</strong>t tissue fillers, injection technique is a<br />

key component to successful augmentation. Zyderm<br />

I, for example, is placed in the superficial dermis by<br />

serial punctures that barely penetrate the skin. The<br />

material is “flowed” into the superficial dermis by<br />

positioning each injection volume at the advancing<br />

edge <strong>of</strong> the preceding injected volume. The continuous<br />

flow smoothly fills the superficial defects. 5<br />

Overcorrection is necessary because the saline<br />

dilutent is reabsorbed during the first 24 hours.<br />

Restylane Hyaluronic Acid<br />

(HA) filler, by Q-Med.<br />

Placing the filler at the appropriate depth is particularly<br />

important to achieve the desired cosmetic<br />

result. If Zyderm is placed too superficially, the<br />

skin looks flat and yellow. 3 If Zyplast (injected into<br />

the mid dermal region) is placed too superficially,<br />

long-lasting overcorrection and beading may<br />

result. If injected into the subdermal region, the<br />

duration <strong>of</strong> correction is reduced. 5<br />

The Restylane products include fillers with HA<br />

particles sized according to the depth <strong>of</strong> deposition<br />

into skin. The most commonly used injection technique<br />

for these products is linear threading. 3 The<br />

physician holds the syringe parallel to the fold,<br />

pierces the skin, and moves the needle forward.<br />

While withdrawing the needle, the physician<br />

presses the plunger to expel the filler into the tissue.<br />

Visual and tactile responses to the injection<br />

guide the treatment. Injections placed too deeply<br />

provide reduced benefits, whereas injections<br />

placed too superficially may result in a ridge or an<br />

uneven skin surface. The epidermis may appear<br />

transparent at first, then spotty red or gray.<br />

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The fillers discussed so far have limited duration in<br />

tissue, requiring patients to return for retreatment<br />

every four to six months to maintain cosmetic benefit.<br />

Others, such as liquid injectable silicone (LIS),<br />

last for years or may be permanent.<br />

Liquid silicone has a long and controversial history<br />

as a filler. Developed in 1945 by Dow Corning<br />

Corp. for military purposes, silicone was introduced<br />

to cosmetic medicine in the 1960s as a filler<br />

gel for breast implants 9 and later for s<strong>of</strong>t tissue<br />

augmentation. 10 Although silicone produces cosmetic<br />

benefits, silicone granulomas have been<br />

reported 11 and injection <strong>of</strong> impure silicones has<br />

resulted in serious complications, 12 some appearing<br />

many years after implantation. 13<br />

A comprehensive review <strong>of</strong> possible causes and treatment<br />

options for granulomas associated with all<br />

injectable dermal fillers will be available in 2006. 14<br />

Adverse reactions and complications (including<br />

granulomas) <strong>of</strong> fillers have been reviewed recently. 15,16<br />

Lips augmented with<br />

liquid silicone.<br />

Two medical-grade silicones (both LIS) are currently<br />

available: (1) Silskin ( Richard-James, Inc.<br />

Peabody, Mass.), which has received an<br />

Investigational Device Exemption for a clinical<br />

trial on facial wrinkles, and (2) Silikon ® 1000 (Alcon<br />

Laboratories, Inc., Forth Worth, Texas), which is<br />

FDA cleared as an injectable tamponade for retinal<br />

detachments. The FDA Modernization Act <strong>of</strong> 1997<br />

permits FDA-cleared devices to be used “<strong>of</strong>f-label”<br />

for any condition within the doctor-patient relationship,<br />

such as s<strong>of</strong>t tissue augmentation.<br />

The risks and benefits <strong>of</strong> using liquid silicone for<br />

s<strong>of</strong>t tissue augmentation have been the subject <strong>of</strong><br />

considerable debate. Experts agree, however, that<br />

the quality <strong>of</strong> results depends on technique, minor<br />

complications may occur even with good technique,<br />

serious complications are rare when small volumes<br />

<strong>of</strong> sterile pure liquid are used, and serious complications<br />

can occur years after treatment. They also<br />

agree that dislocation—in this case, movement <strong>of</strong><br />

silicone from the site <strong>of</strong> injection to another body<br />

site—may result if large volumes are injected.<br />

When this occurs, the silicone is not contained by<br />

tissues into which it is injected, causing the filler to<br />

move due to muscle contraction or gravity. 17<br />

As with temporary fillers, injection technique is<br />

critical to success with LIS. The microdroplet<br />

serial puncture technique has been used extensively<br />

for silicone injections. With this technique,<br />

migration is eliminated because the microdroplets<br />

stimulate fibroplasia and the formation <strong>of</strong> a<br />

collagen capsule that holds them at the implantation<br />

site. Silicone microdroplets displace dermal<br />

connective tissue and new collagen is deposited<br />

around the microdroplets, resulting in augmentation.<br />

The amount <strong>of</strong> new collagen synthesized is<br />

predictable and self-limiting. Injections are made<br />

over several time intervals to assure slow but progressive<br />

collagen formation. Since augmentation is<br />

gradual, undercorrection (rather than overcorrection)<br />

is appropriate. 18 The microdroplet technique<br />

requires several repeat treatments, and the time<br />

interval to visible improvement is longer than with<br />

other fillers. 19<br />

Optimal results are obtained when silicone is injected<br />

beneath the layer in which the defect originates.<br />

For example, injecting LIS just below the dermis is<br />

appropriate for correcting contour depressions in<br />

which dermal and epidermal layers <strong>of</strong> normal thickness<br />

lie above a subdermal layer <strong>of</strong> insufficient<br />

depth. If LIS is injected into the dermal or epidermal<br />

layer, beading and granulomas may result.<br />

Beading and overcorrection can be treated with<br />

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Cosmetic uses <strong>of</strong> CaHA in the skin have been<br />

reported. 21,27,28 Comite and colleagues 19 have evaluated<br />

the product for the treatment <strong>of</strong> HIVassociated<br />

lipoatrophy in three patients. Facial<br />

improvement after treatment ranged from 75% to<br />

90% and significant improvement remained for up<br />

to nine months. Tzikas 28 treated the lips, nasolabial<br />

folds, glabellar rhytides, prejowl depressions,<br />

marionette lines, acne scars, and surgical s<strong>of</strong>t tissue<br />

defects <strong>of</strong> 90 patients. Six months after CaHA<br />

treatment, patients reported good to excellent<br />

Nodules in lip after injection <strong>of</strong><br />

calcium hydroxylapatite (CaHA)<br />

microspheres.<br />

Radiance at 4 months. Packed calcium microspheres, interstitum filled<br />

with fibrin and scattered fibroblasts and macrophages (100x).<br />

intralesional anti-inflammatory corticosteroids. 18 A<br />

comprehensive update on the use <strong>of</strong> LIS for s<strong>of</strong>t<br />

tissue augmentation has been published recently. 20<br />

Radiesse (formerly Radiance, BioForm Medical<br />

Inc., San Mateo, Calif.) is a biocompatible implant<br />

<strong>of</strong> calcium hydroxylapatite (CaHA) microspheres<br />

<strong>of</strong> 25 to 45 microns in diameter, suspended<br />

in a cellulose gel. It has been FDA cleared for the<br />

treatment <strong>of</strong> oral and maxill<strong>of</strong>acial defects, vocal<br />

cord augmentation, and radiographic tissue marking.<br />

Although approved in Europe as a s<strong>of</strong>t tissue<br />

filler, Radiesse has not been FDA cleared for facial<br />

cosmetic use in the United States. 19 Clinical trials<br />

for FDA clearance in the correction <strong>of</strong> nasolabial<br />

folds and HIV lipoatrophy are in progress.<br />

Radiesse has been used in orthopedic and reconstructive<br />

surgery, dentistry, 21 treatment <strong>of</strong> bone<br />

deficiencies, 21,22 and as a bulking agent for stress<br />

urinary incontinence. 23 Its safety pr<strong>of</strong>ile 21,24 has<br />

been established and longevity <strong>of</strong> the injectable<br />

agent appears to be up to nine months, 19,25 but may<br />

be longer.<br />

As a constituent <strong>of</strong> bone, CaHA is biocompatible. It<br />

should not stimulate an immune reaction 21,23,26 and<br />

does not require an allergy skin test. 3,19 Since<br />

CaHA microspheres do not appear to migrate,<br />

calcify, or ossify when injected into s<strong>of</strong>t tissue,<br />

Radiesse has potential as a s<strong>of</strong>t tissue filler. 23,27<br />

results in appearance (74% <strong>of</strong> patients), s<strong>of</strong>tness<br />

(80%), and overall satisfaction (88%). Adverse<br />

effects were temporary and included moderate to<br />

severe pain during injection as well as post-treatment<br />

erythema, edema, and ecchymosis. Mucosal<br />

lip nodules appeared and persisted in seven<br />

patients; four nodules required intervention. Lip<br />

nodules were reported in another study as well. 27<br />

Radiesse nodules are hard and white and consist<br />

mainly <strong>of</strong> clumped calcium microspheres. 25<br />

As to the mechanism <strong>of</strong> action, CaHA microspheres<br />

are believed to form a framework for s<strong>of</strong>t tissue<br />

ingrowth as the gel carrier dissolves. 29 Fibroblasts,<br />

which accumulate on the microsphere surface at the<br />

site <strong>of</strong> injection, hold the microspheres in place as the<br />

new tissue develops. 19 In some patients, a layer <strong>of</strong> fibrin<br />

develops around the microspheres until the beads<br />

are broken down enzymatically into calcium and<br />

phosphate. 25 Radiesse works well for deep folds and<br />

wrinkles; s<strong>of</strong>t tissue contouring, including cheek and<br />

brow enhancement; for scars; for nasal contouring, 29<br />

but not for lip enhancement and superficial lines. 3<br />

8 <strong>Review</strong> <strong>of</strong> <strong>Long</strong>-<strong>Lasting</strong> <strong>Dermal</strong> <strong>Fillers</strong> www.miinews.com


Like other longer-lasting fillers, Radiesse is injected<br />

(threaded) into the dermal-subdermal junction or<br />

lower as the needle is withdrawn. In HIV-infected<br />

patients, the cheeks may require massaging to distribute<br />

the filler evenly. Overcorrection is not<br />

recommended and patients may require a touch-up<br />

session two to four weeks later. 19<br />

nearly two years. Palpable but non-visible subcutaneous<br />

nodules appeared in 22 patients and resolved<br />

without intervention in six patients. A randomized<br />

clinical trial 33 in which PLA was injected into the<br />

deep dermis <strong>of</strong> HIV-infected patients showed that<br />

patient self-perception, anxiety, and depression<br />

decreased with facial lipoatrophy correction.<br />

Polymers <strong>of</strong> poly-L-lactic acid (PLA) have been<br />

used for years in absorbable sutures, s<strong>of</strong>t tissue<br />

anchors, surgical sealant meshes and solid<br />

implants (plates, screws, and pins), and drug delivery<br />

devices. Marketed in Europe as New-Fill ® ,<br />

injectable PLA microspheres <strong>of</strong> 1 to 50 microns in<br />

diameter have been used to enhance wrinkles and<br />

to correct folds and volume losses and scars. 3,30<br />

Sculptra (Dermik Laboratories, Berwyn, Pa.) PLA<br />

was recently cleared by the FDA for restoration<br />

and/or correction <strong>of</strong> the signs <strong>of</strong> facial fat loss<br />

(lipoatrophy) in people with HIV. 30<br />

Sculptra is provided in a vial that must be reconstituted<br />

with 5 mL sterile water and incubated for<br />

at least two hours before use. Serial injections<br />

spaced 0.5 to 1 cm apart are directed to the deep<br />

dermal-subdermal junction. A crisscross and tunneling<br />

(threading) technique with massaging<br />

every three to four injections is recommended for a<br />

face with mild to moderate lipoatrophy. Physicians<br />

should avoid overcorrection and strive to distribute<br />

the dissolved product evenly in the tissue.<br />

Injections into the orbit and perioral regions are<br />

recommended only for physicians with adequate<br />

Photos courtesy <strong>of</strong><br />

Nicholas J. Lowe, MD, FRCP, FACP<br />

Non HIV-Infected patient before treatment with Sculptra.<br />

Non HIV-Infected patient after three treatments with Sculptra.<br />

In a 100-patient clinical study, Laglenne and colleagues<br />

19,31 showed that PLA corrected vertical facial<br />

wrinkles with high patient and physician satisfaction.<br />

Immediate or delayed granulomatous or<br />

allergic reactions were not observed for up<br />

to one year. (Laglenne had developed these<br />

resorbable injectable PLA microspheres in the mid-<br />

1990s). Several years later, Valantin and colleagues 32<br />

treated 50 HIV-infected patients with PLA in an<br />

attempt to correct severe facial lipoatrophy. Total<br />

cutaneous thickness increased steadily for up to one<br />

year and remained significantly above baseline for<br />

experience in the technique. Three to five sessions<br />

spaced four to six weeks apart comprise a typical<br />

course <strong>of</strong> treatment. 30 The injection technique has<br />

been further described for on-label and <strong>of</strong>f-label<br />

uses. 34 An update on the use <strong>of</strong> Sculptra has recently<br />

been published. 35<br />

Sculptra is biocompatible, biodegradable, and<br />

immunologically inert. The reconstituted product is<br />

stable for 72 hours. Local anesthesia is recommended<br />

to reduce pain during treatment. 3 Injections may<br />

trigger sufficient collagen production to prolong<br />

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enefit for 12 to 18 months in HIV-infected<br />

patients. 32,33 Three cases <strong>of</strong> adverse events (giant<br />

cell granulomas) occurring 12 months after skin<br />

augmentation with New-Fill have been reported. 36<br />

Polymethylmethacrylate (PMMA) was synthesized<br />

initially by Roehm in 1902, patented in 1928<br />

as Plexiglas, and has since been used as bone<br />

cement, in dentures, in prosthetic devices, in<br />

Photos courtesy <strong>of</strong> Gottfried Lemperle, MD<br />

intraocular lenses and as a carrier for antibiotics. 37<br />

Since 1985, PMMA has been studied as a s<strong>of</strong>t tissue<br />

augmentation device. 38,39<br />

Polymethylmethacrylate (PMMA) microspheres (200x).<br />

The goal was to develop an augmentation device<br />

that would provide long-lasting augmentation.<br />

One way was to insert a nonresorbable synthetic<br />

material in powder form that would act as a<br />

matrix to stimulate collagen deposition over a long<br />

period <strong>of</strong> time. 25 The search for the appropriate<br />

material led to PMMA, the most widely used artificial<br />

material in medicine.<br />

The first step in developing PMMA for s<strong>of</strong>t tissue<br />

augmentation was to isolate microspheres large<br />

enough to avoid phagocytosis but small enough to<br />

allow injection into the deep dermis through a 26-<br />

gauge needle. Microspheres between 30 and 50 µm<br />

met these requirements and were shown to promote<br />

78% connective tissue encapsulation. 25 Animal<br />

experiments 38 in which PMMA microparticles suspended<br />

in Tween 80 or gelatin medium were<br />

injected into the dermis and subdermis showed that<br />

(1) fibrous capsules had formed around each microsphere<br />

within two weeks, (2) microspheres had<br />

remained intact for seven months, and (3) the<br />

Tween 80 or gelatin had not elicited a tissue reaction.<br />

However, foreign body giant cells were seen in<br />

1.5% <strong>of</strong> all invading cells. The next step was to inject<br />

the microspheres (Arteplast ® ) into human patients<br />

with scars and wrinkles. 39<br />

Between 1989 and 1994, 587 patients were given<br />

Arteplast subdermally. By 1994, granulomas had<br />

developed in 15 patients (2.5%) 6 to 18 months<br />

after treatment. To reduce the rate <strong>of</strong> granuloma<br />

formation, the microspheres were washed by a<br />

complex procedure and coated with high-viscosity<br />

bovine collagen rather than gelatin or Tween 80.<br />

The result was wider spaces between the microspheres,<br />

which facilitates tissue ingrowth much<br />

better than the smaller spaces between clumped<br />

beads. In the improved product (Artecoll ® , R<strong>of</strong>il<br />

Medical International, Breda, The Netherlands),<br />

the granuloma formation rate was less than 0.02%<br />

in 400,000 patients worldwide. 40 Formation and<br />

treatment <strong>of</strong> Artecoll-associated granulomas over<br />

a five-year period have recently been reported. 41<br />

In 2003, the FDA advisory panel recommended<br />

that Artecoll receive U.S. marketing approval. After<br />

final FDA approval for marketing in the U.S., the<br />

product will be manufactured and marketed in the<br />

United States by Artes Medical, Inc. (San Diego,<br />

Calif.) as ArteFill ® . 39,42<br />

Clinical trial results <strong>of</strong> Artecoll were reported in<br />

2004. 42 In the multicenter study, 251 patients<br />

received injections <strong>of</strong> Artecoll or collagen (Zyderm<br />

II or Zyplast) in wrinkles <strong>of</strong> the nasolabial area,<br />

glabella, radial lip lines, and corners-<strong>of</strong>-the-mouth.<br />

Improvement in nasolabial folds was significantly<br />

greater in the Artecoll group six months after treatment<br />

and significant augmentation persisted for<br />

12 months. Adverse events and immunoglobulin<br />

10 <strong>Review</strong> <strong>of</strong> <strong>Long</strong>-<strong>Lasting</strong> <strong>Dermal</strong> <strong>Fillers</strong> www.miinews.com


G levels were similar in both groups and no granulomas<br />

were reported after one year. Artecoll was<br />

injected as the needle was moved back and forth<br />

beneath the wrinkle (tunneling technique). Artecoll<br />

was placed in the reticular dermis just above the<br />

junction between the dermis and the subcutaneous<br />

fat. If the needle was inserted into the papillary<br />

dermis (resulting in a blanching effect), the injection<br />

was halted until the needle was moved deeper.<br />

Complete five-year follow-up results <strong>of</strong> clinical trial<br />

patients will be available in 2006. 43 A recent<br />

report 44 provides additional details <strong>of</strong> efficacy, safety,<br />

and injection technique for Artecoll.<br />

Demonstration <strong>of</strong> PMMA microsphere (ArteFill)<br />

with natural collagen formation.<br />

Photos courtesy <strong>of</strong> Gottfried Lemperle, MD<br />

S<strong>of</strong>t tissue fillers are currently classified on the basis<br />

<strong>of</strong> biodegradability or mechanism <strong>of</strong> action. 45<br />

Collagen, HA gels, PLA microspheres, CaHA, and<br />

hydroxyethyl methacrylate (HEMA) particles are<br />

biodegradeable whereas LIS, certain polyacrylamide<br />

(PAAG) gels, and PMMA microspheres are not.<br />

Regarding mechanism <strong>of</strong> action, fillers either add<br />

volume and cause little foreign body reaction<br />

(volumizers) or they stimulate tissue and cause a<br />

foreign body reaction (stimulators). 45 Volumizers<br />

include silicone, certain polyacrylamides, collagen,<br />

and HA; stimulators include PLA, dextrans,<br />

CaHA, HEMA, and PMMA.<br />

PLA and dextrans cause a foreign body reaction<br />

for a limited time period before they are absorbed,<br />

whereas PMMA microspheres stimulate collagen<br />

deposition indefinitely and are never absorbed.<br />

The primary long-lasting fillers are compared in<br />

Table 1 below.<br />

Table 1: Primary long-lasting fillers used for s<strong>of</strong>t tissue augmentation<br />

Brand Active Carrier Mechanism Biodegradable? FDA Status Persistence Allergy Test ? Anesthetic<br />

Name Ingredient <strong>of</strong> Action For Wrinkles In Tissue<br />

Silikon 1000 PDMS None Volumizer No Off-label Permanent No None<br />

Radiesse* CaHA Cellulose Stimulator Yes Off-label 1- 2 years No None<br />

carboxymethyl<br />

cellulose<br />

Sculptra † PLA Cellulose Stimulator Yes Off-label 1 year No None<br />

carboxymethyl<br />

cellulose<br />

ArteFilI PMMA Bovine Stimulator No Approval Permanent Yes Lidocaine<br />

collagen collagen expected in 2006<br />

PDMS= polydimethylsiloxane; CaHA = calcium hydroxylapatite; PLA = poly-L-lactic acid; PMMA = polymethylmethacrylate<br />

* Formerly Radiance<br />

† New-Fill in Europe<br />

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References<br />

1. Knapp TR, Kaplan EN, Daniels JR.<br />

Injectable collagen for s<strong>of</strong>t tissue augmentation.<br />

Plast Reconstr Surg. 1977;60:398-405.<br />

2. Narins RS, Brandt F, Leyden J, Lorenc ZP, Rubin M, Smith<br />

S. A randomized, double-blind, multicenter comparison <strong>of</strong><br />

the efficacy and tolerability <strong>of</strong> Restylane versus Zyplast<br />

for the correction <strong>of</strong> nasolabial folds. Dermatol Surg.<br />

2003;29:588-595.<br />

3. Narins RS, Bowman PH. Injectable skin fillers.<br />

Clin Plast Surg. 2005;32:151-162.<br />

4. Larsen NE, Pollak CT, Reiner K, Leshchiner E, Balazs EA.<br />

Hylan gel biomaterial: dermal and immunologic<br />

compatibility. J Biomed Mater Res. 1993;27:1129-1134.<br />

5. Klein AW. Skin filling. Collagen and other injectables <strong>of</strong><br />

the skin. Dermatol Clin. 2001;19:491-508.<br />

6. Manna F, Dentini M, Desideri P, De Pita O, Mortilla E,<br />

Maras B. Comparative chemical evaluation <strong>of</strong> two<br />

commercially available derivatives <strong>of</strong> hyaluronic acid<br />

(Hylaform from rooster combs and Restylane from<br />

streptococcus) used for s<strong>of</strong>t tissue augmentation.<br />

J Eur Acad Dermatol Venereol. 1999;13:183-192.<br />

7. Monheit GD. Hylaform: a new hyaluronic acid filler.<br />

Facial Plast Surg. 2004;20:153-155.<br />

8. Friedman PM, Mafong EA, Kauvar AN, Geronemus RG.<br />

Safety data <strong>of</strong> injectable nonanimal stabilized hyaluronic<br />

acid gel for s<strong>of</strong>t tissue augmentation.<br />

Dermatol Surg. 2002;28:491-494.<br />

9. Cronin TD, Gerow FJ: Augmentation mammaplasty:<br />

a new "natural feel" prosthesis. In: Transactions <strong>of</strong> the<br />

Third International Congress <strong>of</strong> Plastic and<br />

Reconstructive Surgery, Series No. 66. Amsterdam,<br />

Excerpta Medica, 1964:41-49.<br />

10. Ashley FL, Braley S, Rees TD, Goulian D, Ballantyne<br />

DL Jr. The present status <strong>of</strong> silicone fluid in s<strong>of</strong>t tissue<br />

augmentation. Plast Reconstr Surg.<br />

1967;39:411-420.<br />

11. Nosanchuk JS. Silicone granuloma in breast.<br />

Arch Surg. 1968;97:583-585.<br />

12. Ellenbogen R, Rubin L. Injectable fluid silicone therapy.<br />

Human morbidity and mortality.<br />

JAMA. 1975;234:308-309.<br />

13. Achauer BM.A Serious complication following medicalgrade<br />

silicone injection <strong>of</strong> the face. Plast Reconstr Surg.<br />

1983;71:251-254.<br />

14. Lemperle G , Gauthier-Hazan N, Wolters M, Eisemann-<br />

Klein M, Zimmermann U. Foreign body granuloma after<br />

all injectable dermal fillers: Their possible causes and<br />

treatment options. Plast Reconstr Surg. 118 (Suppl.):2006<br />

15. Duffy, DM. Complications <strong>of</strong> fillers: overview.<br />

Dermatol Surg. 2005;31 (Part 2):1626-1633.<br />

16. Lowe NJ, Maxwell CA, Patnaik R.<br />

Adverse reactions to dermal fillers: review.<br />

Dermatol Surg. 2005;31(Part 2):1616-1625.<br />

17. Duffy DM. The silicone conundrum: a battle <strong>of</strong> anecdotes.<br />

Dermatol Surg. 2002 ;28:590-594.<br />

18. Orentreich D. Liquid injectable silicone: techniques for<br />

s<strong>of</strong>t tissue augmentation. Clin Plast Surg.<br />

2000;27:595-612.<br />

19. Comite SL, Liu JF, Balasubramanian S, Christian MA.<br />

Treatment <strong>of</strong> HIV-associated facial lipoatrophy with<br />

Radiance FN (Radiesse). Dermatol Online J. 2004;10:2-15.<br />

20. Duffy, DM. Liquid silicone for s<strong>of</strong>t tissue augmentation.<br />

Dermatol Surg. 2005;31:1530-1541.<br />

21. Hobar PC, Pantaloni M, Byrd HS. Porous hydroxyapatite<br />

granules for alloplastic enhancement <strong>of</strong> the facial region.<br />

Clin Plast Surg. 2000;27:557-569.<br />

22. Costantino PD, Friedman CD, Jones K, Chow LC, Pelzer<br />

HJ, Sisson GA Sr. Hydroxyapatite cement. I. Basic<br />

chemistry and histologic properties. Arch Otolaryngol<br />

Head Neck Surg. 1991 ;117:379-384.<br />

23. Mayer R, Lightfoot M, Jung I. Preliminary evaluation <strong>of</strong><br />

calcium hydroxylapatite as a transurethral bulking agent<br />

for stress urinary incontinence. Urology. 2001;57:434-438.<br />

24. Havlik RJ; PSEF DATA Committee. Hydroxyapatite.<br />

Plast Reconstr Surg. 2002;110:1176-1179.<br />

25. Lemperle G, Morhenn V, Charrier U.<br />

Human histology and persistence <strong>of</strong> various injectable<br />

filler substances for s<strong>of</strong>t tissue augmentation.<br />

Aesthetic Plast Surg. 2003;27:354-366.<br />

12 <strong>Review</strong> <strong>of</strong> <strong>Long</strong>-<strong>Lasting</strong> <strong>Dermal</strong> <strong>Fillers</strong> www.miinews.com


References<br />

26. Stein J, Eliachar I, Myles J, Munoz-Ramirez H, Strome<br />

M. Histopathologic study <strong>of</strong> alternative substances for<br />

vocal fold medialization. Ann Otol Rhinol Laryngol.<br />

2000;109:221-226.<br />

27. Sklar JA, White SM. Radiance FN: a new s<strong>of</strong>t tissue<br />

filler. Dermatol Surg. 2004;30:764-768.<br />

28. Tzikas TL. Evaluation <strong>of</strong> the Radiance FN s<strong>of</strong>t tissue<br />

filler for facial s<strong>of</strong>t tissue augmentation. Arch Facial<br />

Plast Surg. 2004;6:234-239.<br />

29. Graivier MH, Jansen DA. The role <strong>of</strong> Radiesse in facial<br />

shaping. Plast Reconstr Surg. In press.<br />

30. Vleggaar D, Bauer U. Facial enhancement and the<br />

European experience with Sculptra (poly-l-lactic acid).<br />

J Drugs Dermatol. 2004;3:542-547.<br />

31. Laglenne et al. Un nouveau produit de comblement des<br />

rides, entirement resorbable. Dermatologie 2000;54:30-33.<br />

32. Valantin MA, Aubron-Olivier C, Ghosn J, Laglenne E,<br />

Pauchard M, Schoen H, Bousquet R, Katz P, Costagliola<br />

D, Katlama C. Polylactic acid implants (New-Fill) to<br />

correct facial lipoatrophy in HIV-infected patients: results<br />

<strong>of</strong> the open-label study VEGA. AIDS. 2003;17:2471-2477.<br />

33. Moyle GJ, Lysakova L, Brown S, Sibtain N, Healy J,<br />

Priest C, Mandalia S, Barton SE. A randomized openlabel<br />

study <strong>of</strong> immediate versus delayed polylactic acid<br />

injections for the cosmetic management <strong>of</strong> facial<br />

lipoatrophy in persons with HIV infection. HIV Med.<br />

2004;5:82-87.<br />

38. Lemperle G, Ott H, Charrier U, Hecker J,<br />

Lemperle M. PMMA microspheres for intradermal<br />

implantation: Part I. Animal research.<br />

Ann Plast Surg. 1991;26:57-63.<br />

39. Lemperle G, Romano JJ, Busso M. S<strong>of</strong>t tissue<br />

augmentation with Artecoll: 10-year history, indications,<br />

techniques, and complications.<br />

Dermatol Surg. 2003;29:573-587.<br />

40. Artecoll Physicians Brochure 2005, R<strong>of</strong>il Medical<br />

International NV, Breda, The Netherlands.<br />

41. Carruthers A, Carruthers JDA. Polymethylmethacrylate<br />

microspheres/collagen as a tissue augmenting agent:<br />

personal experience over five years.<br />

Dermatol Surg. 2005;31:1561-1565.<br />

42. Cohen SR, Holmes RE. Artecoll: a long-lasting injectable<br />

wrinkle filler material: Report <strong>of</strong> a controlled,<br />

randomized, multicenter clinical trial <strong>of</strong> 251 subjects.<br />

Plast Reconstr Surg. 2004;114:964-976.<br />

43. Cohen SR, Berner CF, Busso M, et al.<br />

ArteFill ® /Artecoll ® : A long-lasting injectable wrinkle filler<br />

material. Plast Reconstr Surg. 118 (Suppl.):2006<br />

44. Thaler MP, Ubogi ZI. Artecoll: The Arizona experience<br />

and lessons learned. Dermatol Surg. 2005;31:1566-1576.<br />

45. Nicolau, PJ. <strong>Long</strong> lasting and permanent fillers:<br />

Biomaterial influence over host tissue response.<br />

Plast. Reconstr. Surg. In press.<br />

34. Humble G, Mest D. S<strong>of</strong>t tissue augmentation using<br />

Sculptra. Facial Plast Surg. 2004;20:157-163.<br />

35. Vleggaar, D. Facial volume correction with injectable<br />

Poly-L-Lactic Acid. Dermatol Surg. 2005;31:1511-1518.<br />

36. Beljaards RC, de Roos KP, Bruins FG. NewFill for skin<br />

augmentation: a new filler or failure? Dermatol Surg.<br />

2005;31:772-776.<br />

37. Lemperle G, Hazan-Gauthier N, Lemperle M. PMMA<br />

microspheres (Artecoll) for skin and s<strong>of</strong>t tissue<br />

augmentation. Part II: Clinical investigations.<br />

Plast Reconstr Surg. 1995;96:627-634.<br />

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Clinical Roundtable Discussion<br />

Editor’s Note: The following Clinical Roundtable discussion was moderated by Jean D. Carruthers, MD,<br />

FRCS, who has extensive experience in the research and use <strong>of</strong> dermal fillers. Dr. J. Carruthers and her<br />

colleagues share their expert knowledge and experience with several types <strong>of</strong> long-lasting dermal fillers.<br />

What do you and your patients consider<br />

to be the ideal dermal filler?<br />

Steven R. Cohen, MD: Patients want something<br />

that is effective, is reasonably priced, lasts forever,<br />

and is complication-free. The ideal filler, to me, is<br />

permanent, effective, and very safe.<br />

Mark Rubin, MD: People are looking for a<br />

filler with some persistence. Some believe that a<br />

permanent filler is what everybody is looking for,<br />

but in reality a lot <strong>of</strong> patients don’t want something<br />

permanent.<br />

Jack Friedland, MD: A patient would say, “I<br />

want something permanent at a good price.” That’s<br />

understandable, but I think fillers are ancillary<br />

rather than primary methods <strong>of</strong> treatment. If it’s<br />

permanent, it has to be perfectly done from a technical<br />

standpoint because if there’s a problem, it<br />

takes surgery to change it.<br />

Pierre J. Nicolau, MD: I am a plastic surgeon<br />

so most <strong>of</strong> my patients come to me for a long-lasting<br />

result. That’s different with patients going to see<br />

dermatologists, where they don’t mind going back<br />

every three, four, or six months. So for me, the ideal<br />

filler is easy to use <strong>of</strong>f the shelf, not too expensive,<br />

and fairly long-lasting with no side effects.<br />

Miles H. Graivier, MD: Most people want<br />

something that lasts 10 months to two years. For<br />

me, the ideal filler would be easy to handle and<br />

easy to inject, with minimal potential side effects<br />

— one that allows patients to leave the <strong>of</strong>fice with<br />

a change in their appearance.<br />

Rhoda S. Narins, MD: I like something you can<br />

keep at room temperature, has a syringe design<br />

that makes it easy for me to inject, and lasts nine<br />

months to a year.<br />

How does the mechanism <strong>of</strong> action differ between<br />

temporary and permanent fillers?<br />

Dr. Nicolau: The right question should be, what<br />

is the difference in action between a volumizer<br />

(volume filler) and a stimulator? A volumizer is<br />

neutral in the human body, doesn’t create a foreign<br />

body reaction, and stays as a bulk. Examples are<br />

collagens, hyaluronic acid, silicone, and certain<br />

polyacrylamide gels (PAAGs). The other fillers,<br />

including polymethylmethacrylate (PMMA)<br />

microspheres, poly-L-lactic acid (PLA), dextrans,<br />

calcium hydroxylapatite, and hydroxyethylmethacrylate<br />

(HEMA), are stimulators that<br />

promote a foreign body reaction to create new<br />

collagen and new tissue.<br />

Dr. Graivier: Hyaluronic acid fillers (Restylane)<br />

bind water and form a gel; as you lose volume, the<br />

bond becomes stronger. The fillers maintain an<br />

augmentation effect only while the gel is present.<br />

Particulate products with microspheres (Radiesse<br />

and ArteFill) have a gel or collagen carrier that is<br />

dissipated and replaced by the patient’s own connective<br />

tissue; the microspheres form a scaffold for<br />

the patient’s own tissue ingrowth. Poly-L-lactic<br />

acid (Sculptra) microspheres work differently.<br />

They are a volumizing agent that also stimulates<br />

the patient’s own collagen production.<br />

14 <strong>Review</strong> <strong>of</strong> <strong>Long</strong>-<strong>Lasting</strong> <strong>Dermal</strong> <strong>Fillers</strong> www.miinews.com


Alastair Carruthers, MD: With most temporary<br />

fillers, the correction you get will go away over a<br />

period <strong>of</strong> time. Permanent fillers typically induce<br />

fibroplasia, the laying down <strong>of</strong> collagen around the<br />

filler. These fillers have a “period <strong>of</strong> disappointment”;<br />

you start <strong>of</strong>f with the initial result with some<br />

swelling, the swelling goes away, the carrier goes<br />

away, and then you get your own collagen as fibroplasia<br />

kicks in. It’s very important to warn patients<br />

<strong>of</strong> this period <strong>of</strong> disappointment. Otherwise, they<br />

expect that what they see in the mirror before they<br />

walk out will be permanent, which it’s not.<br />

N- and C-terminal ends have been clipped <strong>of</strong>f, the<br />

collagen is not very allergenic. (When the immune<br />

system attacks collagen, it recognizes the C-terminal<br />

and the N-terminal ends.) The body gets rid <strong>of</strong><br />

the liquid collagen fast, then reacts to the PMMA<br />

particles by producing its own natural collagen<br />

and this provides additional correction.<br />

Dr. Rubin: It’s well-documented that once injected,<br />

PMMA remains in place and the body doesn’t<br />

destroy it. The collagen response to the injection<br />

gives a significant amount <strong>of</strong> the permanent volume.<br />

Photos courtesy <strong>of</strong> Gottfried Lemperle, MD<br />

PMMA filler 3 weeks after implantation. Natural collagen begins to<br />

form and is continuously remodeled.<br />

PMMA filler 3 months after implantation. Ingrowth <strong>of</strong> vessels is<br />

obvious and collagen encapsulates each single microsphere.<br />

Why does a PMMA injectable filler provide<br />

a long-lasting result?<br />

Kevin Smith, MD: Some <strong>of</strong> the correction is<br />

created by the PMMA bulk itself. About 20% <strong>of</strong> the<br />

injected volume is PMMA and the rest is liquid<br />

collagen. The liquid collagen is not cross-linked so<br />

it doesn’t hang around long. And because the<br />

John H. Joseph, MD: PMMA has been used in<br />

the body since the 1930s, so we know the body is<br />

unable to dissolve it. It’s both a passive and an<br />

active filler. As a microsphere is injected under<br />

the dermis, PMMA stimulates the skin to make<br />

collagen, elastin, and fibroblasts.<br />

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What are the advantages <strong>of</strong> using a bovine collagen<br />

carrier gel for a particulate filler?<br />

Dr. Nicolau: Bovine collagen is fairly viscous so it<br />

prevents the clustering <strong>of</strong> microparticles. It also<br />

prevents their displacement.<br />

Dr. A. Carruthers: You don’t want the particles to<br />

settle in the carrier, so collagen helps to hold them<br />

apart. In other words, you don’t have to shake it<br />

because the particles have settled to the bottom <strong>of</strong><br />

the syringe. It’s very easy to inject.<br />

Dr. Rubin: It’s a material that everybody’s used to<br />

using. We are comfortable with its flow characteristics<br />

and behavior. The other benefit is that it’s<br />

slowly degradable. With some products that came<br />

out with beads and gel bases, they found that if<br />

the base dissolves too rapidly, the beads clump<br />

together. You need something that takes several<br />

months to degrade to decrease clumping.<br />

Dr. A. Carruthers: No. My experience with<br />

Artecoll is that it’s less likely to produce a positive<br />

skin test than Zyderm. I had two individuals who<br />

were skin-test positive to Artecoll and were also<br />

positive to Zyderm.<br />

Dr. Narins: No. The collagen in Artecoll has much<br />

lower allergenicity than the collagen in Zyderm<br />

and Zyplast.<br />

Dr. Lowe: They have varied allergenicity, but if<br />

you are allergic to bovine collagen you must be<br />

skin tested before you have another one injected.<br />

When you are starting <strong>of</strong>f with any animal<br />

collagen product, it’s very important to “doubleskin-test”<br />

before the first injection <strong>of</strong> filler. You<br />

have to remember that with the first injection, you<br />

may see no problem at the forearm, but that’s the<br />

sensitizing injection so you don’t actually see the<br />

reaction until the second injection. If the second<br />

injection is in the face, you’ve got trouble.<br />

Dr. Smith: Other carriers such as hyaluronic acid<br />

have been tried, but the electrical properties <strong>of</strong> collagen<br />

help to maintain the product in dispersion.<br />

Dr. Graivier: Once approved by the FDA, ArteFill<br />

will be the only filler on the U.S. market with a collagen<br />

carrier. Dr. Gottfried Lemperle found that<br />

the collagen carrier in ArteFill is different from the<br />

collagen in Zyderm and Zyplast which is 90%<br />

native. Zyderm and Zyplast last three to six<br />

months, but the collagen carrier in ArteFill lasts<br />

only a few weeks. Dr. Lemperle chose that particular<br />

collagen because it kept the microspheres<br />

separated better than the other gel carriers and it<br />

is fairly hypoallergenic.<br />

In your experience, do all bovine collagen<br />

products have the same allergenicity?<br />

Dr. Graivier: No, because the composition <strong>of</strong> the<br />

collagen in ArteFill is different, the likelihood <strong>of</strong><br />

this collagen stimulating an allergic reaction<br />

should be lower.<br />

Temporary allergic reaction 6 weeks after a hyaluronic acid filler.<br />

May be treated by a physician with intralesional corticosteroid.<br />

What is the difference between dislocation and<br />

migration <strong>of</strong> fillers?<br />

Dr. Nicolau: Dislocation is a mechanical phenomenon;<br />

weight or muscular action may move the<br />

implant from where it was placed. For instance, in<br />

the lips (which are always moving), particulate<br />

implants may move along the white line. <strong>Fillers</strong> in<br />

the breast may move because they’re too heavy.<br />

Photo courtesy <strong>of</strong> Nicholas J. Lowe, MD, FRCP, FACP<br />

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Migration is a physiologic phenomenon by which the<br />

filler is carried away by macrophages or other cells.<br />

Dr. Friedland: I have had no problems with<br />

collagen and hyaluronic acid.<br />

Dr. Cohen: Dislocation implies that something<br />

has been moved from its primary site by physical<br />

means, but migration implies that a material is<br />

able to get into a lymphatic or blood vessel and be<br />

transported elsewhere.<br />

Dr. Smith: Dislocation <strong>of</strong> the implant is always an<br />

issue, especially if the patient is manipulating the<br />

filler afterward. The important thing is to tell the<br />

patient not to manipulate the filler.<br />

Dr. Smith: Dislocation might happen after you<br />

inject the filler. The filler can be nicely distributed<br />

about the lips, and then the patient gets home and<br />

tries to reshape the lips by massaging and rubbing<br />

them. But she can wind up moving the filler, like<br />

squeezing the toothpaste inside a tube.<br />

Dr. Joseph: Often, if fillers end up where you<br />

didn’t want them it’s because you didn’t put it in<br />

the right place to begin with. Most doctors don’t<br />

want to say that, but technically they didn’t put<br />

the filler where it was supposed to be. I don’t think<br />

I’ve ever seen migration.<br />

Which technique do you use to inject fillers into<br />

nasolabial folds, glabellar frown lines, and<br />

marionette lines?<br />

Dr. Graivier: The hyaluronic acid fillers<br />

(Restylane, Captique, and Hylaform) are good for<br />

the mid to deep dermis. For fine lines, I inject<br />

Hylaform Fine Line with a 30-gauge needle and<br />

use a serial puncture technique. For the nasolabial<br />

folds, marionette lines, and corner <strong>of</strong> the mouth,<br />

ArteFill will be a nice product and give permanent<br />

augmentation. For that I will use a 26- or 27-gauge<br />

needle with a linear threading technique when I<br />

need to be very precise.<br />

Are you concerned about dislocation or migration<br />

with these fillers?<br />

Dr. Nicolau: The product I use the most is<br />

Artecoll, strictly a permanent filler. Dislocation<br />

has been reported with the polyacrylamide gels,<br />

but in my experience there are no migration or<br />

dislocation problems with Artecoll.<br />

Dr. Cohen: For the nasolabial folds I use a threading<br />

technique and with something like ArteFill,<br />

you have to be in the dermal-subdermal junction.<br />

For other ones such as Restylane, you occasionally<br />

want to be more superficial in the fine wrinkles.<br />

For the marionette lines you might use a combination<br />

<strong>of</strong> threading and a cross-hatching technique<br />

or radial fanning.<br />

Dr. A. Carruthers: For permanent fillers, I have<br />

never seen movement <strong>of</strong> properly injected microdroplets<br />

<strong>of</strong> silicone oil. On the other hand, ArteFill<br />

(or Artecoll) is typically injected outside the muscle<br />

<strong>of</strong> the lip and seems to get pushed through and<br />

shows up on the mucosal surface. That’s presumably<br />

due to the action <strong>of</strong> the orbicularis oris.<br />

Dr. Cohen: The specific material in ArteFill has<br />

been studied very extensively in animals. The particles<br />

are not prone to migration because they are<br />

not able to be phagocytized.<br />

Dr. A. Carruthers: With ArteFill, the technique<br />

is very specific. You move the tip <strong>of</strong> the needle<br />

backward and forward, change the angle slightly,<br />

and lay microstrands in place to gently augment.<br />

It’s always better to undercorrect and come back.<br />

With Artecoll, I always plan on at least two, sometimes<br />

three or four injection sessions. You can put a<br />

temporary filler over the top and then as the temporary<br />

filler goes away, you can add more Artecoll.<br />

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Injection too deep. Injection too superficial. Correct plane for injection. (Lifted needle<br />

demonstrates the thickness <strong>of</strong> the dermis).<br />

Dr. Smith: The main thing is controlling pain and<br />

bruising. I’ve learned to use ice or ice plus vibration.<br />

We ice the intended injection point and the<br />

surrounding tissue for five or 10 seconds. The<br />

assistant usually holds the ice cube within a centimeter<br />

or two <strong>of</strong> the injection site. Patients are<br />

amazed. This technique has revolutionized my<br />

approach to fillers because I haven’t had to use an<br />

injectable or topical anesthetic since August 2005.<br />

Dr. Rubin: Lip border enhancement calls for a<br />

serial puncture technique. The (filler) material<br />

flows on its own down the tunnel. So even though<br />

the technique is not linear threading, it produces a<br />

similar effect. And in the meat or vermillion <strong>of</strong> the<br />

lip, I use serial puncture and then a lot <strong>of</strong> aggressive<br />

massaging in the lip, particularly when I<br />

inject hyaluronic acid.<br />

Dr. Joseph: Artecoll had initial problems because<br />

<strong>of</strong> poor injection technique. It was injected into the<br />

papillary dermis, which you never should do. The<br />

material itself wasn’t as refined as ArteFill is going<br />

to be, so they had some problems with granulomas<br />

and inflammation from too superficial placement.<br />

Which injection technique do you use for lip<br />

enhancement?<br />

Dr. A. Carruthers: I use a similar technique,<br />

bearing in mind that the FDA panel recommended<br />

that lips were a contraindication to the use <strong>of</strong><br />

ArteFill. I would caution people against using<br />

ArteFill in the lips until they cultivate sufficient<br />

expertise in its use in other areas.<br />

Dr. Nicolau: I do it the way I would for any kind<br />

<strong>of</strong> microsphere implant, including ArteFill. It is<br />

very important to prevent lip muscular movements,<br />

so right after the injection I use small<br />

amounts <strong>of</strong> botulinum toxin to weaken the lips for<br />

a few weeks. That way, patients won’t move their<br />

lips much, which prevents dislocation.<br />

Before Treatment.<br />

Nasolabial folds and radial lip<br />

lines 4 years after Artecoll<br />

(PMMA) injection.<br />

Dr. Graivier: I’ve done a lot <strong>of</strong> lip augmentations<br />

with Radiesse and I still have a 12% rate <strong>of</strong><br />

nodule formation. I usually use Restylane or<br />

Captique because patients want to see how they<br />

like their augmented lip, especially when they<br />

are having their lip augmented for the first<br />

time. I don’t recommend lip augmentation with<br />

Radiesse unless you are very experienced and<br />

comfortable treating the nodules that can result<br />

in 12% <strong>of</strong> patients. The edge <strong>of</strong> the lip, or the<br />

white roll, and philtrum column are nice areas for<br />

the longer-lasting or possibly even the permanent<br />

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products, because it doesn’t take a large volume<br />

<strong>of</strong> material. I do a nice linear threading technique<br />

precisely under the white roll and mold it with<br />

my fingers.<br />

What is the potential outcome when injections<br />

are too superficial?<br />

Dr. Cohen: If they’re too superficial, you can get<br />

ridges or bumps.<br />

Dr. Narins: It depends on the filler substance. If<br />

you inject Restylane too superficially, you can get a<br />

bluish color. If you inject Sculptra too superficially,<br />

you can get bumps that are impossible to get rid <strong>of</strong>.<br />

With Silicone or ArteFill you can get bumps as<br />

well. You want to go into the deep dermis with<br />

Artefill, but it’s probably okay to inject into the<br />

upper dermis.<br />

Dr. A. Carruthers: Too superficial typically<br />

means the injection is in the mid-dermis, inducing<br />

fibroplasia. You end up with a little bump that is<br />

<strong>of</strong>ten a little red. Histologically it may appear to<br />

be a granuloma. But when we’re talking about<br />

Artecoll, the granulomas have a very specific clinical<br />

appearance. They are the result <strong>of</strong> an abnormal<br />

reaction to the filler material rather than a natural<br />

reaction to a foreign body.<br />

Dr. Nicolau: With a permanent implant there<br />

may be palpability, and then nodular formation.<br />

There is also a risk <strong>of</strong> infection from contact with<br />

superficial bacteria through the hair follicle or<br />

sweat glands.<br />

What corrective measures should be used when<br />

injections are too superficial?<br />

Dr. Smith: You should be able to identify mistakes<br />

immediately, and then massage the product down<br />

into the deeper tissues right away. You can use<br />

your thumbnail.<br />

Dr. Rubin: With some fillers you can just nick the<br />

spot with the tip <strong>of</strong> a needle and express the injected<br />

material out. With hyaluronic acid gels you can<br />

inject hyaluronase to dissolve the hyaluronic acid.<br />

Dr. Narins: It’s very difficult to treat Sculptra<br />

nodules. Sometimes you have to physically remove<br />

them. Artecoll nodules are easy to treat with injections<br />

<strong>of</strong> cortical steroid. It’s easy to get rid <strong>of</strong><br />

Restylane by injecting Vitrase (hyaluronidase).<br />

Dr. Graivier: In longer-lasting and semi-permanent<br />

products, you can start with a conservative<br />

steroid injection (Kenalog 10%, 0.1 mL) and ask<br />

the patient to return in a month for a repeat injection<br />

if necessary. If the problem is very superficial,<br />

dermabrasion will dissipate the product.<br />

Dr. Cohen: The best measure is to avoid being<br />

too superficial with permanent fillers. They are<br />

more technique-sensitive than a temporary filler<br />

where if it doesn’t work out, the filler is gone in a<br />

few months. With permanent fillers, technique has<br />

to be much better.<br />

What is the potential outcome when injections<br />

are too deep?<br />

Dr. Friedland: If it’s too superficial, you may see<br />

it. If the filler has PMMA you may get a granuloma.<br />

I’ve never seen a granuloma from collagen or<br />

hyaluronic acid in all the years I’ve been doing this.<br />

Dr. Smith: Disappointment. If you go too deep,<br />

you’re just wasting product because you’re not<br />

going to get much correction. You just need to add<br />

a lot more product if you put it in too deep. I just<br />

apologize to the patient and do it again for free. By<br />

disciplining myself that way, I tend not to make<br />

that mistake very <strong>of</strong>ten.<br />

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<strong>Review</strong> <strong>of</strong> <strong>Long</strong>-<strong>Lasting</strong> <strong>Dermal</strong> <strong>Fillers</strong><br />

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Dr. A. Carruthers: Mainly, lack <strong>of</strong> efficacy. The<br />

idea is that if you inject just under the dermis,<br />

then you will get correction relatively easily. If you<br />

inject a bit further away from the dermis, the lifting<br />

effect is transmitted over a wider area so you<br />

don’t get as much lifting specifically where you<br />

want it, but you’re still getting exactly the same<br />

volume correction as you were going to get anyway,<br />

just that it’s a little bit deeper.<br />

hydrodissection. With Radiesse and ArteFill, I<br />

would treat early nodules with aggressive massage<br />

and a conservative Kenalog injection.<br />

Dr. Joseph: Skin slough, lumps, granuloma, and<br />

inflammation.<br />

Dr. Friedland: I was one <strong>of</strong> either the first or second<br />

group to use collagen and I have seen a few<br />

reactions to bovine collagen. Some last a year or<br />

more. I’ve never seen a reaction to human collagen.<br />

Correct plane and depth for injection <strong>of</strong> long-lasting dermal fillers.<br />

Dr. Narins: With some substances such as<br />

collagen (not the new collagen Evolence from<br />

Colbar), if the injection is too deep, it just disappears.<br />

With hyaluronic acid, Sculptra, fat, and<br />

ArteFill, there is no such thing as too deep in<br />

terms <strong>of</strong> serious problems.<br />

Dr. Narins: When done correctly, you see very few<br />

problems. I have seen other people’s complications,<br />

because I am very careful and also that’s what I do<br />

most <strong>of</strong> the time. I have seen lumps from fat that<br />

are very easy to treat, and nodules from overly<br />

superficial injections <strong>of</strong> Scupltra that are very difficult<br />

to treat. In Canada I’ve melted away Artecoll<br />

granulomas with intralesional cortisone.<br />

Dr. Nicolau: I’ve had one nodule that I had to<br />

remove surgically from a wrinkle on the lower lip.<br />

I injected a little too much filler. It was very easy<br />

to fix.<br />

Dr. J. Carruthers Commentary: The aesthetic<br />

benefit the patient achieves with temporary fillers<br />

is 90% technique and 10% substance. With permanent<br />

fillers, it’s 99% technique. The more permanent<br />

the filler is, the more important the technique is.<br />

Dr. Rubin: In the early stages <strong>of</strong> using any new<br />

filler there’s a learning curve. Some people we<br />

injected too deeply and some too superficially. All<br />

resolved on their own. I’ve seen small percentages<br />

<strong>of</strong> allergic reactions, but they’ve been uncommon<br />

with all the fillers we’ve used.<br />

Have you seen complications with these products<br />

in your patients?<br />

What is a granuloma?<br />

Dr. Graivier: It’s important to avoid over-correction<br />

and to bring the patient back in four to six<br />

weeks for follow-up, then add more filler if necessary.<br />

It’s always easier to add than to remove. The<br />

main complication early on is formation <strong>of</strong> nodules<br />

or firmness and clumping, especially with<br />

semi-permanent and permanent fillers. If you<br />

inject Sculptra and get clumping very early in the<br />

first week, you can try to break up the area by<br />

Dr. Graivier: A granuloma, by definition, is a<br />

hyperinflammatory reaction that occurs in every<br />

area that the product was injected at a period<br />

distant from when the initial injection was performed.<br />

This is distinct from a nodule. A nodule is<br />

earlier clumping <strong>of</strong> the product and not an inflammatory<br />

reaction. Treatment <strong>of</strong> a nodule is different<br />

from treatment <strong>of</strong> a granuloma. Every injectable<br />

product has documentation <strong>of</strong> late granulomas.<br />

20 <strong>Review</strong> <strong>of</strong> <strong>Long</strong>-<strong>Lasting</strong> <strong>Dermal</strong> <strong>Fillers</strong> www.miinews.com


Dr. Lowe: A chronic inflammatory reaction within<br />

the skin. It has a mixture <strong>of</strong> chronic inflammatory<br />

cells, <strong>of</strong>ten surrounding a foreign body (i.e., the filler).<br />

Dr. A. Carruthers: A granuloma has a specific<br />

histological appearance. With permanent fillers,<br />

granulomas are related to the size and nature <strong>of</strong><br />

the material injected. Small particles are more likely<br />

to be ingested by macrophages and to produce<br />

this kind <strong>of</strong> a reaction. There do seem to be other<br />

factors involved, one <strong>of</strong> which may be foci <strong>of</strong> infection<br />

elsewhere in the body, such as chronic dental<br />

disease, although that’s not as well established.<br />

Dr. Nicolau: A foreign body reaction is a normal<br />

reaction; a granuloma is an overreaction. The<br />

sheer injection <strong>of</strong> anything will induce a foreign<br />

body reaction. Any product, including collagen,<br />

hyaluronic acid, and so on can induce a granuloma<br />

or inflammatory reaction.<br />

Dr. Friedland: In essence it is the result <strong>of</strong> an<br />

injected substance setting up an antigen-antibody<br />

reaction. We call it a granuloma because it has a<br />

granular kind <strong>of</strong> a texture. It usually appears<br />

where the material was injected.<br />

Dr. Smith: It’s very rare to have a true granuloma.<br />

Nodules are most <strong>of</strong>ten technique-dependent and<br />

are not granulomas. Particularly with Artecoll, the<br />

common mistake that doctors make is being too<br />

ambitious; they inject too much filler in one visit or<br />

the visits were too close together. If you do that,<br />

sometimes you can feel it under the skin, and it’s<br />

just excess fullness and not a granuloma or nodule.<br />

granulomas, Alastair and I found that with conservative<br />

management, all the granulomas resolved<br />

within two years. The practice management problem<br />

is that patients with granulomas tend to<br />

oscillate from doctor to doctor, so it is difficult for a<br />

single physician to obtain long-term experience. To<br />

my knowledge, ours is the only recent long-term<br />

evaluation <strong>of</strong> a cohort <strong>of</strong> patients with granulomas.<br />

We have thus found that permanent fillers can<br />

cause transient problems, but not necessarily permanent<br />

problems.<br />

How do you recommend treating granulomas?<br />

Dr. Graivier: The main thing is not to excise a<br />

granuloma. Treatment has to be very aggressive<br />

by using both injectable steroids and oral steroids,<br />

and sometimes a mixture <strong>of</strong> 5-fluorouracil (5-FU)<br />

and triamcinolone. You can even resort to<br />

methotrexate if the granuloma does not respond to<br />

anything else.<br />

Lips with granuloma 3 years<br />

after Artecoll Injection.<br />

Same patient 1 year later. Granuloma<br />

resolved from triamcinolone injections.<br />

Photos courtesy <strong>of</strong> Alastair Carruthers, MD, FRCP<br />

Dr. Joseph: Most people will never form a granuloma<br />

to bovine collagen, but I’ve seen probably five<br />

<strong>of</strong> them. Why one person’s body reacts and another’s<br />

doesn’t, you never know.<br />

Dr. A. Carruthers: I inject triamcinolone acetonide<br />

in amounts sufficient to suppress the<br />

lumpiness. It is important to avoid injecting too<br />

much and producing steroid atrophy.<br />

Dr. J. Carruthers Commentary: Complications,<br />

including granulomas, can occur with any filler—<br />

not just permanent fillers. In a study <strong>of</strong> an<br />

unselected sequential group <strong>of</strong> patients with<br />

Dr. Smith: Most likely I’d inject Kenalog with a<br />

Becton-Dickinson 31-gauge diabetic needle. We<br />

like Kenalog because it’s a medium-potency, antiinflammatory<br />

steroid with a sustained effect.<br />

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<strong>Review</strong> <strong>of</strong> <strong>Long</strong>-<strong>Lasting</strong> <strong>Dermal</strong> <strong>Fillers</strong><br />

21


You can use this with areas <strong>of</strong> excess fullness too.<br />

Just don’t put in too much and don’t inject highstrength<br />

steroid. With 10 or 40 mg/mL you will go<br />

from a bump to a depression. The 3 mg/mL<br />

strength does a nice job. It’s better to treat lightly<br />

two or three times than to try to blow them away<br />

in one shot.<br />

volume diffusely and that will be particularly<br />

useful in old people for rejuvenating the dorsa <strong>of</strong><br />

the hands. Sculptra also improves the hands<br />

functionally by making the skin a little thicker<br />

and acting like a little bit <strong>of</strong> padding so people are<br />

less likely to injure their hands. Also rejuvenation<br />

<strong>of</strong> the neck.<br />

Dr. Lowe: I use intralesional dexamethasone or<br />

triamcinolone, or NSAIDs. I will also use long-term<br />

antibiotics (tetracyclines).<br />

Dr. Nicolau: It depends on the kind <strong>of</strong> filler.<br />

Granulomas are not treated in the same way<br />

according to the injected product. Some need corticoid,<br />

some need in situ-injected corticoid, and some<br />

need an antimitotic drug (5-FU).<br />

Dr. Friedland: If we can come up with a permanent<br />

filler that causes no reaction, is easy to put in,<br />

stays where it’s put, has a reasonable cost, has reasonable<br />

or no discomfort, and would be like body<br />

tissue, that’s the future. Its use can be purely cosmetic<br />

or in reconstruction; these two applications<br />

go hand-in-hand.<br />

Photos courtesy <strong>of</strong> Nelly Gauthier, MD<br />

Photos courtesy <strong>of</strong> Kevin C. Smith, MD, FRCPC<br />

NewFill Granuloma.<br />

Granuloma resolved after<br />

Kenalog injection.<br />

Neck lines <strong>of</strong> 45 year old woman<br />

before treatment.<br />

Neck lines after Hyaluronic Acid filler<br />

(Restylane) injections.<br />

What does the future hold for permanent fillers?<br />

Dr. Rubin: It’s certainly exciting. The main issue<br />

will be the degree <strong>of</strong> patient acceptance. A lot <strong>of</strong><br />

patient satisfaction or dissatisfaction will come<br />

from injection technique. If we have access to FDAapproved<br />

permanent fillers, it’s going to be<br />

important that everybody learns how to inject<br />

them because these fillers are not so forgiving.<br />

Dr. Smith: The next frontier will be volumizers,<br />

which can do things you don’t do with a focal filler.<br />

A classic one would be Sculptra. It just adds<br />

Dr. Graivier: Permanent fillers would be good in<br />

thick spots with fixation <strong>of</strong> skin and dermis down<br />

to the bone and muscle, such as the nasolabial<br />

folds. These areas only deepen with age.<br />

Marionette lines and prejowl areas will also be<br />

good for a permanent filler. The nose (with scars<br />

from skin cancers, depressions, post-rhinoplastic<br />

problems) and scars with thick, rigid attachment<br />

sites are also good sites for permanent fillers. For<br />

s<strong>of</strong>t tissue contouring such as cheek augmentation,<br />

or chin augmentation, I lean toward an agent<br />

in the semi-permanent range (1-5 years) because<br />

this s<strong>of</strong>t tissue falls and changes with age.<br />

22 <strong>Review</strong> <strong>of</strong> <strong>Long</strong>-<strong>Lasting</strong> <strong>Dermal</strong> <strong>Fillers</strong> www.miinews.com


Dr. Cohen: From a patient care perspective, the<br />

quest for permanent or semi-permanent fillers is<br />

to provide patients with something that has<br />

markedly longer duration. And that is the reason<br />

ArteFill was designed, to have an enduring, effective,<br />

and safe outcome, because that’s what<br />

patients have asked for. Temporary fillers are very<br />

useful, and there are many patients, in whom I<br />

think a temporary filler may be better to use until<br />

the patient has a sense <strong>of</strong> how they like the effect<br />

<strong>of</strong> the filler. Ultimately, the best permanent filler<br />

would be something from an autogenous source<br />

that would be long-lasting. Perhaps the addition <strong>of</strong><br />

stem cells or some type <strong>of</strong> factor that could stimulate<br />

angiogenesis and permit the body’s own cells<br />

(whether fat or other type) to survive, will one day<br />

come into play. For now, the quest continues.<br />

Dr. Nicolau: When fillers can be used as the<br />

equivalent <strong>of</strong> a permanent prosthesis, that would<br />

be ideal—correction <strong>of</strong> deep defects like nose deformities<br />

after surgery or deformities <strong>of</strong> the eyelid,<br />

where you need a deep volume.<br />

Dr. Narins: Eventually someone will distribute<br />

Silicone. ArteFill is expected to come on the market<br />

sometime in 2006, and I don’t think anything<br />

else that’s permanent is close to coming on the U.S.<br />

market right now. Physicians should have expertise<br />

in using all these fillers because one or a<br />

combination <strong>of</strong> them may be better suited, depending<br />

on the patient and situation. Skill is much<br />

more important with permanent products because<br />

the other products disappear.<br />

Photos courtesy <strong>of</strong> Steven Cohen, MD<br />

Photos courtesy <strong>of</strong> Gottfried Lemperle, MD<br />

Pre-treatment.<br />

1 year after PMMA<br />

(Artecoll) injection.<br />

5 years after PMMA<br />

(Artecoll) injection.<br />

10 year PMMA histology.<br />

Dr. Joseph: Pricing will be important. I’ll try anything<br />

if it’s FDA approved, but if it comes in at<br />

$1,000/mL people are going to say “forget it.” I<br />

think the consumer has been tapped out as far as<br />

the money they spend on fillers; they are not willing<br />

to pay the price every time a novel filler comes<br />

out. Even a revolutionary product like Sculptra is<br />

fairly expensive, and Radiesse, when it came out,<br />

was way too expensive. Companies may shoot<br />

themselves in the foot.<br />

Dr. J. Carruthers Commentary: The idea <strong>of</strong> a<br />

permanent filler is a highly alluring concept to the<br />

general public. Some individuals, however, assume<br />

that when the filler is injected, the effect is permanent<br />

and will somehow halt the aging process.<br />

Unfortunately the injected filler does not do this. It<br />

does give a more permanent fill, but if the facial<br />

skin thins and sags a little because <strong>of</strong> the loss <strong>of</strong><br />

collagen and elastin (as a natural part <strong>of</strong> aging),<br />

the aesthetic effect initially given by the filler may<br />

change over time. Further treatments may be<br />

required in subsequent months and years (as aging<br />

occurs) to maintain the initial aesthetic benefits.<br />

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23


CME Test Assessment<br />

1. What classifies a dermal filler as a volumizer?<br />

a. it causes a strong foreign body reaction<br />

b. it always contains collagen<br />

c. it causes little foreign body reaction<br />

d. it always contains microspheres<br />

6. What is a possible result from an injection<br />

that is too superficial?<br />

a. can cause granulomas<br />

b. allergic reaction<br />

c. can cause ridges or bumps<br />

d. painful for patient<br />

2. What classifies a dermal filler as a stimulator?<br />

a. it stimulates tissue ingrowth through a<br />

foreign body reaction<br />

b. it always contains a cellulose or bovine<br />

collagen carrier gel<br />

c. it always contains microspheres<br />

d. all <strong>of</strong> the above<br />

7. What is a possible result from an injection<br />

that is too deep?<br />

a. always causes lumps<br />

b. lack <strong>of</strong> efficacy<br />

c. causes bluish discoloration<br />

d. it will migrate<br />

3. What is dislocation?<br />

a. movement <strong>of</strong> filler by macrophages<br />

b. mechanical movement <strong>of</strong> filler material<br />

c. dissipation <strong>of</strong> filler through dermis<br />

d. a chemical reaction<br />

8. What is the correct dermal plane for<br />

long-lasting fillers ?<br />

a. the epidermal-dermal junction<br />

b. the papillary dermis<br />

c. the dermal-subdermal junction<br />

d. the subcutaneous fat<br />

4. What is migration?<br />

a. movement <strong>of</strong> filler by manipulation<br />

b. only related to silicone fillers<br />

c. mechanical movement <strong>of</strong> filler material<br />

d. movement <strong>of</strong> filler by macrophages<br />

5. Which <strong>of</strong> the following is true<br />

about bovine collagen?<br />

a. it prevents clustering <strong>of</strong> microparticles<br />

b. allergenicity rates vary by product<br />

c. skin testing is required<br />

d. all <strong>of</strong> the above<br />

9. What is a granuloma?<br />

a. clumping <strong>of</strong> the filler<br />

b. same thing as a nodule<br />

c. reaction caused only by hyaluronic acid<br />

d. a late, chronic inflammatory reaction <strong>of</strong> all<br />

injected sites<br />

10. What is the primary treatment option<br />

for granulomas?<br />

a. surgical excision<br />

b. treatment with steroid creams<br />

c. injection <strong>of</strong> intralesional corticosteroids<br />

d. observation<br />

24 <strong>Review</strong> <strong>of</strong> <strong>Long</strong>-<strong>Lasting</strong> <strong>Dermal</strong> <strong>Fillers</strong> www.miinews.com


CME Registration<br />

<strong>Review</strong> <strong>of</strong> <strong>Long</strong>-<strong>Lasting</strong> <strong>Dermal</strong> <strong>Fillers</strong><br />

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To receive CME credit for the completion <strong>of</strong> this activity, mail or fax the completed Registration, Post Test,<br />

and Evaluation Forms located at the back <strong>of</strong> this publication to: Ciné-Med, Inc., CME Department, 127 Main<br />

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CME Test Assessment Answer Sheet<br />

Please complete the post-test by circling the correct answer on the answer sheet. You must achieve<br />

a score <strong>of</strong> 70% or greater in order to have demonstrated understanding <strong>of</strong> the content.<br />

1. a b c d<br />

6. a b c d<br />

2. a b c d<br />

7. a b c d<br />

3. a b c d<br />

8. a b c d<br />

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Evaluation<br />

<strong>Review</strong> <strong>of</strong> <strong>Long</strong>-<strong>Lasting</strong> <strong>Dermal</strong> <strong>Fillers</strong><br />

Please rate each question on a scale <strong>of</strong> 5 to 1, with 5 being the highest and 1 being the lowest.<br />

1. Objectives: To what extent were the objectives achieved? Excellent Poor<br />

A. Identify the mechanism <strong>of</strong> action for CaHA, LIS,<br />

PLA & PMMA dermal fillers (volumizer vs. stimulator). 5 4 3 2 1<br />

B. Identify the difference between dislocation and migration 5 4 3 2 1<br />

<strong>of</strong> filler material.<br />

C. Identify the characteristics <strong>of</strong> bovine collagen. 5 4 3 2 1<br />

D. Identify the outcomes for various injection planes. 5 4 3 2 1<br />

E. Define granulomas and their primary treatment option. 5 4 3 2 1<br />

2. Content: To what extent did the program: Excellent Poor<br />

A. Increase your knowledge <strong>of</strong> the topic. 5 4 3 2 1<br />

B. Present clear and organized content. 5 4 3 2 1<br />

C. Meet your personal / educational objectives. 5 4 3 2 1<br />

D. Help to improve patient care. 5 4 3 2 1<br />

E. Cause you to make changes in your practice. 5 4 3 2 1<br />

If you felt the content was not free <strong>of</strong> commercial bias, please explain: ___________________________<br />

__________________________________________________________________________________________________<br />

3. Overall Activity: 5 4 3 2 1<br />

4. How long did it take you to complete this program? ________<br />

Are there any educational topics that are not being sufficiently addressed?<br />

__________________________________________________________________________________________________<br />

__________________________________________________________________________________________________<br />

__________________________________________________________________________________________________<br />

To receive CME credit, please mail or fax completed registration, post-test, and evaluation forms to:<br />

Cine-Med, Inc., CME Department, 127 Main Street North, Woodbury, CT 06798 Fax: 203-263-4839<br />

26 <strong>Review</strong> <strong>of</strong> <strong>Long</strong>-<strong>Lasting</strong> <strong>Dermal</strong> <strong>Fillers</strong> www.miinews.com


Notes


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