Soft Tissue Augmentation E-Book
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Soft Tissue Augmentation E-Book


Obtenez un accès à la bibliothèque pour le consulter en ligne
En savoir plus
401 pages

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Soft Tissue Augmentation, 3rd Edition helps you make optimal use of these techniques and provide the optimum results your patients expect. Drs. Alistair and Jean Carruthers provide you with evidence-based, procedural how-to's and step-by-step advice on proper techniques, pitfalls, and tricks of the trade, equipping you to successfully incorporate the very latest procedures into your busy practice!

  • Consult this title on your favorite e-reader, conduct rapid searches, and adjust font sizes for optimal readability. Compatible with Kindle®, nook®, and other popular devices.

  • Offer your patients the best care and avoid pitfalls. Evidence-based findings and practical tips equip you with the knowledge you need to recommend and discuss the most effective treatment options with your patients.

  • Proceed confidently with current, to-the-point guidance on the cosmetic use of traditional and new fillers edited by pioneers in the field, Drs. Jean and Alastair Carruthers. 
  • Expand your repertoire and refine your skills with a wealth of color illustrations, photographs, and procedural videos (including lip augmentation and treatment of hands and feet) depicting cases as they appear in practice.
  • See how non-invasive cosmetic procedures apply to real-life situations with new case studies and pearls throughout.
  • Stay on top of cutting-edge techniques and topics including darker skin and fillers; platelet rich plasma; and tower technique of filler injection as well as new and novel non-permanent fillers including Elastin and Soft Tissue Augmentation; and a combination of Carboxymethyl Cellulose (CMC) and Polyethylene Oxide (PEO).
  • Take advantage of a dynamic and up-to-date focus on the latest soft tissue techniques with 25 new chapters and the unmatched guidance of expert contributors - many new to this edition.
  • Browse the fully searchable text online at Expert Consult, along with expanded video content and downloadable images.


Derecho de autor
United States of America
Surgical incision
Platelet-rich plasma
The Only Son
Maintenance therapy
Chronic progressive external ophthalmoplegia
Pharmaceutical formulation
Medical procedure
Silicone oil
Dermatologic surgeon
Mycophenolate mofetil
Carboxymethyl cellulose
Polylactic acid
Adverse event
Reconstructive surgery
Surgical oncology
Medical record
Sun protection
Biological agent
Diabetic neuropathy
Caucasian race
Pain management
Soft tissue
Health care
Tetralogy of Fallot
Clinical trial
Oxidizing agent
Local anesthetic
Poly(methyl methacrylate)
Randomized controlled trial
X-ray computed tomography
Data storage device
Growth factor
Major depressive disorder
Cutis laxa
Polyméthacrylate de méthyle
Baby Boom
Maladie infectieuse


Publié par
Date de parution 26 septembre 2012
Nombre de lectures 0
EAN13 9781455737772
Langue English
Poids de l'ouvrage 2 Mo

Informations légales : prix de location à la page 0,0426€. Cette information est donnée uniquement à titre indicatif conformément à la législation en vigueur.


Soft Tissue Augmentation
Procedures in Cosmetic Dermatology Series (Expert Consult-Online and Print)
Third Edition

Jean Carruthers, MD, FRCSC, FRC (OPHTH), FASOPRS
Clinical Professor, Department of Ophthalmology and Visual Science, University of British Columbia, Vancouver, BC, Canada

Alastair Carruthers, MA, BM, BCh, FRCPC, FRCP(Lon)
Clinical Professor, Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
Table of Contents
Instructions for online access
Cover image
Title page
Series Preface First edition
Chapter 1: Introduction
Chapter 2: Fillers: evolution, regression, and the future
Fat as a filling agent
Collagen (Zyderm®, Zyplast®, Cosmoderm®, Cosmoplast®, Evolence®)
Hyaluronic acids (Restylane®, Perlane®, Juvéderm® Ultra, and Ultra Plus)
Poly-L-lactic acid (Sculptra®)
Calcium hydroxylapatite (Radiesse®)
Polymethylmethacrylate (Artefill®)
Chapter 3: NASHA™ family
Basic science
Choosing the right NASHA™
Patient evaluation
Patient preparation
Physician preparation
Treatment techniques
Site-specific treatment strategies
Postoperative care and complication management
Chapter 4: Juvéderm® family
Juvéderm formulations
Contraindications and safety considerations
Using Juvéderm®
Clinical choices
Volumizing with Juvéderm® gels
Chapter 5: Non-permanent fillers: Belotero®/Esthélis® and Teosyal®
Hyaluronic acid dermal fillers
Chapter 6: Radiesse® / Radiesse® with lidocaine
Indications for calcium hydroxylapatite
Specific characteristics of calcium hydroxylapatite
Mechanism of action
Injection techniques
Adverse events
Comparative research studies
Outcomes in subjects with Fitzpatrick skin types IV–VI
Safety outcome of calcium hydroxylapatite
Large-particle calcium hydroxylapatite injection
Patient satisfaction
Chapter 7: Poly-L-lactic acid
Product and mechanism of action
Poly-L-lactic acid: technical considerations
Prevention and treatment of adverse events
Patient selection, expectations, and satisfaction
Pathophysiology of the aging face: structural and morphologic
Chapter 8: Artefill®: a third-generation polymethylmethacrylate in collagen soft tissue filler
Patient selection / treatment areas
Patient evaluation and injection technique
Pitfalls and how to correct them
Post-injection care
Clinical trials
Efficacy at 5 years compared with efficacy at 6 months
Chapter 9: New and novel fillers: highlighting elastin and soft tissue augmentation, platelet-rich plasma and a combination of carboxymethyl cellulose (CMC), and polyethylene oxide (PEO)
Elastin and soft tissue augmentation
Platelet-rich plasma (PRP)
Carboxymethyl cellulose plus polyethylene oxide dermal filler (Laresse®)
Chapter 10: Liquid injectable silicone
Basic science
Mechanism of action
Indications and patient selection
Patient preparation
Injection technique
Side effects and managing complications
Chapter 11: Aquamid®
Patient selection
Technique / treatment
Chapter 12: Bio-Alcamid®
Clinical use of Bio-Alcamid®
Complications of Bio-Alcamid®
Chapter 13: Forehead and temporal recontouring using calcium hydroxylapatite pre-mixed with lidocaine
Patient evaluation
Selecting the right filler
Materials, injection sites, and injection techniques
Safety considerations and adverse events
Conclusion and discussion
Chapter 14: Glabella/central brow
Epidemiology and patient selection
Anatomical considerations
Decision-making: selection and preparation of filler product, selection of injection plane
Pre-procedural consultation, assessing and preparing the patient
Injection technique
Post-procedural course and recovery
Avoidance and management of adverse events
Tips for maximizing patient satisfaction
Chapter 15: Volumetric treatment of the brows
The ‘local preview’
The injection
Intra-arterial injection
Who is a candidate for brow volume treatments?
Chapter 16: Infraorbital hollow and nasojugal fold
Candidates for augmentation of the infraorbital hollow
Appropriate filling agents
Augmentation techniques
Adjunctive therapy
Chapter 17: Nose
The attractively proportioned nose and face
Ethnic differences
Vascular patterns of the nose (Fig. 17.3)
Types of filler
Injection technique (Fig. 17.4)
Injection techniques by nasal region
Injection techniques by each type of nose
Adverse effects
Chapter 18: Cheeks
Anatomical and technical considerations when filling the cheeks
Poly-L-lactic acid and hydroxylapatite
Volumizing hyaluronic acid
Chapter 19: Perioral filling
Anatomical considerations
Ideal filling agents for perioral rejuvenation
Pain management
Injection techniques
Perioral complications
Chapter 20: Lip augmentation
The aging process on the lips
An approach to achieving youthful lips
Filler products
Injection techniques for lip rejuvenation
Potential side effects
Chapter 21: Melomental folds
Basic principles for melomental fold correction
Injection strategies for melomental fold correction
Choosing the proper filler
Adjunctive treatments
Chapter 22: Hands and feet
Soft tissue augmentation of the hands
Soft tissue augmentation of the feet
Chapter 23: Buttocks
Aesthetic characteristics of the buttocks
Gluteal augmentation with fat grafting
Correction of gluteal depressions with hyaluronic acid gels
Chapter 24: Earlobe rejuvenation
Anatomy and classification of earlobes
Use of fillers for earlobe rejuvenation
Chapter 25: Tower technique of filler injection
Anatomical considerations
Biological characteristics of filler materials
New concepts in injection techniques
Chapter 26: Complications of temporary fillers
Injection site reactions
Edema and ecchymosis
Nodules and papules
Inflammation (hypersensitivity reactions)
Chapter 27: Complications of permanent fillers
Products (Box 27.1, Table 27.1)
Treatment sites
Evaluation methods
Chapter 28: Reversers
Filler complications
Other enzymatic reversers
Conservative ‘reversers’
Antibiotics, corticosteroids, and 5-fluorouracil
Invasive reversal techniques
Chapter 29: Consent for photography: legal issues
Fillers used in investigational studies
Medical education, teaching, or publicity
Media photography during filler injections
Telemedicine or internet
Maintenance of photographs and other images
Liability reduction
Chapter 30: Pre- and post-treatment photography
Technical considerations
Viewing photographs at follow-up
Chapter 31: Conclusions
How will medical fillers change?

SAUNDERS is an imprint of Elsevier Inc.
© 2013, Elsevier Inc. All rights reserved.
Figures 4.1 – 4.3 © William P. Coleman III MD
First edition 2005
Second edition 2008
Third edition 2013
No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: .
This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility.
With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.
ISBN: 978-1-4557-2782-7
Ebook ISBN: 978-1-4557-3777-2

Printed in China
Last digit is the print number: 9 8 7 6 5 4 3 2 1
Seven years ago we embarked on an effort to produce Procedures in Cosmetic Dermatology , a series of high quality, practical, up-to-date, illustrated manuals. Our plan was to provide dermatologists, dermatologic surgeons, and others dedicated to the pursuit of functional knowledge with detailed portable books accompanied by high quality “how to” DVD’s containing all the information they needed to master most, if not all, of the leading edge cosmetic techniques. Thanks to the efforts of world class volume editors, master chapter authors, and the tireless and extraordinary publishing staff at Elsevier, the series has been more successful than any of us could have imagined. Over the past seven years, 15 distinct volumes have been introduced, and have been purchased by thousands of physicians all over the world. Originally published in English, many of the texts have been translated into different languages including Italian, French, Spanish, Chinese, Polish, Korean, Portuguese, and Russian.
Our commitment has always been to ensure that the practical, easy to use information conveyed in the series is also extremely up-to-date, incorporating all the latest methods and materials. To that end, given the rapidly changing nature of our subspecialty, the time has now come to inaugurate the third edition. During the next few years, refined, enlarged, and improved texts will be released in a sequential manner. The most time-sensitive books will be revised first, and others will follow.
This series is an ever evolving project. So in addition to third editions of current books, we will be introducing entirely new books to cover novel procedures that may not have existed when the series began. Enjoy and keep learning.

Jeffrey S. Dover, MD FRCPC, Murad Alam, MD, MSCI
Series Preface First edition
While dermatologists have been procedurally inclined since the beginning of the specialty, particularly rapid change has occurred in the past quarter century. The advent of frozen section technique and the golden age of Mohs skin cancer surgery has led to the formal incorporation of surgery within the dermatology curriculum. More recently technological breakthroughs in minimally invasive procedural dermatology have offered an aging population new options for improving the appearance of damaged skin.
Procedures for rejuvenating the skin and adjacent regions are actively sought by our patients. Significantly, dermatologists have pioneered devices, technologies and medications, which have continued to evolve at a startling pace. Numerous major advances including virtually all cutaneous lasers and light-source-based procedures, botulinum exotoxin, soft tissue augmentation, dilute anesthesia liposuction, leg vein treatments, chemical peels, and hair transplants have been invented, or developed and enhanced by dermatologists. Dermatologists understand procedures and we have special insight into the structure, function, and working of skin. Cosmetic dermatologists have made rejuvenation accessible to risk-averse patients by emphasizing safety and reducing operative trauma. No specialty is better positioned than dermatology to lead the field of cutaneous surgery while meeting patient needs.
As dermatology grows as a specialty, an ever-increasing proportion of dermatologists will become proficient in the delivery of different procedures. Not all dermatologists will perform all procedures, and some will perform very few, but even the less procedurally directed amongst us must be well versed in the details to be able to guide and educate our patients. Whether you are a skilled dermatologic surgeon interested in further expanding your surgical repertoire, a complete surgical novice wishing to learn a few simple procedures, or somewhere in between, this book and this series are for you.
The volume you are holding is one of a series entitled ‘Procedures in Cosmetic Dermatology’. The purpose of each book is to serve as a practical primer on a major topic area in procedural dermatology.
If you want to make sure you find the right book for your needs, you may wish to know what this book is and what it is not. It is not a comprehensive text grounded in theoretical underpinnings. It is not exhaustively referenced. It is not designed to be a completely unbiased review of the world’s literature on the subject. At the same time, it is not an overview of cosmetic procedures that describes these in generalities without providing enough specific information to actually permit someone to perform the procedures. And importantly, it is not so heavy that it can serve as a doorstop or a shelf filler. What this book and this series offer is a step-by-step, practical guide to performing cutaneous surgical procedures. Each volume in the series has been edited by a known authority in that subfield. Each editor has recruited other equally practical-minded, technically skilled, hands-on clinicians to write the constituent chapters. Most chapters have two authors to ensure that different approaches and a broad range of opinions are incorporated. On the other hand, the two authors and the editors also collectively provide a consistency of tone. A uniform template has been used within each chapter so that the reader will be easily able to navigate all the books in the series. Within every chapter, the authors succinctly tell it like they do it. The emphasis is on therapeutic technique; treatment methods are discussed with an eye to appropriate indications, adverse events, and unusual cases. Finally, this book is short and can be read in its entirety on a long plane ride. We believe that brevity paradoxically results in greater information transfer because cover-to-cover mastery is practicable.
We hope you enjoy this book and the rest of the books in the series and that you benefit from the many hours of clinical wisdom that have been distilled to produce it. Please keep it nearby, where you can reach for it when you need it.

Jeffrey S. Dover, MD FRCPC

Murad Alam, MD

“May you live in exciting times” (Chinese proverb)
This Chinese proverb is actually referred to as “the Chinese curse” when the word “exciting” is replaced with the original word “interesting”. But exciting is just exactly where the new world of fillers is. So, with great humility we offer this transposition.
Since our second edition in the Procedures in Cosmetic Dermatology Series, there have been major changes in the design and pattern of usage of fillers: a radical change from a two dimensional intracutaneous to three dimensional subcutaneous volumizing approach.
The use of CT and MRI scans has given a pictorial and thus believable improvement in our understanding of the various causes of facial deflation. We always saw the loss of facial fat associated with aging, but improved understanding of specific facial fat compartmentalization with age-related atrophy and descent has enabled us to more accurately reflate collapsed compartments. Loss and inward rotation of facial bone in upper, mid and lower face begins earlier in women than in men, but the trends in age related bony atrophy are just as important in creating the aged, tired appearance of “middle age”.
The improvement in our understanding of facial skin descent and expansion (dermatochalasis) due to collagen and elastin loss, its treatment and prevention have iced the facial cake. An appreciation of the similarities and differences in treating facial skin in all Fitzpatrick and Glogau skin types is so important. We must respect the differences in the aging process in skin of colour. The instinctive cultural approach to the proportions of facial beauty has been enhanced by improvements in our mathematical understanding of desirable facial proportions in different cultures. After all, it is important to put the replacement volume where it will be seen to improve the facial aesthetic.
The most commonly used two and three dimensional fillers are the Hyaluronic Acid-derived family. They are reliable to work with and well tolerated in human tissue because of the commonality of HA morphology through nature (so no skin testing is required).
The concept of filler eraseability has further elevated the popularity of the HA fillers and hyaluronidase is in every office. Currently collagenase (Xiaflex) is only approved for the treatment of Dupuytren’s contractures, but we anticipate that it may be proven to be of use in collagen-formed lumps and nodules. Moreover, when other fillers come to market we can hope that an “eraser” will be available at the same time.
Longer lasting semi-permanent and permanent fillers also have their place in our therapeutic armamentarium. The calcium hydroxylapatite fillers, poly-L lactic acid, liquid injectable silicone and PMMA in bovine collagen suspension are all approved for facial augmentation, and we expect more classes of fillers to become available.
Finally, we turn to the most important feature of all: our patients! No-one likes pain, and the introduction of mixing local anesthetic with fillers spearheaded by Marianno Busso MD has indeed allowed many more patients to avail themselves of this successful treatment. His work has stimulated us to “dilute” fillers so as to produce a smoother result with fewer lumps.
Finally, we feel the world of fillers will change yet again with their perception as drugs not devices. In other words, using the presence of a filler to cause collagen deposition and long-term natural correction is a very important concept.
The filler world has expanded dramatically in the past few years. We hope that you enjoy this world as much as we do.


Jean Carruthers
Vancouver, BC, Canada
July 2012

Raúl Banegas, MD
Director, Plastic Surgery, Centro Arenales, Buenos Aires, Argentina

Frederick C. Beddingfield, III BA, MPhil, PhD, MD
Assistant Clinical Professor of Medicine, Division of Dermatology, David Geffen School of Medicine, University of California at Los Angeles; Vice President and Global Head, Dermatology Clinical R and D, Allergan Inc., Irvine, CA, USA

Dario Boccanera, MD
Chief of Plastic Surgery, Ospedale Fatebenefratelli, Milan, Italy

Trevor M. Born, MD, BSc, FRCS(C)
Private Practice, Toronto, ON, Canada and New York, NY, USA; Lecturer, Department of Plastic and Reconstructive Surgery, University of Toronto, ON, Toronto, Canada

Harold J. Brody, MD
Clinical Professor of Dermatology, Emory University School of Medicine, Atlanta, GA, USA

Heike Buntrock, MA
Research Assistant, Department of Cosmetic Science, Division of Chemistry, University of Hamburg, Hamburg, Germany

Mariano Busso, MD
Senior Attending, Internal Medicine, Mercy Hospital, Miami, FL, USA

Valerie D. Callender, MD
Associate Professor of Dermatology, Howard University College of Medicine, Washington, DC; Medical Director, Callender Dermatology and Cosmetic Center, Glenn Dale, MD, USA

Steven R. Cohen, MD, FACS
Private Practice, FACESplus Aesthetic Facility, La Jolla, CA; Clinical Professor, Division of Plastic Surgery, University of California, San Diego, CA; Director, Craniofacial Surgery, Rady Children’s Hospital of San Diego, CA, USA

Kyle M. Coleman, MD
Board Certified Dermatologist, Private Practice, Austin, TX, USA

William P. Coleman, III MD
Clinical Professor, Department of Dermatology; Adjunct Professor, Department of Surgery (Plastic Surgery), Tulane University Health Sciences Center, New Orleans, LA, USA

W. Patrick Coleman, IV MD
Dermatologist, Private Practice, New Orleans, LA, USA

Davi de Lacerda, MD, FAAD
Dermatologist, Clinica Médica Dr. Davi de Lacerda, São Paulo; Researcher, Brazilian Center for Dermatological Studies (CBED), Porto Alegre, RS, Brazil

Jeffrey S. Dover, MD, FRCPC, FRCP
Associate Professor of Clinical Dermatology, Yale University School of Medicine, New Haven, CT; Adjunct Professor of Medicine (Dermatology), Dartmouth Medical School, Hanover, NH; Adjunct Associate Professor of Dermatology, Brown Medical School, Providence, RI; Director, SkinCare Physicians, Chestnut Hill, MA, USA

Steven Fagien, MD, FACS
Private Practice, Aesthetic Eyelid Plastic Surgery, Boca Raton, FL, USA

Neil F. Fernandes, MD
Chief Resident, Department of Dermatology, The Mount Sinai School of Medicine, New York, NY, USA

Rebecca Fitzgerald, MD
Dermatology Private Practice, Los Angeles; Assistant Clinical Instructor, Dermatology, University of California, Los Angeles (UCLA), Los Angeles, CA, USA

Timothy C. Flynn, MD
Clinical Professor, Department of Dermatology, University of North Carolina, Chapel Hill, NC; Medical Director, Cary Skin Center, Cary, NC, USA

Marc D. Glashofer, MD, MS
Director, Mohs Surgery and Cosmetic Dermatology, Island Dermatology, Long Beach, NY, USA

Richard G. Glogau, MD
Clinical Professor of Dermatology, University of California Medical Center, San Francisco, CA, USA

David J. Goldberg, MD, JD
Director, Skin Laser and Surgery Specialists of New York and New Jersey, Hackensack, NJ; Clinical Professor of Dermatology and Director of Laser Research, Mount Sinai Medical School, New York, NY; Clinical Professor of Dermatology and Director of Dermatologic Surgery, UMDNJ-New Jersey Medical School, NJ; Adjunct Professor of Law, Fordham Law School, New York, NY, USA

Greg J. Goodman, MBBS, FACD, MD
Associate Professor, Monash University; Chief of Surgery, Skin and Cancer Foundation Inc, Carlton, VIC, Australia

Emmy M. Graber, MD
Assistant Professor, Department of Dermatology, Boston University; Director, Boston University Cosmetic and Laser Center; Associate Director, Resident Training Program, Boston University, Boston, MA

Vanessa Hartmann, MD
Medical Doctor, Division of Evidence-Based Medicine, Klinik für Dermatologie, Charité-Universitätsmedizin Berlin, Berlin, Germany

David J. Howell, PhD, RRT
Independent Medical Writer, San Francisco, CA, USA

Shannon Humphrey, MD, FRCPC, FAAD
Clinical Instructor, Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada

Derek H. Jones, MD
Associate Clinical Professor, Dermatology, University of California at Los Angeles; Founder and Director, Skin Care and Laser Physicians of Beverly Hills, Los Angeles, CA, USA

Michael S. Kaminer, MD
Assistant Professor of Clinical Dermatology, Yale University School of Medicine, New Haven, CT; Adjunct Assistant Professor of Medicine (Dermatology), Dartmouth Medical School, Hanover, NH; Adjunct Assistant Professor of Dermatology, Brown Medical School

Martina Kerscher, MD, PhD
Professor; Dermatologist, Department of Cosmetic Science, Division of Chemistry, University of Hamburg, Hamburg, Germany

Jenny Kim, MD, PhD
Associate Clinical Professor of Clinical Medicine, Division of Dermatology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles; Chief of Dermatology, Department of Dermatology, Veterans Affairs Greater Los Angeles Healthcare System Veterans Affairs, Los Angeles, CA, USA

Haydee M. Knott, MD
Cosmetic Dermatologic Surgery Fellow, Department of Dermatology, University of California San Francisco, San Francisco, CA, USA

Val Lambros, MD, FACS
Assistant Clinical Professor, Plastic Surgery, University of California at Irvine, Irvine, CA, USA

Nicholas J. Lowe, MD, FRCP, FACP
Consultant Dermatologist, Cranley Clinic, London, UK; Clinical Professor of Dermatology, UCLA School of Medicine, Los Angeles, CA, USA

Philippa Lowe, MB, ChB, LLB
Clinician and Research Physician, Cranley Clinic, London, UK

Ian A. Maher, MD, FAAD
Assistant Professor, Mohs Surgeon, Department of Dermatology, Virginia Commonwealth University, Richmond, VA, USA

Bassel H. Mahmoud, MD, PhD
Resident, Department of Dermatology, Henry Ford Hospital, Detroit, MI, USA

Stephen H. Mandy, MD, FAAD
Director, South Beach Dermatology; Volunteer Professor, University of Miami Department of Dermatology, Miami, FL, USA

Kavita Mariwalla, MD
Assistant Clinical Professor, Department of Dermatology, Columbia University, New York, NY, USA

Gary D. Monheit, MD, FAAD, FACS
Private Practice, Total Skin and Beauty Dermatology Center, PC; Associate Clinical Professor, Departments of Dermatology and Ophthalmology, University of Alabama at Birmingham, Birmingham, AL, USA

Rhoda S. Narins, MD
Medical Director, Dermatology Surgery and Laser Center; Clinical Professor of Dermatology New York University Medical Center; Chief of Dermatology Emeritus at White Plains Hospital Medical Center, New York, NY, USA

Andrew A. Nelson, MD
Assistant Clinical Professor, Department of Dermatology, Tufts University School of Medicine, Boston, MA; Private Practice, Nelson Dermatology, St. Petersburg, FL, USA

David M. Ozog, MD, FAAD
Director of Cosmetic Dermatology; Vice-Chair of Operations, Division of Mohs and Dermatological Surgery, Henry Ford Hospital, Detroit, MI, USA

Rita V. Patel, MD
Dermatopharmacology Fellow, Department of Dermatology, Mount Sinai School of Medicine, New York, NY, USA

Chad L. Prather, MD
Surgical Director, Department of Dermatology, Louisiana State University Health Sciences, Center School of Medicine, New Orleans, LA; Private Practice, Dermasurgery Center, Baton Rouge, LA, USA

Berthold J. Rzany, MD, ScM
Private Practice for Dermatology and Aesthetic Medicine, Rzany and Hund, Berlin, Germany

Nazanin Saedi, MD
Laser and Cosmetics Fellow, SkinCare Physicians, Chestnut Hill, MA, USA

Gerhard Sattler, MD
Fellow of Dermatology; Clinical Director of Rosenparkklinik, Darmstadt, Germany

Kyle Koo-II. Seo, MD, PhD
Clinical Associate Professor, Dermatology, Seoul National University College of Medicine; Director, Dermatology, Modelo Clinic, Seoul, Korea

Massimo Signorini, MD
Chief of Surgery, Istituto Dermatologico Europeo, Milan, Italy

Kevin C. Smith, MD, FRCPC
Private Practice, Niagara Falls Dermatology and Skin Care Centre Ltd., Niagara Falls, Ontario, Canada

Hema Sundaram, MD, FAAD
Founder and Medical Director, Sundaram Dermatology, Cosmetic & Laser Surgery, Rockville, MD, USA

Ada R. Trindade de Almeida, MD
Dermatologist, Dermatologic Clinic, Hospital do Servidor Público Municipal de São Paulo and private office, São Paulo, Brazil

Heidi A. Waldorf, MD
Associate Clinical Professor, Department of Dermatology, Mount Sinai School of Medicine, New York; Director, Laser & Cosmetic Dermatology, Department of Dermatology, Mount Sinai Medical Center, New York; Private Practice, Waldorf Dermatology & Laser Associates, PC, Nanuet, NY, USA

Susan H. Weinkle, MD
Private Practitioner, Bradenton, FL, USA; Assistant Clinical Professor, Dermatology, University of South Florida, Bradenton, FL, USA

Anthony S. Weiss, PhD
Professor, Molecular Bioscience, University of Sydney, Sydney, NSW, Australia

Robert A. Weiss, MD, FAAD, FACPh
Associate Professor, Johns Hopkins University School of Medicine; Director, Maryland Laser Skin and Vein Institute, Baltimore, MD, USA

Luitgard G. Wiest, MD
Private Practice, AB-Privatärztliches Zentrum München, Munich, Germany

Birgit Woerle, MD
Dermatologist; Phlebologist, Rosenparkklinik, Darmstadt, Germany
Dr Stuart Maddin is the godfather of Canadian dermatology. When we first returned to Vancouver from our postgraduate training in 1977, Alastair was enticed to write part of Stuart’s latest textbook. This led to San Francisco fellowships in 1982: in dermatologic surgery for Alastair and in the ophthalmological use of botulinum toxin A for Jean. Stuart’s vision of the future of procedural dermatology has since been proven indelibly and we are both so grateful to him for his charm, intellect, continuous energy and belief in our work.
Fortunately for this new world of fillers, the demographics were perfect. The baby boom generation was just starting to deflate as bovine collagen was FDA approved in the early 1980s! In these very early days we were also surrounded by dermatologists who were equally fascinated by the revolutionary new ability to treat the aging process: Hal Brody, Bill Coleman, Rick Glogau, Arnie Klein, Nick Lowe, Steve Mandy, Gary Monheit, Rhoda Narins, Sam Stegman, Ted Tromovitch, and Luitgard Wiest, amongst others. We have learned so much from you all: you have made this path the best!
A look at the authors of this book will show that the magic continues: new ideas, superb chapter contributions and videos have come from the Coleman family, from Steve Fagien, Shannon Humphrey, Derek Jones, Bert Rzany, Kyle Seo, Ada Trindade de Almeida, and Susan Weinkle, amongst others. We thank you.
Our office clinical and research teams are responsible for huge amounts of data collection, photography and patient followup. Without their dedication and their joy in this work we would never have the data to write about and teach with. We humbly thank you all.
Our three sons, their partners and our grandsons have given us so much love and encouragement over the years. We love you all and we cherish all the times we have shared together. Now that this book is finished, there will be even more time!
Jean and Alastair Carruthers
We dedicate this volume to our children and their families. Our sons were young when the botulinum toxin story began and they have regarded the efforts of their parents to cope with this accidental discovery with tolerance and increasing pride over the years. We have appreciated the support and encouragement they have given us (rather than the other way round). The love they have given us means we are indeed fortunate!


Jean Carruthers
To the women in my life: my grandmothers, Bertha and Lillian, my mother, Nina, my daughters, Sophie and Isabel, and especially to my wife, Tania. For their never-ending encouragement, patience, support, love, and friendship
To my father, Mark – a great teacher and role model; to my mentor, Kenneth A. Arndt for his generosity, kindness, sense of humor, joie de vivre, and above all else curiosity and enthusiasm

Jeffrey S. Dover
Elsevier’s dedicated editorial staff has made possible the continuing success of this ambitious project. The new team led by Belinda Kuhn, Martin Mellor and the production staff have refined the concept for the second edition while maintaining the series’ reputation for quality and cutting-edge relevance. In this, they have been ably supported by the graphics shop, which has created the signature high quality illustrations and layouts that are the backbone of each book. We are also deeply grateful to the volume editors, who have generously found time in their schedules, cheerfully accepted our guidelines, and recruited the most knowledgeable chapter authors. And we especially thank the chapter contributors, without whose work there would be no books at all. Finally, I would also like to convey my debt to my teachers, Kenneth Arndt, Jeffrey Dover, Michael Kaminer, Leonard Goldberg, and David Bickers, and my parents, Rahat and Rehana Alam.

Murad Alam
1 Introduction

Jean Carruthers, Alastair Carruthers

Summary and Key Features

• Volumization is the key to aesthetic success with facial fillers
• Changes in the concept of beauty, visualization of age-related changes in the face, and validated assessment scales have aided in achieving optimal outcomes
• Reversers and better pain management have enhanced augmentation procedures
• The future holds great promise and expectation for fillers as both drug and delivery vehicle
We have come full circle in the aesthetic approach to the face with soft-tissue-augmenting agents. The volumizing effect of the first filler – autologous fat – was studied over a century ago when it was harvested and inserted into the face. With the development of synthetic fillers, such as hyaluronans, calcium hydroxylapatite, poly- l -lactic acid, and silicone, it became possible to inject fillers specifically into different tissue layers, although still using a two-dimensional approach along visible linear lines, folds, and wrinkles. The emergence of fillers with superior lift capabilities, while still maintaining the desired position, opened the door to the concept of volumizing as not only a possibility but also the accepted norm for achieving optimal aesthetic results, in addition to more superficial filler placement.
In addition to the manufacture of tissue-friendly, long-lasting fillers, we have become aware of more etiologic detail about the anatomical structure of facial aging. Computed tomography (CT), magnetic resonance imaging (MRI) scans, and anatomical cadaver dissection have allowed us to visualize accurately the underlying bony structures, the facial fat pads, and the changes in the overlying facial skin. Studies of a new, descriptive language of age-related facial changes with sequential photographic facial scales have been published, demonstrating their value in improving communication not only with our patients in our clinics, but also with each other as we work toward better treatments, often in multiple research centers simultaneously.
Patient-reported outcomes (PROs) have become the standard for assessing treatment outcomes from the client’s point of view. Published validated questionnaires, such as the Facial Line Outcomes (FLO) and Self-Perception of Age (SPA), can be used easily in the clinic as well as in the research setting. Several validated PROs are used both by patients and by the treating and evaluating physician – such as the Lip Fullness Scale (LFS) and Look and Feel of the Lips (LAF) scale, as well as the severity scales for Perioral Lines at Rest (POL), Perioral Lines at Maximum Contraction (POLM), and Oral Commissure Severity (OCS). Aesthetic medical research has introduced a new outstandingly important paradigm – the patient’s opinion – into the worlds of medical treatment and research.
Mathematical evaluation of facial beauty has also been helpful in trying to achieve the outcomes desired in all cultures. Most interestingly, although there is a trend toward ‘average’ beauty, there is some differentiation between cultures. Whereas the concept of ‘phi’ and the Fibonacci numbers has been well studied in Caucasian actresses and models, the same precepts do not necessarily hold in subjects of Asian ancestry. The Buddha believed the beautiful female face should be ‘round like the moon’ with rosebud lips, connoting fertility and purity respectively. By contrast, the ‘Marquardt mask’ (a model of the ideal human face constructed from the ‘golden ratio’) seems to fit the more heart-shaped Caucasian face. Asian and African lip fullness and proportion also diverge from the Caucasian standards of beauty – in which the upper lip is often about two-thirds the size of the lower – with equal fullness of both upper and lower lips.
Local anesthesia for facial injections has largely evolved away from trigeminal nerve blocks (which also relax the muscles of facial expression, making the end point harder to judge). Instead, topical anesthesia applied directly to the skin and adding lidocaine, or lidocaine with epinephrine, to the filling agent effectively manages pain in most areas of the face. The addition of saline to dilute the filler decreases cohesiveness, allowing for smooth delivery and the ability to distribute the product evenly by gentle massage.
Reversibility has also become a cornerstone of facial filler injections. Hyaluronidase is an enzyme that will catabolize any hyaluronic acid (HA) filler, sometimes within 24 hours. New classes of fillers may be produced with custom-made ‘erasers’ in the future. Post-treatment bruising can now be treated immediately using intense pulsed light at moderate settings (4(10)4, 560 nm filter, four passes), which allows the bruise to be absorbed within 24–48 hours instead of 7–10 days.
Lastly, Voorhees and Glogau have pointed out that fillers used to be considered devices, rather than drugs. However, the concept of fillers as mechanical lifting agents has been joined by the recognition of filling effects on the daily metabolism of the skin. We know now that cross-linked HA increases collagen deposition around the filler, leading to long-term correction. Moreover, we have all noted the increased luminosity of the skin in cheeks augmented by HA. Many of us have considered using fillers as vehicles to deliver drugs, cosmeceuticals, and stem cells that could affect the elasticity, turgor, and texture of aging skin into the subcutaneous space.
The past century has seen an explosion of development of new fillers and their global acceptance by a patient population that would rather look restored and younger without the trauma and downtime of surgery. Indeed, the introduction of non- or minimally invasive injectable procedures represents a significant shift in the approach to facial rejuvenation. According to the American Society of Plastic Surgeons, the use of filling agents increased by 144% between 2000 and 2008 in the USA, from fewer than 700 000 to 1.6 million procedures performed – a figure that increased by an additional 11.3% by 2010. This trend is expected to continue: through 2013, worldwide sales of dermal fillers are expected to expand by more than 8.4% per year on average (from nearly $800 million in 2008 to more than $1.1 billion) in 2013.

Further reading

American Society of Plastic Surgeons. Report of the 2009 statistics. National Clearinghouse of Plastic Surgery Statistics. Online. Available , 2010. 12 October 2011
American Society of Plastic Surgeons. Report of the 2010 statistics. National Clearinghouse of Plastic Surgery Statistics. Online. Available , 2010. 12 October 2011
Carruthers A, Carruthers J, Hardas B, et al. A validated lip fullness rating scale. Dermatologic Surgery . 2008;34(suppl 2):S161–S166.
Carruthers A, Carruthers J, Hardas B, et al. A validated marionette lines rating scale. Dermatologic Surgery . 2008;34(suppl 2):S167–S172.
Carruthers A, Carruthers J, Hardas B, et al. A validated crow’s feet rating scale. Dermatologic Surgery . 2008;34(suppl 2):S173–S178.
Carruthers A, Carruthers J, Hardas B, et al. A validated hand grading rating scale. Dermatologic Surgery . 2008;34(suppl 2):S179–S183.
Carruthers JDA, Glogau R, Blizter A, the Facial Consensus Group Faculty. Advances in facial rejuvenation: botulinum toxin type A, hyaluronic acid dermal fillers, and combination therapies: consensus recommendations. Plastic and Reconstructive Surgery . 2008;121(suppl):S5–S30.
Carruthers J, Carruthers A, Monheit GD, et al. Multicenter, randomized, parallel-group study of onabotulinumtoxinA and hyaluronic acid dermal fillers (24-mg/mL smooth, cohesive gel) alone and in combination for lower facial rejuvenation: satisfaction and patient-reported outcomes. Dermatologic Surgery . 2011;36(suppl 4):2135–2145.
Carruthers J, Flynn TC, Geister TL, et al. Validated assessment scales for the mid face. Dermatologic Surgery . 2012;38:32–332.
Fagien S, Carruthers J. A comprehensive review of patient reported satisfaction with botulinum toxin type A for aesthetic procedures. Plastic and Reconstructive Surgery . 2008;122:1915–1925.
Medical Insight. Facial injectables: maintaining volume as the economy recovers. Online. Available , 2010. 12 October 2011
2 Fillers
evolution, regression, and the future

Richard G. Glogau, Haydee M. Knott

Summary and Key Features

• The first pre-modern era filler was fat
• The first commercial modern era US Food and Drug Administration (FDA)-approved filler was bovine collagen
• The first non-commercial modern era non-FDA approved filler was silicone
• Collagen was offered in 0.5 mL and 1 mL syringes for correction of ‘two-dimensional’ problems, i.e. wrinkles, scars
• Collagen had two major problems: delayed hypersensitivity and brief duration
• The introduction of botulinum toxin eliminated dynamic movement as a cause of wrinkles and lines, and allowed true volume deficits to be appreciated
• The introduction of hyaluronic acid (HA) gel fillers from Europe was a game changer, initially because of duration of effect; other benefits were seen later
• With HAs, attention shifted from ‘two-dimensional’ to ‘three-dimensional’ problems, i.e. from lines and wrinkles to subcutaneous atrophy and fat loss
• Fillers that followed, e.g. polylactic acid, calcium hydroxylapatite, polymethylmethacrylate, focused more on host response and endogenous collagen production than true volume replacement, mimicking the phenomenon seen with micro-droplet silicone
• Almost all fillers in the foreseeable future are entering the USA from Europe
• Newer fillers seek ability to control length of duration, enhanced stimulation of dermal collagen, reversibility, and greater lift
The chronology of the development of soft tissue augmentation in the field of dermatology has followed a distinctly non-linear path. The remarkable arrival of literally dozens of injectable filler materials on the modern European, global, and domestic scenes is, however, a direct reflection of the increasingly sophisticated understanding of the aesthetic challenges of the human face. What began with the introduction of collagen as a treatment for a line or wrinkle led to use of fillers for treatment of dynamic lines of facial expression, e.g. nasolabial folds, and most recently to the concept of volumizing the face. This progression of the conceptual understanding of treating the aging face has moved from the flat world – two-dimensional problems such as a static wrinkle – to incomplete solutions for the dynamic lines of movement – e.g. glabellar lines with filler. It is fascinating that the initial movement into three-dimensional correction began with the dramatic improvement seen in lip volume with the initial collagen fillers championed by Arnold W. Klein MD in the 1980s. This initial success in volume correction sustained both the product and our interest in volume as a therapeutic goal for many years, but clearly the lack of duration of the product and the inability to achieve significant volume correction with 1 mL syringes of collagen hampered the recognition of volume correction in non-lip areas: mid-face, temple, brow, and perioral tissue – where the newer fillers are so much more effective. But the litany of fillers that follows shows that each filler has come along at a different point as we moved from static lines, to dynamic lines, to volume and the problem of three dimensions in the face.

Pearl 1
The US market is lacking the range of ‘fine line’ products that are available in Europe. Nothing has replaced collagen for the management of fine lines.
After the introduction of botulinum toxin to the physician’s arsenal, muscle movement could be eliminated as a contributing factor to facial aging and the true impact of volume loss could be more completely appreciated. We began to understand that the partial responses seen with fillers in dynamic lines of expression were overshadowed by the dramatic effect of botulinum toxin on movement in the glabella, and the transition to three-dimensional thinking was under way. Suddenly fillers were needed to address the atrophy of the tissues beneath the skin – a process that changed the round faces of youth to the flat and hollow convexities of aging faces. With the demographics of the post-World War II ‘baby boomers’, the need for volume replacement has never been more obvious and multiple targets for soft tissue augmentation lay before us: premalar cheeks, mid-face, chin, jowl sulcus, cheek hollows, the brow, etc., etc.
Yet vestiges of the initial single line wrinkle-fillers linger on, specifically the 1 mL syringes that still dominate the marketplace. How is the volume of filler originally designed to treat a line / wrinkle supposed to provide the quantities of volume required for all the three-dimensional filling that we and our patients now require? One might as well expect to play an entire symphony with a single stringed violin as to meet all the aesthetic demands of the aging human face with a 1 mL syringe. But let us turn to the early 1970s, when the modern filler era truly began.

Fat as a filling agent
The first attempts at soft tissue augmentation revolved around the surgical use of fat. Dr Neuber is recognized as the first to perform human fat auto-grafting. In a documented presentation in 1893, he stated that he had performed successful fat auto-grafting for several years. Dr Neuber performed auto-graft transfer in a 20-year-old man suffering from a tuberculous ostitis in childhood leaving him with a deeply retracted scar below the infraorbital margin. Dr Neuber incised a small piece of subcutaneous fat, corresponding to the size of the scar, which he then inserted and sutured leaving a nice cosmetic result.
But the modern era of fat transplantation awaited the development of liposuction surgery in 1974 by Dr Giorgio Fischer MD in Rome, and in 1978 by Drs Yves-Girard Illouz MD and Pierre Fournier MD in Paris. In the 1980s Dr Fournier began micro-lipoinjections in which 13-gauge needles attached to ordinary syringes could be used to collect fat for transplantation. The issue with fat transplantation was that longevity varied from patient to patient. Average fat survival rates were from 25% to 30% persistence when injected into the cheeks, forehead, and nasolabial folds. Despite the abundance of readily available donor material, the procedures were cumbersome, required separate local anesthesia, involved greater risks of bruising, etc., and were generally more time consuming than using an off-the-shelf injectable filler agent such as collagen. The attraction of fat as a filling agent faded in the late 1980s, and has recently become of greater interest with the current research into fat as a source of stem cells. However, in the 1970s the first novel filling agent of the modern era was collagen.

Collagen (Zyderm ® , Zyplast ® , Cosmoderm ® , Cosmoplast ® , Evolence ® )
Collagen is the most abundant protein in skin. Collagen implant material was first developed by four Stanford doctors in the early 1970s: Rodney Perkins, John Daniels, Edward Lock, and Terrence Knap. In 1977, they reported the successful injection of human-, rabbit-, and rat-derived collagen into subcutaneous tissue of rats. This successful experiment led them to try injecting the scars and depressions of volunteers with both human- and bovine-derived collagen. These volunteers had a 50–85% improvement that was sustained over 3–18 months. Following extensive clinical trials in the late 1970s, Zyderm ® 1 implant (35 mg/mL of solubilized collagen) was approved by the US Food and Drug administration in 1981 ( Fig. 2.1A ), and Zyderm ® 2 (65 mg/mL of solubilized collagen) was approved in 1983. Both products were a relatively non-viscous suspension that allowed for injection through a 30-gauge needle. Because 2–3% of treated patients developed localized allergic reactions associated with these injections, pre-treatment skin testing with 0.1 mL subcutaneous challenges was recommended prior to using the Zyderm ® 1 and 2 implants.

Figure 2.1 The first 18 years of modern soft tissue filling were dominated by collagen: ( A ) Zyderm ® , a bovine product, and later ( B ) Cosmoplast ® , a human-derived collagen.
The principal champion of collagen was Dr Arnold Klein, who reported the use of injectable bovine collagen in more than 1000 patients in 1983. At that time, he noted success in treating supple acne scars, steroid- or disease-induced areas of atrophy, glabellar furrows, crow’s feet, post-rhinoplasty irregularities, depressed skin grafts, and various other soft tissue defects such as depressed scars that could be distended. He stressed overcorrection of defects and a superficial placement of the injectables.
Drs Stegman & Tromovitch published their experience with injectable bovine collagen and included their observations in a text on cosmetic dermatologic surgery in 1984 and a second edition in 1990. In the early 1980s numerous investigators reported treatment for these same indications and also for residual cleft lip scars, facial hemiatrophy, and depressed Mohs surgery scars. As of 1983, more than 10 000 patients had been treated with Zyderm ® collagen.
All forms of injectable bovine collagen were mildly immunogenic. The threat of bovine spongiform encephalopathy from prion disease mandated the use of closed herds as the only suitable source of solubilized collagen. Non-bovine collagen sources were developed from human tissue culture lines, which eliminated the allergic reactions seen with the bovine products. Cosmoderm ® and Cosmoplast ® ( Fig. 2.1B ) had very different flow characteristics than Zyderm ® and Zyplast ® and lacked the allergic profile of bovine collagen, but their very limited duration of effect (generally 3–4 months) and the desire to move away from protein-based fillers led to their abandonment by the marketplace once the hyaluronic acid (HA) gels arrived on the scene. But for 18 years, from 1981 to 2003 when Restylane ® was approved by the FDA, collagen was the only commercially available FDA-approved product in the US market. The only other product that was in use during that period was silicone, and it had a more checkered history to be reviewed later. The true expansion of the commercially available fillers in the US market came instead with the introduction of the HA gels.

Hyaluronic acids (Restylane ® , Perlane ® , Juvéderm ® Ultra, and Ultra Plus)
HA was discovered from the vitreous humor of cows. HA is the main polysaccharide in human extracellular matrix tissue. It acts as a scaffold for collagen and elastin to bind to. Because it binds to water, it augments and hydrates the skin. The skin loses HA as it ages, which leads to decreased movement and elasticity. HA, when used in commercial filler agents, consists of repeating polymer chains of the polysaccharide with interval cross-links of agents that bind the polymers together. By varying the type of cross-linking material and its amount, the characteristics of the gel can vary in the degree of hardness, amount of lift, duration of survival, and resistance to degradation by heat or enzymes. At present the source of the HA used in commercial products is bacterial, leading to the designation of this class of fillers as NASHA ™ (non-animal-sourced hyaluronic acid gel) gel, which distinguishes them from the earlier bovine and human-sourced collagen products. Hyaluronic gel products can be found either as biphasic types, in which varying sized particles predominate, or as monophasic types, in which the HA is a homogeneous solution.
After years of use outside the USA, Restylane ® (Q-med, Uppsala, Sweden) became the first HA to enter the US market with FDA approval on 12 December 2003, 9 months after the FDA approval of the Cosmoderm ® human collagen implants (see ). This was a watershed event that marked the end of 17 years of domination of the US filler market by the collagen products. Restylane ® ( Fig. 2.2A ) has an HA concentration of 20 mg/mL with a gel bead size of 250 µmol and 100 000 units per mL; there is an estimated 0.5–1.0% cross-linking with butanediol diglycidyl ether. Perlane ® (Q-med, Uppsala, Sweden) contains 20 mg/mL of HA with a larger gel bead size of 1000 µmol and 10 000 units per mL, and less than 1% cross-linking. Perlane ® is positioned as a more robust HA filler in the Q-med line.

Figure 2.2 ( A ) The ‘game changer’ Restylane ® and ( B ) the market leader Juvéderm ® both created unprecedented demand for filler as they represented a quantum leap over earlier collagen technology.
The ephemeral nature of some fillers in the US market can be illustrated by the fate of Hylaform ® (Inamed, Santa Barbara, CA), which the FDA approved in April 2004. Hylaform ® had 5.5 mg/mL of HA and 20% cross-linking with divinyl sulfone. Hylaform Plus ® (Inamed, Santa Barbara, CA), approved on 13 October 2004, had 5.5 mg/mL, larger gel particle size, and 20% cross-linking. Both products were HA gels derived from rooster cockscombs; they were withdrawn because of the market’s desire to move away from animal-sourced products and the lack of duration of effect of the less concentrated Hylaform ® . In addition Inamed, the manufacturer of Hylaform ® , was acquired by Allergan in 2006. By this acquisition Allergan obtained distribution rights to the competing HA filler, Juvéderm ® ( Fig. 2.2B ), which is manufactured by Corneal Laboratories (Pringy, France). Juvéderm ® is a homogeneous rather than particular form of HA gel and has become the leading product in the US market. Allergan then completed its purchase of Corneal in January 2007, leaving no further purpose for Hylaform ® in the Allergan portfolio.
HA fillers as a class have become the most popular type of filler in the US market and, in one form or another, worldwide. They are reversible with hyaluronidase, which is an important safety consideration. They provide more immediate ‘lift’ than the collagens, last much longer, and require no allergy skin testing prior to treatment. They can be easily injected through a small-gauge needle, and they eliminate the problems of products that contain animal-derived protein. As a result they have virtually eliminated collagens from the market.

Pearl 2
Reversibility of the hyaluronic acid products remains an overwhelming advantage for products that are completely elective in the current use.
The next class to consider is the so-called ‘stimulant injectables’: those that rely to varying degrees upon the host response of fibroplasia to produce a change in tissue volume. The oldest of these is silicone.

The term ‘silicone’ was initially coined by a British chemist to describe a family of polymers containing the element silicon. Siloxane is an acronym used to describe compounds containing repeating units of silicone, oxygen, and methane. Silicone was explored by Dow Corning Corporation to produce materials for the military in the 1940s. The first medical use of silicone rubber was by Dr De Nicola in 1950, when it was used to make a prosthesis of a urethra in a man who was unable to void. The liquid silicones used for medical purposes are long polymers of dimethylsiloxanes. Injectable silicones are colorless, odorless, tasteless clear fluids whose viscosity varies according to the degree of polymerization.
In 1959, the Dow Corporation introduced medical grade silicone. It established a center for research called the Aid to Medical Research in which it distributed medical grade silicone to physicians. The use of silicone soon took off and Dow created a special plant and registered it with the FDA. In 1963 Dow developed a more purified medical grade 360 silicone. The ‘360’ refers to centistokes viscosity of the agent. Dow Corning 360 was injected into subcutaneous tissues of rats and human volunteers and it was noted to cause minimal inflammation and was well tolerated. However, complications from silicone were reported when large volumes were injected. The FDA determined that silicone injections would be considered ‘drug use’. It was observed by Ben-Hur and colleagues to form paraffinoma-like granulomas on histological examination. Dow soon developed a highly purified medical grade silicone called MDX 4-4011. An FDA-approved investigation was halted in 1967, then in 1978 the FDA narrowed its scope of the study of silicone. In the 1970s and 1980s, several studies were published (e.g. by Selmanowitz & Orentreich) that purported the safety of the microdroplet technique. Studies by Barnett & Barnett and Zappi et al also reported that injection of minute amounts with a fine-bore needle was safe and effective with very few adverse effects.
Silikon 1000 ® ( Fig. 2.3A ) is a silicone oil with a viscosity of 1000 centistokes. It was approved for use in postoperative retinal tamponade during vitreoretinal surgery. Under the FDA’s modernization act of 1997, the so-called ‘off-label’ use of approved products and devices by licensed physicians is recognized as a legitimate process by which the scope and practice of medicine are enlarged and expanded. Many dermatologists use Silikon 1000 ® ‘off label’ for the treatment of acne scars, HIV lipodystrophy, traumatic fat atrophy, rhinoplasty defects, and some facial aging where volume repair gives an effective result. Illegal use of adulterated industrial grade silicone fluids by laypersons continues to produce sensational adverse reactions including deaths – a reality that has colored the public’s perception of this valuable tissue augmentation agent. Illegal use of non-medical-grade product, together with the controversy surrounding silicone breast implants fanned by FDA Commissioner David Kessler MD in 1992 when he called for a ban on silicone implants, meant that silicone has remained in the background as a filler for some time. The lack of interest of commercial sponsorship of necessary long-term safety studies virtually guarantees it will remain an ‘off-label’ use for the foreseeable future.

Figure 2.3 ( A – D ) Variations on the theme, generally presented as stimulatory agents that promote collagen response in the host. Currently they are all FDA approved, but remain niche products rather than enjoying the broad market appeal of the hyaluronans.

Poly-L-lactic acid (Sculptra ® )
The FDA accepted ‘non-inferiority’ comparative trials to evaluate the fillers that came after collagen. Perhaps as a result of these clinical trial designs, manufacturers continued to present the marketplace with single syringes of approximately 1.0 mL in volume. However, the HIV epidemic created a compelling need for volume restoration because of the pan-facial atrophy associated with HIV / AIDS and protease inhibitor therapies. The FDA approved poly- l -lactic acid (PLLA) (Dermik, Laboratories, Berwyn, PA) in August 2004 for the correction of facial atrophy secondary to HIV and therapy for AIDS. Off-label use for areas such as the nasolabial folds began almost immediately. The FDA then granted a second approval for treatment of nasolabial folds and facial wrinkles to the sponsor, Sanofi-Aventis US, in August 2009, and it is marketed as Sculptra ® ( Fig. 2.3B ). PLLA is a filler with durations reportedly of as much as 18–24 months. Treament requires that the filler be prepared in advance using sterile preserved water and that the patient come in for a series of three injections over the course of several months. The PLLA material is thought to stimulate fibroblasts in the host to produce collagen. The volume of PLLA injected in any one session usually approaches 5–10 mL. Although PLLA continues to have its advocates, the initial failure to appreciate the need for dilution prior to use, lack of reversibility, and dependence on multiple treatments to achieve results have limited wider utilization of the product. The desire to achieve ‘permanent’ results has spurred the introduction of other products that promise, and occasionally deliver, the possibility of longer durations – among them fillers that contain particles that resist biological degradation, such as calcium hydroxylapatite and polymethylmethacrylate (PMMA).

Calcium hydroxylapatite (Radiesse ® )
Calcium hydroxylapatite (Radiesse ® , now owned by Merz Aesthetics, formerly BioForm Medical, WI) was FDA approved on 22 December 2006 for the augmentation of moderate to severe facial lines and folds and for facial soft tissue loss from HIV-related lipoatrophy ( Fig. 2.3C ). It consists of 30% concentration of 25–45 µm calcium hydroxylapatite spherical particles suspended in sodium carboxymethylcellulose gel. It lasts approximately 1 year or more in most patients. It is inherently biocompatible because it is identical in composition to bone material. Off-label use has included volume restoration for dorsal hands and post-rhinoplasty contour correction. Lack of immediate reversibility and contraindication for use in the lips limit applicability to some extent, but the product has a steady niche market.

Polymethylmethacrylate (Artefill ® )
PMMA is composed of non-resorbable PMMA 20% and 80% bovine collagen and was FDA approved as Artefill ® ( Fig. 2.3D ) in October 2006 (Artes Medical, San Diego, CA) following earlier European use as Artecoll ® dating from 1998. Following corporate upheaval involving the original management under the founder, Gottfried Lemperle, the product was purchased out of bankruptcy in 2009 by Cowen Healthcare Royalty Partners and reorganized as Suneva Medical. Artefill ® is a chemically inert and biocompatible synthetic implant used in bone and dental implants. Skin allergy pre-screening tests are needed owing to bovine collagen content. The body degrades the collagen carrier within 1–3 months. The PMMA microspheres are non-biodegradable and their persistence is extremely long lasting to permanent. The use of PMMA is appropriate for patients with well-defined deep facial wrinkle lines. Granulomas appear to be less common with the current product, down to 0.01% range, but sensitivity to the bovine collagen component and the animal derivation of the collagen remain issues. Clinical trials for acne scarring are reportedly under way following reports (e.g. by Epstein & Spencer) of utility in this indication.

Pearl 3
Many practitioners add lidocaine 1.0–2.0% with or without epinephrine to achieve added pain control and to minimize bruising associated with needle trauma.

Pearl 4
Monotherapy has gone the way of the silent movies. Current therapies use fillers, neurotoxins, energy-based systems, and topical therapy to refill, relax, rejuvenate, and retexture the facial skin.


‘Après nous le deluge’
Mme de Pompadour, 1757
The list of filler products that are commercially available outside of the USA is protean. While admittedly many of these are refinements of existing technologies (better cross-linking, different particle size, combined with anesthetic, etc.), many are new classes of products that are different from those currently available in the USA ( Fig. 2.4 ), e.g. polyacrylamide gels, cross-linked dextran, carboxymethylcellulose, hypromellose, etc. There are over 200 commercial products outside the USA. But we would predict that we shall see fillers moving beyond the traditional concept of inert medical devices into the realm of true biologicals: materials that will improve the texture, elasticity, radiance, and possibly color, of the skin itself. Just as the last 40 years has been the movement from two to three dimensions, the next two decades will see movement from the macro- to the microlevel and fillers will become systems for active metabolic manipulation and protection of the aging skin. The challenge for us as clinicians will be to sort through the hype and be able to choose the products that will offer the balance of risk and benefit. Given the preternatural attraction of the public for the newest and the greatest, we will have our work cut out for us.

Figure 2.4 Examples of only two products pursuing FDA approval: the first is a polyacrylamide gel, Aquamid ® , which is a permanent injectable gel implant; the second, Ellansé ® , contains polycaprolactone smooth microspheres suspended in an aqueous carboxymethylcellulose gel vehicle. There will be many more fillers pursuing approval in the US market, to be sure.

Pearl 5
Future fillers may further the metabolic host response currently seen, leading to some confusion in the regulatory sphere over devices versus drugs.

Pearl 6
The ideal filler is yet to arrive.

Conflicts of interest

Dr. Glogau has served as a consultant and/or clinical investigator to Allergan, Medicis, Merz, Contura and earlier to Collagen Corporation and Innamed. Dr. Knott has no financial conflicts of interest to disclose.

Further reading

Barnett JG, Barnett CR. Treatment of acne scars with liquid silicone injections: 30-year perspective. Dermatologic Surgery . 2005;31(11 pt 2):1542–1549.
Epstein RE, Spencer JM. Correction of atrophic scars with Artefill: an open-label pilot study. Journal of Drugs in Dermatology . 2010;9(9):1062–1064.
Fischer G. First surgical treatment for modelling the body’s cellulite with three 5-mm incisions. Bulletin of the International Academy of Cosmetic Surgery . 1976;2:35–37.
Fournier PF. Facial recontouring with fat grafting. Dermatology Clinics . 1990;8(3):523–537.
Fournier PF, Otteni FM. Lipodissection in body sculpturing: the dry procedure. Plastic and Reconstructive Surgery . 1983;72(5):598–609.
Illouz YG. Body contouring by lipolysis: a 5-year experience with over 3000 cases. Plastic and Reconstructive Surgery . 1983;72(5):591–597.
Kessler D. Statement on silicone gel breast implants. [cited 11 November 2011]. Online. Available , 1992.
Klein AW. Implantation technics for injectable collagen. Two and one-half years of personal clinical experience. Journal of the American Academy of Dermatology . 1983;9(2):224–228.
Knapp TR, Kaplan EN, Daniels JR. Injectable collagen for soft tissue augmentation. Plastic and Reconstructive Surgery . 1977;60(3):398–405.
Kupper T. Suneva giving wrinkle filler another try [cited 2 November 2011]. Online. Available , 2009. – article
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Zappi E, Barnett JG, Zappi M, et al. The long-term host response to liquid silicone injected during soft tissue augmentation procedures: a microscopic appraisal. Dermatologic Surgery . 2007;33(suppl 2):S186–S192. discussion S192
3 NASHA™ family

Gary D. Monheit, Rhoda S. Narins, Kavita Mariwalla

Summary and Key Features

• NASHA™ are a safe, reliable class of dermal fillers that have low potential for allergic response
• NASHA™ fillers are non-permanent and thus ideal to use for treatment-naïve patients and for beginning injectors as they can be easily dissolved with hyaluronidase
• The type of injection technique selected (serial puncture, linear, fanning or cross-hatching) should be based on anatomical site
• Common areas for injection include the nasolabial folds, followed by the melolabial folds, jowls, and lips. Injection into the glabella is contraindicated owing to the risk of necrosis unless it is used with a tiny needle and injected superficially pulling back on the plunger before injection
• Depth of the fold or amount of volume replacement required are the key components to consider prior to product brand selection
• NASHA™ fillers can be layered on top of each other or on top of other semipermanent fillers
• Hyaluronic acid fillers can last from 3 to 6 months depending on location and amount of product previously injected; they last for longer in areas of low mobility and shorter in areas of greater movement
• Postoperative sequelae are usually edema and bruising lasting only a few days

The use of an exogenous material to augment soft tissue can be traced back to Neuber in 1893, who used fat transplanted from the arms to correct facial defects. Since that time, substances used to volumize the face have changed rapidly and include both biodegradable and non-biodegradable products. The class of compounds known as non-animal stabilized hyaluronic acids (‘NASHA™’) comprises biodegradable fillers with an average duration of action of 6–12 months. This chapter will review the current NASHA™ products available in the US marketplace and provide injection tips for the most common facial areas injected. Potential complications will be presented, as will advice on how to manage patient expectations.

NASHA™ are commonly used to correct moderate to severe facial lines and restore volume loss that occurs during the natural course of aging. Since the US Food and Drug Administration (FDA) approval of Restylane ® in December 2003, the NASHA™ injectable market has continued to expand. According to the American Academy of Aesthetic Plastic Surgeons, there were approximately 1 315 121 hyaluronic acid (HA) injections performed in 2010 alone, with an estimated $1.9 billion spent on injectables in general. This does not include procedures performed by dermatologists or other healthcare practitioners.
Knowing where to place these fillers is as important as understanding the subtle differences between them. In general, NASHA™ injectables are safe, confer a soft look, and are predictable in their volumizing capacity.

Basic science
HA or hyaluronan is an anionic, hydrophilic, non-sulfated glycosaminoglycan that is abundant in human connective tissue. The chemical structure of this substance is uniform throughout Nature and lacks a protein component allowing it to have little to no potential for immunologic reaction in humans when injected. As one of the chief components of the extracellular matrix, HA stabilizes intercellular structures and forms part of the fluid matrix in which collagen and elastic fibers become embedded. The average 70 kg person has approximately 15 g of hyaluronan in the body, of which one-third is degraded and synthesized daily.
HA contributes to cell proliferation and migration as well as tissue repair. With age, HA concentration in the skin decreases, resulting in reduced dermal hydration, which manifests as an increase in lines and folds. In addition, excessive exposure to ultraviolet B rays causes cells in the dermis to stop producing HA. In its natural form, the half-life of HA is 1–2 days and is metabolized by the liver to carbon dioxide and water. As a compound, it can absorb up to 1000 times its molecular weight in water; its mechanism of action as a filler is mainly through hydration.
The hyaluronic acid molecule is stabilized with cross-linked hydroxyl groups. It is this cross-linking that confers longevity to the product in the skin and the degree of cross-linking one of the distinguishing features of NASHA™ products. Because of this structural matrix, the degradation curve of implanted HA is not linear. Rather, the product retains its effect until the structural complex around the HA molecule is broken down. Once the unbound HA is exposed, efficacy is then lost ( Fig. 3.1 ). As a result, patients will often suddenly notice a change in their appearance rather than experience a gradual loss over time. In addition, patients sometimes feel they look worse after HA injection than they did prior to it; however, this is more of a function of selective memory. This is why taking pre-injection photographs is so important. As with natural hyaluronan, HA fillers can be instantly dissolved with the enzyme, hyaluronidase.

Figure 3.1 Conceptual degradation curve of NASHA™ fillers. Note that the line is not linear, which correlates to the cross-linking agents used to stabilize the filler in the skin. Free hyaluronic acid has a half-life of 1–2 days in human skin.

Choosing the right NASHA™
The main difference between commercially available NASHA™ products on the current US market is the viscosity of the product. The higher the concentration of HA, the stiffer is the product and the longer it lasts in tissue ( Table 3.1 ). The larger the particle and the greater the concentration of the filler, the greater the lift you get. It should be noted, however, that not all of the HA in a given filler is cross-linked. Some is free, fragmented or only lightly cross-linked so that the gel can actually flow out of the syringe with ease. As discussed above, the cross-linking is what confers longevity to the product and this does vary between brands. In Restylane ® and Juvéderm ® , 1,4-butanediol diglycidyl ether is the cross-linking agent, which forms ether linkages in the HA chain. This same type of ether linkage is formed by diglycidyl sulfone found in Prevelle ® Silk. In addition to cross-linking, it is worth mentioning that not all HA products are packaged in the fully hydrated state. As mentioned earlier, NASHA™ fillers create volume via hydration and, for this reason, patients will often look better or more filled 24 hours after treatment with products like Restylane ® and Juvéderm, which are not completely saturated in the syringe. With that in mind, it is prudent not to overcorrect when using NASHA™ products.
Table 3.1 Hyaluronic acid (HA) concentration of commercially available NASHA™ products Trade name HA concentration Particle size * Restylane ® 20 mg/mL ~260 µm Perlane ® 20 mg/mL ~1000 µm Juvéderm ® 24 mg/mL 50–500 µm (very cohesive) Juvéderm ® Ultra Plus 24 mg/mL Homogeneous gel Prevelle ® Silk 5.5 mg/mL ~250 µm Hydrelle ® 28 mg/mL Not available Hylaform ® Plus 5.5 mg/mL ~700 µm
* Even very cohesive products are particulate. The particle sizes of commercially available NASHA™ fillers are shown. In comparison, the particulate sizes of non-NASHA™ products are as follows: Radiesse ® (25–45 µm), Artefill ® (over 30–50 µm), Sculptra ® (40–60 µm), Dermalive ® (20–120 µm).

Patient evaluation
Prior to injection with any dermal filler, a careful patient history should be obtained. Pertinent items to note in this history include a history of herpes simplex virus, pregnancy or breastfeeding, history of keloid formation, presence of any autoimmune disease, and allergy to lidocaine as most of the fillers now come pre-mixed with lidocaine ( Box 3.1 ). A medication history should include use of multivitamins, fish oil, vitamin E, blood thinners, aspirin, ibuprofen, and Gingko biloba, as all of these can predispose the patient to bruising. Unless medically necessary, the patient should be advised to discontinue these medications 14 days prior to treatment. In addition, alcohol use within 48 hours of injection can cause an increase in bruising tendency.

Box 3.1
NASHA™ products currently available pre-mixed with lidocaine

Restylane ®
Perlane ®
Juvéderm ®
Juvéderm ® Ultra Plus
Prevelle ® Silk
Hydrelle ®
If the patient has had fillers in the past, it is recommended that the physician document how long ago, where the fillers were placed, and if the patient was satisfied with the results. In addition to history, pre-injection photography is a must. These authors prefer at least three views: frontal, left side at an oblique angle, and right side at an oblique angle. If a patient is having a specific area corrected, a closeup picture of that area is also advisable. Informed consent must be obtained and the patient should be aware of the financial cost of the procedure prior to opening the first syringe. We also advise that baseline facial asymmetry be discussed with the patient and noted in the chart. From a physician standpoint, it is important to inform your malpractice coverage carrier of your intention to use fillers as many uses are considered off-label.

Patient preparation
Patients should be asked to remove their makeup and the areas to be injected should be cleansed with alcohol or a skin-cleansing solution that does not stain the skin. If there are any areas of infection, injection should be deferred. If the area is to be marked, these authors recommend using a white eyeliner pencil or an erasable marker. Use of gentian violet can create a tattoo if the needle is inserted through the marked line. Patients should be in a seated or reclined position to maximize comfort while allowing the skin to drape naturally. For this reason, it is not advisable to have the patient lie down as this can distort the natural contours of the face. Hair should be pulled back with a bandana or covered and pulled back with a surgical bonnet. The physician may decide to use a topical or local anesthetic prior to injection. If so, this should be completely removed prior to injection.

Pearl 1
If using a custom-formulated topical anesthetic such as BLT (7% betacaine, 7% lidocaine, and 7% tetracaine) be sure to monitor the amount of surface area that is covered with the medication as toxicity can result with high concentrations of anesthetic over large surface areas.

Physician preparation
A note that includes a detailed facial diagram is helpful to document precisely where filler is placed, and labels from each syringe used should be put in the patient chart for traceability. One should also anticipate adverse events, so we recommend that any physician who is using NASHA™ products carry hyaluronidase in case of arterial occlusion or if the product needs to be dissolved rapidly, nitropaste in the event of purple dusky discoloration upon injection, and juice and crackers in the event a patient has a vasovagal episode. If the decision is made to use a topical numbing medication prior to injection, topical steroids should also be kept on hand in the event of an allergic contact reaction. Lastly, it is helpful to have aluminum chloride at concentrations of 20% or higher available in the event of excessive bleeding at a needle insertion point, although most bleeding can be stopped with pressure alone.

Treatment techniques
Several injection techniques exist for the addition of HA fillers to the face and depend mainly on the area of the face that is to be augmented. The four main techniques are illustrated in Figure 3.2 . Each has its own advantages and disadvantages and all are based upon a transcutaneous approach.

Figure 3.2 Filler techniques: ( A ) serial puncture technique from a side view; ( B ) linear-threading technique from a side view; ( C ) fanning technique from a frontal view; ( D ) cross-hatching technique from a frontal view. Key: Orange line is the skin fold.

Serial puncture
In this method ( Fig. 3.2A ), the bevel of the needle is pointed up and the product is dispensed in a droplet-like fashion along the fold that is to be lifted. Depending on the size of the aliquot, the physician may have to massage the area to prevent nodule formation. A disadvantage of this technique is that the patient will experience multiple needle sticks. Examples of areas to use this method include: depot in the infraorbital area with massage into the medial canthal region, acne scarring, and droplet into the lip tubercles ( Table 3.2 ). Serial puncture is common for superficial dermal injections.
Table 3.2 Recommended injection technique by facial area Area Technique Nasolabial folds Serial puncture, threading, fanning or cross-hatching; sharp needle or blunt-tipped cannula can be used Melolabial folds Fanning or cross-hatching; sharp needle or blunt-tipped cannula can be used Jowls Serial puncture (depot) or linear threading Cheeks Fanning or cross-hatching; blunt-tipped cannula can be used Lips – vermilion border Linear threading Lips – tubercles Serial puncture

Linear threading
The physician points the bevel of the needle up and through one insertion point that is usually at the inferior pole of the fold, the needle is advanced forward, and the product is dispensed in a retrograde fashion as if laying down a cord ( Fig. 3.2B ). This technique is suboptimal in deeper folds as it does not address the underlying structural support needed to lift certain areas of the face. Examples of areas to use this method include: nasolabial folds and jawline ( Table 3.2 ). This can also be done using a blunt-tipped cannula.

Though the insertion point is similar to the linear-threading technique, in this method the needle is not removed from the skin but rather redirected in various directions in a fan-like motion, laying down product underneath the fold ( Fig. 3.2C ). A blunt-tipped cannula can be used for this technique, which is excellent to help prop up deep folds by addressing the overhang that occurs from adjacent skin. Examples of areas to use this method include: nasolabial folds, corners of the mouth, and temples ( Table 3.2 ). A combination of linear threading and fanning are commonly used together for volume correction.

Several parallel cords are placed in one direction and then overlapped with cords placed perpendicularly creating a strut-like scaffold beneath the fold ( Fig. 3.2D ). Though the patient will experience several needle sticks and the placement of filler in multiple planes can lead to more bruising, this method is ideal for treatment areas that require significant volume. Examples of areas to use this method include: cheeks, jowls, and marionette lines ( Table 3.2 ). Like the other techniques, this can also be done with a blunt-tipped cannula.

Pearl 2
Injection technique should vary according to the region of the face, the depth and tissue plane of the injection and also on the thickness of the NASHA™ filler being used. Whereas fanning and cross-hatching provide excellent structural support and enhance volume, they can lead to increased bruising. Similarly, the serial puncture technique allows for more precise microdroplet placement of filler, but can be painful for the patient. A blunt-tipped cannula minimizes bruising.

Site-specific treatment strategies

Nasolabial folds
Correction of the nasolabial fold is an FDA-approved on-label indication for all NASHA™ products and is the most common site for correction with NASHA™ fillers. The folds or ‘laughter lines’ occur as a result of movement of the malar fat pads medially and inferiorly with age along with a generalized loss of skin elasticity. Fine lines can appear in this area as early as the third decade of life. It is important when assessing the nasolabial fold to note the presence or absence of a heavy cheek. If the cheek has dropped substantially, or if the patient is overweight with substantial contribution to the fold from the inferomedial cheek, the fold will be very deep and several syringes of NASHA™ will be required before a noticeable result is achieved. If this is the case, consider volumizing the cheek in the area of the zygoma along with filler in the fold. This will result in an overall lifting and pulling of the skin back to its original physiological position. For the deep fold itself, the cross-hatch technique is the best one to employ, or one may consider layering a NASHA™ product over another product that is placed in deeper tissue (e.g. Restylane ® over Perlane ® ). For shallow to medium folds, a NASHA™ product alone can suffice and the fanning technique can be used starting at the inferior pole. In this case, cheek augmentation is not necessary. Whether to start from the superior or inferior portion of the pole is a matter of physician preference. At the completion of injection place a gloved thumb on top of the fold and two fingers on the inside of the mouth on the other side of the fold. Gently mold the product to make sure that no nodules or bumps are present. Hyaluronic acid fillers are maleable and can be molded after injection.
It is important to remember basic anatomy when injecting the nasolabial folds. The nasal artery runs near the ala so it is critical when injecting the superior portion of the nasolabial fold that one pulls back on the syringe plunger to make sure no flash of blood is seen. Injecting slowly with small alloquots helps avoid this problem. This will prevent accidental intra-arterial injection.

Case Study 1
Intra-arterial Occlusion?
A patient presents for correction of medium depth nasolabial folds. She has no notable medical history, takes no medications, and is treatment naïve. After injection of a total of 1 mL of hyaluronic acid filler into each nasolabial fold, the patient seems pleased with the results. She is told to ice the area for 10 minutes in every hour and to expect some mild discomfort the following day with some temporary edema. The following morning the patient calls the office to report a patchy red and blue hue of her nasal tip. She denies any pain.
She comes to the office and on examination she has a livedo pattern on the nasal tip that is dark red with a mild dusky hue.
While one may suspect accidental intra-arterial injection, the delayed discoloration indicates that the cause may be compression of the artery due to edema and product placement rather than overt injection of material into the arterial lumen and embolism, which would be seen by an immediate tissue reaction blanching and then discoloration. Using 12–20 units of hyaluronidase, inject slowly into the nasofacial sulcus making sure to pull back on the syringe prior to injection. Massage gently to enhance dissolution of any hyaluronic acid gel in the area. In addition, apply a small amount of nitrous paste to the nose and advise the patient to use warm compresses to the area for the next 24 hours. The patient should be re-evaluated daily until color returns to normal. Do not replace the hyaluronic acid in the area until full resolution of symptoms is achieved.

Pearl 3
If you see multiple lines lateral to the nasolabial fold, resist the urge to fill them as they are usually due to dynamic movement. Filling each line may improve their appearance at rest but will appear as cords upon animation.

Melolabial folds
With time, the area below the oral commissure hollows, pulling down the corners of the mouth, creating melolabial lines, and contributing to jowls. The loss of volume is due to structural bone changes that occur with age; principally, as a person ages, the maxilla and chin grow away from the face and bone resorption decreases maxillary and mandibular height. Along with skin laxity, the result is a sagging appearance of the lower face that responds well to filler use. This location is especially susceptible to bruising after filler injection and it is important to massage the area after injection to prevent lumps. Because of the need for structural support, the fanning or cross-hatch technique is recommended, as is the use of a thicker HA such as Perlane ® or Juvéderm ® Ultra Plus. Typically 0.5 mL is adequate to volumize each melolabial fold, though larger amounts are needed to volumize the lower face.

Pearl 4
Although most patients can tolerate injection into the nasolabial folds, the melolabial fold tends to be more sensitive. Consider a mental nerve block which will anesthetize not only this area but also portions of the lower lip. Use 0.2 mL of plain lidocaine 1% and inject in the sulcus next to the second premolar. This injection pain can be reduced with a 15-second application of benzocaine 20% (Hurricane ® gel) to the mucosa prior to injection.

Fat and soft tissue descent along the mandible obscures the bony definition of the jaw, which is considered a hallmark of the youthful face. HA fillers can be used to fill in the pre-jowl sulcus, thereby minimizing the appearance of the jowls. Filler is placed directly against the mandible and molded in a downward sweeping motion with the fingers around the jawline. The best technique to use for this is either a depot or linear threading. Placement of filler in the jowl area not only gives the illusion of a stronger bone line but also creates a relative tucking of the excess skin in the submental area. Of the available HA products, Juvéderm ® Ultra Plus or Perlane ® is recommended for treatment.

Pearl 5
In elderly patients, the mental nerve is particularly exposed in this area of the face as it is covered only by thin platysma and skin. Therefore, to prevent nerve injury from the needle tip, be sure to stay in the upper subcutaneous or dermis, which is higher than in other parts of the face owing to the thin skin in the jowl area.

With age, the orbicularis oculi muscle loses both its tone and its ability to act as a sling around the orbital rim. Subsequently, descent of the orbicularis and malar soft tissue complex prevails. Aging of the mid-face is dominated by descent of these malar fat pads (of which there are a total of seven), resulting in a loss of convexity and a flattened or even concave appearance of the cheeks. Filling the cheeks may result in softening of the nasolabial folds but requires injection in a deep subcutaneous or fascial plane. If using NASHA™ products, more than one syringe may be needed. It is important when injecting in this area that the patient be asked to smile so that the physician does not inadvertently create a chipmunk appearance in the patient. It is important to fan or cross-hatch injections and blend the cheeks back towards the temple so that the person does not appear to have implants at rest.
Anatomically, one must keep in mind bony structure and face shape as related to race and gender. It is also important to have a discussion with the patient with regards to the hollow below the zygoma as many people want fuller cheeks but do not want to lose this line of definition on the face. Layering filler in this area is successful, as is use of more viscous HA products. If injecting in the upper part of the cheek near the infraorbital region, a thinner filler such as Restylane ® or Juvéderm ® Ultra should be used. The tear trough or infraorbital hollow is a special area most responsive to a hyaluronic acid filler. Small alloquots are placed deeply below the obicularis muscle along the orbital rim with a linear threading technique. Care must be taken not to overfill this area as it may lead to eyelid edema and nodularity.

Pearl 6
Though it is possible to fill the cheeks through an intraoral approach caution should be used owing to the resident bacteria present in oral flora. Biofilm can be created, which can lead to severe complications. These authors recommend a transcutaneous approach when using HA products.

By the second decade of life, lip volume has reached full thickness in both men and women and starts decreasing by the mid-30s. In addition to the lips themselves, the vermilion border tends to thin, the corners of the mouth begin to slope downwards, and fine lines appear on the upper and lower cutaneous lip, which over time elicit the complaint of ‘lipstick bleeding.’ The philtral ridge should not be overlooked either as this flattens with the elongation of the cutaneous upper lip. Injection of the lips is a staged process and should be done with Restylane ® or Juvéderm ® Ultra rather than the more viscous HA products. Usually an infraorbital nerve block and mental nerve block are required for patient comfort, but it should be noted that it is important to work quickly after these blocks as the numbing will distort the position of the patient’s lips. In addition, expect significant swelling and more bleeding in this area than in other parts of the face, which can cause a physician to overcorrect one area in response to edema rather than actual volume change. It is important to note any baseline asymmetry in the lips as well as the presence of any scars, which can make filling more difficult. Lip injections of hyaluronic acid are placed in 3 planes: 1) volume filling within the lip muscle 2) linear threading of the vermillion line 3) superficial injeciton of rhytides. The vermillion injection gives contour, shape and lift to the lip. Identify the white roll at the border of the lip and, starting at the corner of the mouth, insert the needle and use a linear-threading technique to inject into the white roll in an anterograde fashion. Repeat on the other side making sure to fill to the apex of cupid’s bow. Overfilling of the border will result in a platypus-like appearance of the lips. After crisping of the vermilion border (which by default will evert the lip and create the appearance of fullness) consider a droplet injection into each of the two tubercles of the upper and lower lip to give a more pronounced pout.

Case Study 2
‘I only want to fill my upper lip’
A 56-year-old woman presents for filler of the lips. She is most bothered by her upper lip, which she feels has grown increasingly thin with time. She is insistent that she does not want to fill her lower lip because she is happy with the shape of it.
On examination, she has a flattened philtrum consistent with normal aging changes and has significant volume loss of the upper lip compared with the lower lip.
While one must be considerate of a patient’s request, it is appropriate to offer expert guidance so that the patient is not disappointed with the end result. Though patients may insist that filler be placed in only the top or bottom lip, it is important to maintain the lip ratio so that the result looks as natural as possible. The lower lip should always be more full than the upper lip. The ideal ratio of upper lip to lower lip is 1 : 1.6, which is based on the concept of the Fibonacci proportion. It is important to mention this to the patient so that, once filling of the upper lip is complete, the patient understands if some product must be added to the lower lip to maintain this ratio.

Postoperative care and complication management
In general, NASHA™ fillers are safe, effective and easy to use. Complications are generally limited to edema and bruising. After injection, patients are advised to ice the area for up to 10 minutes in every hour. Reusable ice packs can be given to the patient or they can use a bag of frozen peas, which is easy to mold over the area. In the lips, patients are encouraged not to purse their lips or fold them on top of each other, which may cause product movement in the first 6 hours. The following day, patients are advised to expect additional edema as hydration occurs. This may result in a feeling of soreness, which can be relieved with acetaminophen. Bruising can occur up to 72 hours after treatment. Anecdotally, Arnica forte can be used to prevent bruising, but no definitive evidence exists to suggest that this is always successful. The Tyndall effect is possible if the product is placed too superficially, as are nodules or lumps. The only way to correct this is to dissolve the product with hyaluronidase, keeping in mind that this will deplete some native HA in the epidermal matrix as well. Complications such as intra-arterial injection are possible though rare. Extra care is needed in the glabella where the risk of intra-arterial injection is high. If an entire syringe of product is not used on a patient, some physicians store the product for up to 6 months, carefully labeling the product with the patient’s name. Since a physician cannot guarantee sterility of the product once it has been injected, we do not recommend this approach.

The NASHA™ family of dermal fillers is a good choice for novice injectors, treatment naïve patients, and for patients with moderate aging changes. The range of products available in the marketplace is fairly diverse and, once implanted into the mid-to-deep dermis, creates reproducible results with ease. The success of NASHA™ is as dependent on the injectable as it is on the injector and proper technique.

Further reading

Bachmann F, Erdmann R, Hartmann V. Adverse reactions caused by consecutive injections of different fillers in the same facial region: risk assessment based on the results from the Injectable Filler Safety study. Journal of the European Academy of Dermatology and Venereology . 2011;25:902–912.
Bellew SG, Carroll KC, Weiss MA, et al. Sterility of stored nonanimal, stabilized hyaluronic acid gel syringes after patient injection. Journal of the American Academy of Dermatology . 2005;52:988–990.
Brody HJ. Use of hyaluronidase in the treatment of granulomatous hyaluronic acid reactions or unwanted hyaluronic acid misplacement. Dermatologic Surgery . 2005;31:893–897.
Carruthers J, Carruthers A. A prospective, randomized, parallel group study analyzing the effect of BTX-A (Botox) and nonanimal sourced hyaluronic acid (NASHA™, Restylane) in combination compared with NASHA™ (Restylane) alone in severe glabellar rhytides in adult female subjects: treatment of severe glabellar rhytides with a hyaluronic acid derivative compared with the derivative and BTX-A. Dermatologic Surgery . 2003;29:802–809.
Carruthers A, Carey W, de Lorenzi C, et al. Randomized, double-blind comparison of efficacy of two hyaluronic acid derivatives, Restylane Perlane and Hylaform, in the treatment of nasolabial folds. Dermatologic Surgery . 2005;31:1591–1598.
Cohen JL. Understanding, avoiding and managing dermal filler complications. Dermatologic Surgery . 2008;34:S92–S99.
Day DJ, Littler CM, Swift RW, et al. The wrinkle severity rating scale: a validation study. American Journal of Clinical Dermatology . 2004;5:49–52. 2004
Hamilton RG, Strobos J, Adkinson NF. Immunogenicity studies of cosmetically administered nonanimal-stabilized hyaluronic acid particles. Dermatologic Surgery . 2007;33:S176–S185.
Hanke CW, Rohrich RJ, Busso M, et al. Facial soft-tissue fillers conference: assessing the state of the science. Journal of the American Academy of Dermatology . 2011;64:S66–S85.
Hexsel D, Brum C, Schilling de Souza J, et al. A phase II, randomized, double-blind clinical trial comparing safety and efficacy of a metallic cannula versus a standard needle for dermal filler injections (hyaluronic acid gel) for the treatment of nasogenian folds. Journal of the American Academy of Dermatology . 2011;64:AB164.
Hirsch RJ, Cohen JL, Carruthers JD. Successful management of an unusual presentation of impending necrosis following a hyaluronic acid injection embolus and a proposed algorithm for management with hyaluronidase. Dermatologic Surgery . 2007;33:357–360.
Kablik J, Monheit GD, Yu L, et al. Comparative physical properties of hyaluronic acid dermal fillers. Dermatologic Surgery . 2009;35:302–312.
Leonhardt JM, Lawrence N, Narins RS. Angioedema acute hypersensitivity reaction to injectable hyaluronic acid. Dermatologic Surgery . 2005;31:577–579.
Lupo MP, Smith SR, Thomas JA, et al. Effectiveness of Juvéderm Ultra Plus dermal filler in the treatment of severe nasolabial folds. Plastic and Reconstructive Surgery . 2008;121:289–297.
Matarasso SL, Carruthers JD, Jewell ML, et al. Consensus recommendations for soft-tissue augmentation with nonanimal stabilized hyaluronic acid (Restylane). Plastic and Reconstructive Surgery . 2006;117:S3–S43.
Monheit GD, Davis B. Nasolabial folds. In: Carruthers J, Carruthers A. Soft tissue augmentation . 2nd edn. Philadelphia, PA: Elsevier; 2008:105–126.
Monheit GD, Baumann LS, Gold MH, et al. Novel hyaluronic acid derm filler: dermal gel extra physical properties and clinical outcomes. Dermatologic Surgery . 2010;36:1833–1841.
Narins RS, Bowman PH. Injectable skin fillers. Clinical Plastic Surgery . 2005;32:151–162.
Narins RS, Jewell M, Rubin M, et al. Clinical conference: management of rare events following dermal fillers – focal necrosis and angry red bumps. Dermatologic Surgery . 2006;32:426–434.
Narins RS, Coleman WP, Donofrio LM, et al. Improvement in nasolabial folds with a hyaluronic acid filler using a cohesive polydensified matrix technology: results from an 18-month open-label extension trial. Dermatologic Surgery . 2010;36:1800–1808.
4 Juvéderm ® family

William P. Coleman, III., Kyle M. Coleman, W. Patrick Coleman, IV.

Summary and Key Features

• Juvéderm ® features a proprietary cross-linking process that results in a concentration of 24 mg/mL of hyaluronic acid; this unique process results in a soft, viscous, non-beaded gel and is designed to improve the durability of this filler
• Juvéderm ® is available in the USA as Juvéderm ® Ultra, Juvéderm ® Ultra Plus, Juvéderm ® Ultra XC, and Juvéderm ® Ultra Plus XC
• Juvéderm ® Voluma ® is also available in many countries. Voluma ® is a 20 mg/mL smooth hyaluronic acid preparation with high cohesivity and viscosity. These features provide extra ‘lift’ when injected into tissue
• Like all hyaluronic acid fillers Juvéderm ® can be dissolved using hyaluronidase
• The most common areas for treatment are the lips, nasolabial furrows, commissures, chin, and nasojugal depressions
• Many dermatologists prefer Juvéderm ® for the perioral areas, especially the lips, over other hyaluronic acid fillers because it is a ‘soft’ filler that feels more natural to the patient in sites where a hard texture would be more discernable
• Some dermatologists prefer the pre-mixed lidocaine-loaded XC Juvéderm ® gels, while others like the flexibility of diluting the gels with lidocaine in the clinic
• Juvéderm ® Voluma ® has been developed specifically for volumizing by treating the three-dimensional aspects of facial aging

Although dozens of hyaluronic acid (HA) fillers are available for soft tissue augmentation, each has its own unique characteristics. The Juvéderm ® family of fillers are well known to physicians as soft and ‘easy to inject’ gels. Juvéderm ® products are distributed in the USA by Allergan Inc., Santa Barbara, CA. They were approved by the US Food and Drug Administration (FDA) in September 2006 and began to be marketed at the beginning of 2007.
All Juvéderm ® products are composed of hyaluronic acid, or hyaluronan, a polymer found naturally in human skin, eye, muscles, and joints, as well as in the connective tissue of all mammals. It is the most abundant glycosaminoglycan in human tissue, and plays a role in dermal water retention while binding collagen and elastin fibers. Thus, HA contributes to the integral structure of the skin. HA is not species specific, regardless of its source, so bacterial-derived HA is well tolerated by humans. In its natural form, HA breaks down within hours when injected into the skin. To produce longevity, it must be cross-linked. Although there are many methods for cross-linking HA, Juvéderm ® features a proprietary cross-linking process called Hylacross ® , which results in a concentration of 24 mg/mL of HA. This unique process results in a soft, viscous, non-beaded gel and is designed to improve the durability of this filler.
Juvéderm ® was approved by the FDA after a multicenter double-blind, randomized clinical trial by Baumann and co-workers in which it was compared with bovine collagen; the 24-week study revealed superior persistence in patients injected in the nasolabial areas with Juvéderm ® . After a subsequent FDA-approved clinical trial by Pinsky et al demonstrating that, after a single treatment, the effects could last up to 12 months, the FDA granted a label extension in June 2007. More recently, Allergan released a formulation of Juvéderm ® that was pre-mixed with lidocaine (XC) to diminish the pain of injection. Levy and colleagues determined that this new mixture was more comfortable for patients in a split-face comparison. Subsequent research by Raspaldo et al confirmed that the addition of lidocaine did not reduce the long-term durability of the product.

Juvéderm formulations
Juvéderm ® is available in a variety of formulations. In the USA, it is distributed as Juvéderm ® Ultra, Juvéderm ® Ultra Plus, Juvéderm ® Ultra XC, and Juvéderm ® Ultra Plus XC ( Table 4.1 ). Juvéderm ® Ultra Plus contains a cross-linked composition of 8% versus 6% in Juvéderm ® Ultra, making it a more robust filler. The two XC Juvéderm ® products contain 0.3% lidocaine but are otherwise identical to the Ultra formulations. In some countries Juvéderm ® Voluma ® is also available. Voluma ® is a 20 mg/mL smooth HA preparation with high cohesivity and viscosity. These features provide extra ‘lift’ when injected into tissue.

Table 4.1 Different formulations of Juvéderm ®
Juvéderm ® injectable gel is a sterile, biodegradable, non-pyrogenic, viscoelastic, clear, colorless, homogenized gel implant ( Fig. 4.1 ). It consists of cross-linked HA produced by bacterial fermentation by Streptococcus equus . The gel is formulated to a concentration of 20–24 mg/mL and suspended in a physiological buffer. The package insert states that the product is approved for ‘injection into the mid- to deep dermis for correction of moderate to severe facial wrinkles and folds (such as nasolabial folds)’ but is commonly used by physicians for a variety of soft tissue augmentation indications.

Figure 4.1 Syringes of Juvéderm ® Ultra and Ultra Plus.

Contraindications and safety considerations
The package insert states that Juvéderm ® is contraindicated in patients with severe allergies and in those sensitive to bacterial proteins, since trace amounts survive the manufacturing process. The gel must not be injected intravascularly and if done so may lead to embolization and tissue necrosis. It should also not be injected into sites of obvious inflammation, such as active acne or where infection is present.
The safety of injecting more than 20 mL per 60 kg of body weight has not been established nor has injection into patients prone to keloids, hypertrophic scars or pigmentary abnormalities. However, clinical experience by Taylor et al in injecting HA fillers into patients of color has been demonstrated to be similar to Caucasians; and in the original clinical trial (described on the package insert), more than one-third of subjects were of Fitzpatrick skin phototypes IV, V, or VI. No safety studies have been done on pregnant females, on those breast feeding, or on children under 18; so, caution is prudent in considering the timing of treating these individuals. Bleeding and bruising are increased in patients on aspirin, non-steroidal inflammatory agents, fish oil, or warfarin.
Laser and/or chemical peeling procedures of many depths may or may not affect the longevity of Juvéderm ® injections, especially if performed close to the time of the injection. The package insert also warns of inflammatory reactions if these procedures are performed soon before or after the filler injection, but there are no good clinical studies to support or refute this. Theoretically, the deeper the peel or laser (or dermabrasion) penetrates the dermis, the more likely it is that there will be an effect on the performance of a filler injected soon before or after. In addition, swelling due to treatments performed immediately prior to injections may skew contour and lead to unwanted results.
Minor problems such as redness, pain, tenderness, itching, firmness, swelling, bumps/lumps, and discoloration have been reported; but all of these can be easily treated and often resolve spontaneously. Like all HA fillers, Juvéderm ® can also be dissolved using hyaluronidase. So, this provides a convenient way to remove visible bumps/lumps and also persistent allergic nodules or biofilm formation, as was described by Brody.

Pearl 1
Significant bruising can be treated effectively with vascular lasers, such as pulse dye lasers. Treated bruises will resolve much faster and may even be hardly noticeable the following day. Settings will vary based upon the device used.

Pearl 2
Hyaluronidase can be used to dissolve any unwanted material after Juvéderm ® injection. However, it should be noted that allergic reactions to thimerosal-containing formulations of hyaluronidase have been reported.

Using Juvéderm ®
The most common areas for treatment with Juvéderm ® products are the lips, nasolabial furrows, commissures, chin, and nasojugal depressions ( Box 4.1 ). Prior to treatments the patient should undergo detailed informed consent with the physician, reviewing all the risks and benefits of using this filler. After answering all questions and obtaining written permission, the physician can begin treatment. A topical anesthetic cream applied to the skin for at least 10 minutes (longer if possible) makes the process more comfortable. For the perioral area, injectable local anesthesia such as a submucosal field block is also helpful in reducing discomfort. However, if too much volume of anesthetic is injected, it may distort the contours enough to confuse the injector. Niamtu states that, after application of a topical dental anesthetic, small aliquots of plain lidocaine can be injected at several locations at the sulcus produced by the attached gingival and the unattached mucosa in the upper and lower lips. Additional injection points on the undersurface of the nasolabial fold between the mucosa and the skin extend the field of anesthesia. This normally gives excellent anesthesia for infiltration of Juvéderm ® into the nasolabial furrows, commissures, and lips.

Box 4.1
Areas amenable to treatment with Juvéderm ®

Nasolabial folds
Marionette lines
Nasojugal folds
Infraorbital hollows
Nasal contouring
Depressed scars

Pearl 3
Both Juvéderm ® Ultra and Juvéderm ® Ultra Plus can be used to effectively elevate the commisures of the lips. A small volume of the material should be injected horizontally into the most lateral aspects of the upper and lower lips to produce a more upturned corner of the mouth.
Because infection is a risk of any injection, sterility should be maintained as far as possible. After marking the intended injection sites, an antibacterial scrub should be applied such as 4% w/v chlorhexidine gluconate. Alcohol is an inferior choice and provides only a brief period of antisepsis.
Before approaching the patient, the physician should confirm that the needle is firmly locked into the syringe; then the plunger should be depressed (while pointing it away from the patient) until a small amount of gel flows out of the needle to prime the needle and ensure adequate flow. Typically, a combination of serial puncture and linear-threading injection techniques is used. The Juvéderm ® gel should be placed deep enough in the dermis that surface lumps are not produced. If the material flows too superficially, the lumps can usually be massaged into the proper contour. Juvéderm ® gel is quite soft and can be molded quite easily immediately after injection, using fingers and/or cotton-tipped applicators. Determining the end point of the filling injection takes experience, but overcorrection is discouraged. Generally, it is better for the physician to undercorrect and then have the patient return for a secondary injection than to overcorrect. This is especially true of treatment of the periocular area where overfilling can result in visibility of the injected product. Injections should create a more youthful appearance to the treated area ( Fig. 4.2 ).

Figure 4.2 ( A ) Before and ( B ) after treatment with Juvéderm ® Ultra XC to the infraorbital hollows. Notice the decrease in shadowing and the more youthful appearance to the area.

Pearl 4
If after injection the physician is not able to massage an area of nodularity into place, the material can be extruded by using a 25- or 27-gauge needle to puncture the skin. This avoids the need for hyaluronidase treatment and allows one more control over the amount of product removed.
If blanching occurs, the physician should stop injecting and immediately massage the treated area. If blanching remains, a vessel may be occluded and topical nitroglycerin paste should be applied and/or hyaluronidase injected. Grunebaum et al found that delayed treatment of occluded vessels may lead to skin necrosis.

Pearl 5
If nitroglycerin is used topically, the patient should be warned of the potential for severe headache, bradycardia, and hypotension.
Immediately afterward, the patient should apply ice to the treated areas and should be instructed to avoid making extensive facial expressions, which may make the gel move from its intended location, for at least 2 hours. This includes excessive chewing or talking. Heavy exercise or exposure to excessive heat may increase swelling and bruising. It is wise to have patients avoid alcoholic beverages and anticoagulant medications such as aspirin, non-steroidal inflammatory agents, fish oil, or warfarin for 1 day after treatment. Most patients can return to social occasions the following day (see Case study 1 ).
Case Study 1
A 42-year-old female patient calls the office 12 days after injection of Juvéderm ® Ultra to the periocular area complaining of persistent bruising. When she arrives in the clinic, you examine the patient. There is a noticeable bluish discoloration bilaterally at the lower margin of the lower lid.
The Juvéderm ® Ultra was placed too superficially and is visible owing to the Tyndall effect. This is more common in the area of the eye owing to the thinness of the skin. The area needs to be treated with hyaluronidase to resolve the discoloration. Future injections should be carried out deep to the orbicularis muscle to avoid this complication.

Clinical choices
Many dermatologists prefer Juvéderm ® for the perioral areas, especially the lips, over other HA fillers. Juvéderm ® has a well-deserved reputation as a ‘soft’ filler that feels more natural to the patient in sites where a hard texture would be more discernable. More often, patients are looking for subtle improvements that do not appear ‘overdone’ ( Fig. 4.3 ). The choice to use the Ultra or the Ultra Plus gel is more personal since there is no good clinical evidence that one performs significantly better than the other in specific sites. One might theorize that the more robust Ultra Plus would last longer and feel firmer in the tissues; however, there is no compelling evidence to support this.

Figure 4.3 ( A ) Before and ( B ) after treatment with Juvéderm ® Ultra Plus to the lips. Notice the excursion produced and the natural appearance of the philtrum and border.
A more controversial clinical debate revolves around the XC formulations of Juvéderm ® . Before introduction of this product, dermatologists were commonly pre-mixing lidocaine with Juvéderm ® products. Although this practice helped with pain during injection, it had the unintended beneficial consequence of changing the flow characteristics of the gels. Juvéderm ® mixed with lidocaine in a ratio anywhere from 1 : 0.3 to 1 : 1 allowed the physician to modulate the texture and ease of flow of the material to suit clinical situations. Even now, more dilute formulations are being used by many dermatologists in the USA to replace the discontinued Cosmoderm ® and Zyderm ® collagen, which could be used superficially in the dermis to fill fine lines. Also, lidocaine could be employed in a variety of concentrations to achieve more or less anesthesia, and using lidocaine with epinephrine conferred the additional benefit of vasoconstriction and was potentially less bruising. After becoming accustomed to these advantages, many dermatologists did not embrace the pre-mixed lidocaine-loaded XC Juvéderm ® gels, which did not allow the flexibility of onsite lidocaine mixing. Still others would argue that potential complications could occur from onsite mixing, including contamination, mixing errors, etc., and that the pre-mixed formulation is proven to be safe and effective. Raspaldo et al also confirmed that ‘no significant drop in rheology (flow and deformation of the gel under stress) or extrusion force was noted with the addition of lidocaine, thus confirming that lidocaine does not degrade HA or the gel network’. This would suggest that there is some suspicion that onsite mixed Juvéderm ® gels might have diminished longevity compared with the pre-mixed preparations; however, this has not been satisfactorily confirmed.

Pearl 6
All formulations of Juvéderm ® can be diluted with lidocaine to produce a less viscous material for more superficial filling. There are, however, no studies that have quantified the effects this has on longevity of the material.

Volumizing with Juvéderm ® gels
Although Juvéderm ® Ultra, Juvéderm ® Ultra Plus, Juvéderm ® Ultra XC, and Juvéderm ® Ultra Plus XC are used by some dermatologists for replacing volume loss of soft tissue, the most common applications are to treat wrinkles and folds. Juvéderm ® Voluma ® has been developed specifically for treating the three-dimensional aspects of facial aging (see Case study 2 ; Fig. 4.4 ). Available in Canada and other countries, the 20 mg/mL is positioned as a ‘smooth, cohesive HA filler’, according to Carruthers et al. Allergan uses a unique manufacturing process, mixing both low and high molecular weight HA polymer chains, to increase cross-linking and produce a product of both high viscosity and high cohesivity. This process theoretically reduces migration from deep injection sites. Because of its increased viscosity, Juvéderm ® Voluma ® is packaged with two 23-gauge 1-inch (25 mm) ultra-thin wall needles and two 18-gauge 70 mm cannulas. There is a known incompatibility between sodium hyaluronate and quaternary ammonium salts such as benzalkonium chloride. The package insert therefore advises the user never to put Juvéderm ® Voluma ® in contact with these products, or with substances treated with these products.

Figure 4.4 ( A ) Before and ( B ) after treatment of the lips with Juvéderm ® Voluma ® .
Reproduced with permission from Dermatologic Surgery: Carruthers J, Carruthers A, Tezel A, et al 2010 36:1886-1892
Case Study 2
A thin, 49-year-old female comes to the clinic with a complaint of ‘looking old’. Examination of the patient reveals good skin quality with atrophy of the cheek and mid-face. Pictures are taken of the patient for pre-treatment documentation.
Using the pictures, the patient is shown the areas that are atrophic and the resultant effect on her face as a whole. Given all the options for facial volumization, she chooses treatment with Juvéderm ® Voluma ® because of its longevity and its ability to be reversed with hyaluronidase.
You explain to the patient that she should avoid alcohol, aspirin and other blood thinners. The patient is marked for treatment. After topical anesthesia has been in place for at least 10 minutes, the area is cleansed with chlorhexidine. Injections are carried out deeply in the cheek to create lift and volume. After treatment patient is given an ice pack and advised to avoid strenuous exercise or excessive use of facial muscles for 24 hours.
A maximum of 2 mL of Juvéderm ® Voluma ® should be used in a single treatment area, according to the package insert. Because it is injected deep to the dermis, submuscularly, or under the periosteum, this filler is much more likely to cause significant swelling, itching, and erythema than the Juvéderm ® Ultra series, which is used more superficially. Also, patients with a history of streptococcal disease should have double skin-testing before use. Physicians intending to inject this material should have a good knowledge of facial anatomy as the filler is to be placed deeply. Caution should be taken with antisepsis where patients have prior facial implants, hard or soft, to avoid biofilm production.
Because it is reversible with hyaluronidase, Juvéderm ® Voluma ® is more flexible and safer than poly- l -lactic acid and polymethylmethacrylate. It also has been shown by both Hoffmann and Raspaldo to maintain correction for up to 18 months. -->

Further reading

Baumann LS, Shamban AT, Lupo MP, et al. Comparison of smooth-gel hyaluronic acid dermal fillers with cross-linked bovine collagen: a multicenter, double-masked, randomized, within-subject study. Dermatologic Surgery . 2007;33:S128–S135.
Brody HJ. The use of hyaluronidase in the treatment of granulomatous hyaluronic acid reactions or unwanted hyaluronic acid misplacement. Dermatologic Surgery . 2005;31:893–897.
Carruthers J, Carrauthers A, Tezel A, et al. Volumizing with a 20-mg/mL smooth, highly cohesive, viscous hyaluronic acid filler and its role in facial rejuvenation therapy. Dermatologic Surgery . 2010;36:1886–1892.
Grunebaum LD, Allemann IB, Dayan S, et al. The risk of alar necrosis associated with dermal filler injection. Dermatologic Surgery . 2009;35:1635–1640.
Hoffmann K. Volumizing effects of a smooth, highly cohesive, viscous 20-mg/mL hyaluronic acid volumizing filler: prospective European study. BMC Dermatology . 2009;9:9.
Juvéderm 2011 [package insert]
Levy PM, De Boulle K, Raspaldo H. A split-face comparison of a new hyaluronic acid facial filler containing pre-incorporated lidocaine versus a standard hyaluronic acid facial filler in the treatment of naso-labial folds. Journal of Cosmetic and Laser Therapy . 2009;11(3):169–173.
Monheit GD, Coleman KM. Hyaluronic acid fillers. Dermatologic Therapy . 2006;19(3):141–150.
Niamtu J, III. Simple technique for lip and nasolabial fold anesthesia for injectable fillers. Dermatologic Surgery . 2005;31:10–11.
Pinsky MA, Thomas JA, Murphy DK, et al. Juvéderm vs. Zyplast Nasolabial Fold Study Group. Juvéderm injectable gel: a multicenter, double-blind, randomized study of safety and effectiveness. Aesthetic Surgery Journal . 2008;28:17–23.
Raspaldo H. Volumizing effect of a new hyaluronic acid sub-dermal facial filler: a retrospective analysis based on 102 cases. Journal of Cosmetic and Laser Therapy . 2008;10:134–142.
Raspaldo H, De Boulle K, Levy PM. Longevity of effects of hyaluronic acid plus lidocaine facial filler. Journal of Cosmetic Dermatology . 2010;9(1):11–15.
Rohrich RJ, Monheit G, Nguyen AT, et al. Soft-tissue filler complications: the important role of biofilms. Plastic and Reconstructive Surgery . 2010;125:1250–1256. Online. Available
Taylor SC, Burgess CM, Callender VD. Safety of nonanimal stabilized hyaluronic acid dermal fillers in patients with skin of color: a randomized, evaluator-blinded comparative trial. Dermatologic Surgery . 2009;35:1653–1660.
Voluma 2011 [package insert]
Wahl G. European evaluation of a new hyaluronic acid filler incorporating lidocaine. Journal of Cosmetic Dermatology . 2008;7:298–303. -->
5 Non-permanent fillers
Belotero ® /Esthélis ® and Teosyal ®

Berthold J. Rzany, Heike Buntrock, Vanessa Hartmann, Martina Kerscher

Summary and Key Features

• Belotero ® , Esthelis ® , and Teosyal ® are three hyaluronic acid families produced in Switzerland
• Good clinical data are available only for Belotero ® Basic and Teosyal ® Deep Lines
• At 6 months Belotero ® Basic and Teosyal ® Deep Lines still show at least a one-grade difference after treatment of the nasolabial folds
• Belotero ® Basic and Teosyal ® Deep Lines have a good safety profile

Switzerland is not only the home of high mountains and chocolate but also the home of two companies that produce three hyaluronic acid (HA)-based filler families: Belotero ® , Esthelis ® , and Teosyal ® .

Hyaluronic acid dermal fillers
HA-based dermal fillers are currently the most popular, non-permanent injectable materials available for the correction of age-related changes of the face and beyond the face (wrinkles, and volume loss). HA fillers derive from bacterial fermentation from a specific streptococcus strain ( Streptococcus equi ), a bacterium non-pathogenic for humans. As natural HA does not persist in tissues for more than 24 hours, it needs to be chemically stabilized by cross-linking techniques. Most HA-based fillers are stabilized by 1,4-butanediol diglycidyl ether (BDDE).
How to differentiate the different HA fillers? There are certain possibilities:

Those with good clinical data and those without
Those for more superficial and those for deeper injections
Those with a few products and those with product families
Those easy to inject and those more difficult to inject
Cheaper ones and more expensive ones.
So let’s take these aspects and look at the fillers that will be discussed in this chapter. One small note beforehand: all of the HA gels discussed here are of non-animal origin (bacterial fermentation) and are cross-linked by BDDE.

For this chapter a Medline search was performed with the aim of identifying clinical trials on the fillers discussed here. To reduce bias only randomized controlled clinical trials (RCTs) with a study size of above 50 and case series with a study size of above 100 were included in this overview.

Belotero ®
Belotero ® is produced by the Swiss company Anteis SA and distributed by Merz Pharmaceuticals. The stabilizer is BDDE and according to the manufacturer two cross-linking processes are used leading to a cohesive and polydensified matrix, which is supposed to ease injection while maintaining long-lasting results. Belotero ® offers three different formulations: Belotero ® Soft, Belotero ® Basic and Belotero ® Intense ( Table 5.1 , Figs 5.1 and 5.2 ).

Table 5.1 Product overview of the Belotero ® family

Figure 5.1 (A) A 56-year-old patient at baseline and ( B ) 14 days and ( C ) 182 days after a single injection of 1 mL Belotero ® Intense.

Figure 5.2 Upper lip augmentation in a 45-year-old man: ( A ) before and ( B ) 4 months after 1.7 mL of Teosyal ® Kiss.
We could find only one RCT for Belotero ® Basic with an open extension phase, by Narins and colleagues. Furthermore we were able to detect two large German case series: one by Dirting et al focusing on Belotero ® Basics and one by Pavicic on Belotero ® Intense.

Randomized controlled trial
The aim of the trial was to compare the safety and effectiveness of Belotero ® Basic with that of bovine collagen (probably Zyplast ® , but name not given) in the correction of moderate to severe nasolabial folds (NLFs) in a split-face study. The study included 118 patients who were randomized to receive Belotero ® Basic and bovine collagen on contralateral sides of the face. NLF severity was measured using the Wrinkle Severity Rating Scale (WSRS, 5 points). The initial treatment was evaluated after 2 weeks, and an optional touch-up to optimal cosmetic correction was permitted if needed. Subjects returned every 2 weeks (up to 24 weeks) for evaluation. Safety was assessed using spontaneous adverse event (AE) reporting. A mean volume of 1.97 mL of Belotero ® Basic was injected. The mean change from screening at week 24 was 1.08 ± 0.74 as assessed by the blinded investigator. Belotero ® Basic resulted in a significantly greater reduction in the mean change on the WSRS score than bovine collagen at weeks 8 ( p = 0.009), 12 ( p = 0.001), 16 ( p = 0.001), and 24 ( p = 0.001). There were no significant differences between the two groups in the proportion of AEs considered related to the injection site procedure. Most AEs were mild to moderate in severity and resolved within 7 days.

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