Injectable Fillers: Principles and Practice

Injectable Fillers: Principles and Practice EDITED BY

Derek Jones,

MD

Clinical Associate Professor, Department of Medicine, Division of Dermatology, David Geffen School of Medicine, University of California at Los Angeles

A John Wiley & Sons, Ltd., Publication

Injectable Fillers: Principles and Practice

Companion – CD-ROM This book is accompanied by video of procedures described in the text: • Radiesse and Evolence Breeze for augmentation of the cheeks, oral commissures, lateral brow, nasolabial fold and lips Injector: Jean Carruthers, MD

• Hyaluronic Acid: Juvederm Ultra and Ultra Plus for augmentation of the nasolabial folds, oral commissures, labial mental groove, and lips Injector: Derek Jones, MD

• Sculptra for treatment of facial lipoatrophy (non-HIV) Injector: Derek Jones, MD

• Liquid Injectable Silicone (Silikon-1000) for treatment of HIV-associated facial lipoatrophy Injector: Derek Jones, MD

Total running time: 50 minutes

Injectable Fillers: Principles and Practice EDITED BY

Derek Jones,

MD

Clinical Associate Professor, Department of Medicine, Division of Dermatology, David Geffen School of Medicine, University of California at Los Angeles

A John Wiley & Sons, Ltd., Publication

This edition first published 2010, © 2010 by Blackwell Publishing Ltd Blackwell Publishing was acquired by John Wiley & Sons in February 2007. Blackwell’s publishing program has been merged with Wiley’s global Scientific, Technical and Medical business to form Wiley-Blackwell. Registered office: John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK Editorial offices: 9600 Garsington Road, Oxford, OX4 2DQ, UK The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK 111 River Street, Hoboken, NJ 07030-5774, USA For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www. wiley.com/wiley-blackwell The right of the author to be identified as the author of this work has been asserted in accordance with the Copyright, Designs and Patents Act 1988. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books. Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. This publication is designed to provide accurate and authoritative information in regard to the subject matter covered. It is sold on the understanding that the publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought. The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting a specific method, diagnosis, or treatment by physicians for any particular patient. The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of fitness for a particular purpose. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. Readers should consult with a specialist where appropriate. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom. Library of Congress Cataloging-in-Publication Data Injectable fillers : principles and practice / [edited by] Derek Jones. p. ; cm. Includes bibliographical references. ISBN 978-1-4051-9289-7 1. Tissue expansion. 2. Fillers (Materials) 3. Surgery, Plastic. 4. Face–Surgery. I. Jones, Derek, 1965[DNLM: 1. Face. 2. Cosmetic Techniques. 3. Dermatologic Agents. 4. Injections. 5. Rejuvenation. WE 705 I505 2010] RD119.5.T57I55 2010 617.9′52–dc22 2009030111 ISBN: 9781405192897 A catalogue record for this book is available from the British Library. Set in 9.5 on 13 pt Meridien by Toppan Best-set Premedia Limited Printed in Singapore 1st impression 2010

Contents Preface, vi Contributors, viii 1 The Cosmetic Patient Consultation, 1 Phil Werschler 2 Guidelines for Local Anesthesia in Use of Injectable Fillers, 8 Mariano Busso 3 Hyaluronic Acids: Basic Science, 19 Nowell Solish and Kenneth Beer 4 Calcium Hydroxylapatite Microspheres in Facial Augmentation, 27 Alastair Carruthers and Jean Carruthers 5 Evolence and Evolence Breeze, 43 Jean Carruthers and Alastair Carruthers 6 Poly-L-Lactic Acid, 54 Rebecca Fitzgerald and Danny Vleggaar 7 Liquid Injectable Silicone, 75 Chad L. Prather 8 Hydrogel Polymers, 91 Naissan O. Wesley 9 Artefill: the First to Last, 103 Adam M. Rotunda and Rhoda S. Narins 10 Complications from Soft-Tissue Augmentation of the Face: A Guide to Understanding, Avoiding, and Managing Periprocedural Issues, 121 Marc D. Glashofer and Joel L. Cohen 11 The Mathematics of Facial Beauty: A Cheek Enhancement Guide for the Aesthetic Injector, 140 Arthur Swift 12 Hyaluronic Acids: Clinical Applications, 158 Derek Jones and Timothy C. Flynn Index, 175 “This book is accompanied by a CD-ROM with videos showing procedures described in the book.”

v

Preface

Since the Food and Drug Administration (FDA) approval of the first injectable hyaluronic acid for correction of facial wrinkles in 2003, there has been an explosion of natural and synthetic fillers in the medical cosmetic market and millions of procedures are now performed annually. At the time of writing, we currently have 14 injectable devices approved by the FDA from which to chose: five collagen products of bovine (Zyplast, Zyderm), porcine (Evolence) or human origin (Cosmoplast, Cosmoderm); six hyaluronic acid products (Restylane/Perlane, Juvéderm Ultra and Ultra Plus, Elevess, Prevelle Silk); calcium hydroxylapatite (Radiesse); and the synthetic poly-L-lactic acid (Sculptra) and the permanent polymethylmethacrylate (Artefill). Liquid injectable silicone (Silikon-1000) is available only off-label as a permanent injectable filler. There is no “one best” filler or “one right way” to achieve a beautiful and natural result. Although the hyaluronic acids dominate the marketplace, all of these fillers have an important and useful role, and are often used to best effect in combination. The goal of this book is to present the basic science, review safety and efficacy data that have led to FDA approval, and outline patient selection, safe, and effective injection techniques, and appropriate indications for each filler. It should be noted that most FDA studies leading to approval have formally studied most fillers only in the nasolabial fold. Other indications that are outlined (such as volumizing the lip and cheek) in this book are considered “off-label” in the USA, meaning that, although it is legal to inject these areas, the FDA has not reviewed safety or efficacy data and granted a formal indication for such use. Lastly, a procedural DVD, running for about 1 hour, is included with this book and demonstrates appropriate injection techniques for most of the fillers discussed. When assessing volume loss in the face, the physician will do best to not concentrate only on one area (such as the nasolabial fold) as a discrete entity, but assess multiple areas of volume loss (lips, cheeks, oral commissures) in relationship to each other and tailor the treatment plan accordingly. A great deal of effort has been put in to teach the reader how to avoid complications and, when they may occasionally

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vii

happen, how to properly identify and treat them. The novice should thoroughly master the anatomy of the skin and subcutaneous tissue of the face, including vascular, muscular, and neural structures, before starting actual injections. In general when injecting, I advocate a very slow, steady, and deliberate injection technique with absolute attention given to the correct plane of injection (intradermal, subcutaneous, epiperiosteal), which is different for each filler and is crucial to achieving a good result. Derek Jones

Contributors

Kenneth Beer MD Director, Kenneth Beer MD PA, Esthetic, Surgical and General Dermatology Voluntary Assistant Professor Department of Dermatology University of Miami West Palm Beach Florida, USA

Mariano Busso MD Private practice in South Florida Voluntary Assistant Clinical Professor at the University of Miami Coral Gables Florida USA

Alastair Carruthers MA, BM, BCH, FRCPC, FRCP (Lon) Clinical Professor Department of Dermatology and Skin Science University of British Columbia Vancouver Canada

Jean Carruthers MD, FRCS (C), FRC(Ophth) Clinical Professor Department of Ophthalmology and Visual Sciences University of British Columbia Vancouver Canada

Joel L. Cohen MD Director, About Skin Dermatology and DermSurgery Associate Clinical Professor University of Colorado Department of Dermatology Englewood Colorado, USA

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Contributors Rebecca Fitzgerald MD Dermatology Private Practice Los Angeles Assistant Clinical Instructor David Geffen School of Medicine University of California Los Angeles USA

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

Marc D. Glashofer MD, MS Dermatologic Surgeon Island Dermatology Long Beach New York USA

Derek Jones MD Founder and Director Skin Care and Laser Physicians of Beverly Hills Clinical Associate Professor Dermatology David Geffin School of Medicine University of California Los Angeles USA

Rhoda S. Narins MD Director, Dermatology Surgery and Laser Center Clinical Professor of Dermatology New York University School of Medicine New York USA

Chad L. Prather MD Director, Dermasurgery Center Baton Rouge Louisiana Clinical Assistant Professor Department of Dermatology Louisiana State University New Orleans USA

Adam M. Rotunda MD Assistant Clinical Professor, Division of Dermatology (Medicine) David Geffen School of Medicine University of California Los Angeles USA

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Contributors

Nowell Solish MD, FRCP Assistant Professor, Dermatology University of Toronto Toronto Canada

Arthur Swift MD, Cm, FRCS(C) Director West Mount Institute of Plastic Surgery and Victoria Park Memorial Spa Montreal, Canada Clinical Lecturer, Department of Plastic Surgery, McGill University Montreal Canada

Danny Vleggaar MD Medical Director, Centre Dermato-Cosmetique ‘Roseraie’ Geneva Switzerland

Phil Werschler MD, FAAD, FAACS Assistant Clinical Professor of Medicine/Dermatology University of Washington School of Medicine Seattle USA

Naissan O. Wesley MD Skin Care and Laser Physicians of Beverly Hills Los Angeles, California USA

C H APTER 1

The Cosmetic Patient Consultation Phil Werschler Department of Medicine/Dermatology, University of Washington School of Medicine, Seattle, Washington, USA

As aesthetic, or cosmetic, dermatologists, an integral part of successful practice includes the “cosmetic patient consult” (CPC). Although this term is used liberally, its actual definition remains somewhat nebulous. Certainly, there are portions that are universally agreed upon, such as consent form signing, price quotation, and pre-treatment photographs. However, there are many more less well-defined components to the process that are equally important to both the treating provider and the treated patient for optimal outcome. For the purposes of this introductory chapter, certain assumptions will be made about the CPC process. Chief among these is the accomplished skill set of the treating provider, whether a physician, mid-level provider, registered nurse, or aesthetician/office staff. It is assumed that the CPC will not be performed for the benefit of training the staff in the particular procedure. It is also assumed that the office possesses the requisite resources and capabilities to fully perform and complete the particular procedure being offered. Finally, it is also assumed that the CPC is being conducted in “good faith,” i.e. with full disclosure of the training, experience, and outcomes of the same or similar procedures being fully discussed.

Cosmetic office practice With that as a background, the next step is to determine the cosmetic office practice (COP) level of the dermatology practice. First proposed in the mid-1990s by Craze and Werschler,1 this is a simplified method of determining the relative contribution of resources that a practice devotes to the development of “desire” dermatology. Using a four-point scale, this descriptive methodology is capable of generally categorizing the relative level of sophistication of a dermatology practice toward the delivery of elective cosmetic services. Injectable Fillers: Principles and Practice. Edited by Derek Jones. © 2010 Blackwell Publishing

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Chapter 1

Briefly, the four levels are described as follows: 1. Non-cosmetic, i.e. no particular skills, resources, equipment, marketing, or other efforts made beyond that of the usual general “disease”focused dermatology practice. 2. Some cosmetic, usually represented by a particular focus of expertise of equipment, skills, or other assets that provide elective services. A good example of this would be a center of excellence in lasers within a dermatology practice. 3. Balanced, or blended, practice of disease and desire dermatology: usually represented by a broad range of skills across multiple areas of expertise, all being considered in the “core scope” of dermatology and dermatologic surgery. Many practices in the USA and Canada are considered “balanced.” 4. All cosmetic, or a practice that typically offers only elective services that would be considered cosmetic in nature. These practices may exceed the usual scope of dermatology to reflect the unique skill sets of the providers. Examples of this could include facelift and breast augmentation procedures. Considering that most dermatology offices today operate at the second and third levels of COP (focused or balanced) and those that aspire to these levels all share the same basic challenges, the following discussion targets COP levels 2 and 3.

The three components of CPC The three essential components to a successful CPC consist of the setting, education, and assessment. These three integrated pieces are the proverbial three-legged stool: if any one is missing, the result is an unbalanced and hazardous situation. Of the three, the provider is most crucial in the assessment and, in some cases, assessment cannot be performed without the treating provider. Depending on the personal preferences of the provider, both the setting and education can be either a “hands-on” or “hands-off” affair.

Setting Understanding organizational selling is the first step in achieving a proper “setting” for the CPC process. Although many physicians mistakenly believe that the initial face-to-face contact is the most important step in the process of a successful CPC, it is actually close to the last step of the process. For most cosmetic dermatology practices, there is a preframed geographically determined catchment area. If the practice has been in existence for any significant length of time, there is usually limited general

The Cosmetic Patient Consultation

3

public awareness of the types of procedures and products available. This awareness may be founded on reputation, advertising, marketing efforts, location, etc. Identifying and controlling this “general awareness” is really the first step of the setting for the CPC. Although this chapter is not intended to discuss marketing, advertising, and communication efforts for cosmetic dermatology practices, suffice it to say that this is a commonly overlooked area of practice development. Expert consultation is certainly available for those interested in pursuing further evaluation in this area. What organizational selling means to the cosmetic dermatology practice is the education of all employees on the products, services, and procedures offered by the business. Organizational selling does not mean that every office employee is a salesperson; indeed the actual selling of a product or service needs to be a tightly managed affair. Organizational selling is the systematic, methodical process of educating internally on the resources and capabilities of the entire office. This includes the unique assets of the providers, the equipment, the office setting, design, accreditation, etc. In its truest form, it means that any employee, from the billing clerk to the records clerk to the Mohs’ technician to the medical assistant, is capable of responding to a question, a request, a phone call, or even a third party inquiry about the services offered. This type of education takes dedicated training and frequent communication from the leadership of the office to be relevant and effective. It is essential to the success of the cosmetic dermatology practice. This type of staff training also facilitates the entire process of the setting in that it allows the prospective cosmetic patient to progress seamlessly from being an interested party to an office visitor without receiving any conflicting information. Organizational training also supports collateral information dissemination, such as telephone information scripting, patient handouts, brochures, internet presence, etc. Ideally, the prospect (individuals are not patients until they are actually treated; during the consultative process they are technically a prospect) continues to receive the same, non-conflicting information flow from the first contact with the office (internet, telephone, direct mail, etc.) to their first visit, to the actual consultation, to the day of procedure, and finally to the time of completion of follow-up of any procedure(s) performed. This process should be seamless from the patient’s perspective. Once the patient reaches the office for the scheduled consultation, great care should be taken to ensure that he or she is promptly and politely received. As dermatology differs so greatly from plastic surgery in terms of office patient numbers and flow, it is recommended that consultations not be scheduled during busy clinic hours if performed by the provider.

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Chapter 1

In addition, consideration should be given to alternate times and days of the week, including weekends, for scheduling of the CPC. Further, certain types of procedures or services may be offered in a group setting, such as an evening office information seminar. A good example of this would be new skin care products or services that are generally applicable to larger number of individuals. The actual consultation may be performed by a dedicated patient cosmetic coordinator or by the treating provider, depending on the particular preferences of the office and the nature of the procedure. Certainly, the information needed for a simple botulinum toxin injection requires a more basic level of education than that needed for liposuction. There should be a defined time limit for the consultation; this avoids the potential issue of “not enough time” in the patient’s mind. Commonly, this is 30 minutes and can be varied for different types or combinations of procedures. More than 30 minutes may be excessive, and can actually be counterproductive if the conversation is not kept tightly focused. The actual location of the CPC needs to be carefully evaluated. Although there is no actual correct or incorrect way to locate the consultation, it is generally felt that a separate room is best. This can be the physician’s office, an exam room, or ideally a dedicated space within the office. Sometimes referred to as the “closing” room, a dedicated space provides optimal comfort for both the prospect and the consultant. The dedicated consultation room also has many advantages, including privacy, décor, and ready access to all materials including printed, video, internet, and even photographic. The space is kept free of staff transit during the consultation, and generally there is a different ambiance in the room. Here, patients feel much more comfortable discussing their personal desires and fears, feel more relaxed, and less nervous than in an exam room. The room should be well lit for exam and use of a mirror. Mirrors should include hand-held, magnifying, and full-length varieties. Some offices even use a dressing room-style three-way mirror, especially if body work such as liposuction is discussed. The furnishings should include as a minimum one or two large comfortable chairs and perhaps a small couch. Remember, frequently a cosmetic consult consists of more than just the prospect, and can include spouse/partner, family member(s), or friend. The room may have a completely different interior design and color scheme to the rest of the office, including floor coverings, window treatments, and furnishings. It should be equipped with the necessary hardware and software to access and schedule the patient procedure in private. All necessary collateral materials, including consent forms, lab requisitions, release of information requests, etc., should be readily on hand. The room should be kept spotless at all times and be supplied with fresh bottled water and possibly hot water/coffee for patient convenience.

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The room should be very quiet, even adding extra soundproofing materials if necessary. The necessary diplomas, certificates, awards, etc. should be displayed as a form of external reference for the reassurance of the client. Finally, it is recommended that a clock be prominently displayed in easy view. This helps to establish a timeline for both parties. Consultations can always be extended and/or rescheduled if more time is necessary. With regard to the actual time scheduling of consultations, it is recommended that they not be performed on a “back-to-back” timeline. This is because the consultant should have sufficient time between clients to perform the needed chart documentation, write any personal notes, including a thank-you note to the client, and prepare for the next consultation. Generally, 15 minutes is sufficient for these tasks. Also, this 15minute block in the schedule helps to maintain an on-time performance for late-arriving patients, phone messages, follow-up calls, etc.

Education The ideal CPC is really an exercise in patient education. Generally, in dermatology, the prospective patient will arrive with a narrow set of desires and expectations. They may not know which dermal filler they desire, but they know that they would like bigger lips or higher cheekbones. They usually have some limited education and knowledge from a friend who has had a similar procedure or from a fashion magazine or internet site. Their primary purpose of the consultation is to determine three things: Do you do this procedure (skill)? Do you want to do it to me (appropriate candidate)? How much does it cost? The role of the consultant is to answer these three questions in an expanded format and to include risks, benefits, and alternatives available, whether through this office or another (fillers vs facelift; plastic surgeon vs dermatologist) more appropriate specialty. In addition, the consultant needs to help determine if the patient has the appropriate mental capacity and awareness to give consent and be able to comply with any needed follow-up care or visits. Although the treatment provider will ultimately make this decision, the consultant can play a vital screening role in the process. Once the prospect has been given the basics of education, support materials may be used, such as brochures and consents. These are add-on materials, and should not be used in place of a consultation. Some offices use additional customized materials such as DVDs and photograph albums. Others use reprints of journal articles, website printouts, etc. Regardless of the materials used, all should be documented in the patient chart, and all CPCs should result in a medical chart, even if the prospect has never been and is never treated in the future by the office. This is thorough record keeping, and is an essential part of smart medicolegal practice.

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For some procedures this entire education process is a simple matter. It may be accomplished in a few minutes, documented, and scheduled or performed before the patient leaves the office. For other procedures, it may be just the first step in a lengthy process that may include several pre-treatment visits and sessions to include photography, review of lab work, consultation with referring physicians, and pre-procedure physical examination and even psychological screening questionnaires. With regard to price quotes, there are generally two schools of thought: the first is that every patient is a unique treatment challenge, and prices are individually determined based on these unique attributes. The other is to use a predetermined price list, and if deviations are needed these are explained to the patient individually. Dermatology offices, given the nature of the procedures performed, typically use price lists. Regardless of the approach, the price quote needs to be openly discussed and agreed upon by the patient before performing the procedure. The best method to accomplish this is with the use of consultation sheets. These are two- or three-piece carbon-copy-type forms with a listing of procedures and prices typically hand written on a graphic of the face and/or body. The patient receives a copy of the completed form either at the end of the consultation or in the mail in a day or two after the consult. The other copy is placed in the chart. For price quotes, there is typically a 90-day guarantee that the price will be honored. This allows the prospect to have a reasonable time to consider the options and the procedure before committing. If they have additional questions, they can follow up with a phone call or a second consultation. For the actual cosmetic consultation, office policies very widely with regard to charging: most offices do not charge when the consultation is not performed by the physician. When the physician is using his or her time to do the actual 30-minute consult, it is common to charge a fee. Typically, this ranges from US$100 to $500. This fee is applied to the first procedure. Somewhat different from our plastic surgery colleagues, most cosmetic dermatology procedures are less than $5000, with many in the $1000–2500 range. Therefore, the rationale is that it is difficult to recoup lost revenue with these smaller charges, and the consult fee is one method to minimize these lost fees. The cosmetic coordinator should follow up in 7–10 days (with permission) if the prospect has not scheduled the procedure or contacted the office for additional information. This closure provides for a call to action, and increases the efficiency rate of the cosmetic coordinator. Frequently prospects have a few remaining questions and, if answered to their satisfaction, they will book the procedure. When booking, similar to paying the first night when making a hotel reservation, the usual approach is to pay half of the quoted procedure price to “reserve” the appointment slot; the second half is then usually paid the day of the procedure, before having it done. For cancellation or

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“no-shows,” there should be a very clear and precise written policy that is signed when the appointment is made. Commonly, a 24- to 48-hour cancellation is required to receive a refund. Anything less than 24 hours, unless an emergency, is problematic for the office. Some offices, as a gesture of goodwill, will apply all or a portion of the forfeited deposit to the next appointment if scheduled at the time of cancellation. Good judgment is necessary to manage these last minute no-shows and cancellations. For some minor procedures such as toxins and fillers, where there is a variable in the final price, a deposit of $100 is common to book the appointment. This can be requested by the front office scheduling desk at the time that the appointment is made to facilitate patient convenience.

Assessment For the actual procedure on any specific patient, it is clearly the responsibility of the treating provider to determine to the appropriateness of the patient and the requested procedure. This may consist of the actual physical evaluation, a mental status evaluation, comorbidities and overall health status, and any other complicating factors. Remembering the acronym “ICG/RBE” for informed consent given and risks and benefits explained for the particular patient is an excellent way to approach the assessment. Some patients are clearly not good candidates for their desired procedures. Although this alone is not cause to withhold or deny cosmetic treatment, it should always be explored with the patient. Some, by virtue of age, health, medication, risk tolerance, timeline, or budget, may actually be better candidates for a suboptimal treatment than one would expect. The facelift patient who requests non-surgical facial tightening may be doing so because of a variety of valid reasons. However, if they discuss the procedure as a shortcut or budget version of what they really desire, or because their spouse or significant other wants them to have it done, it may be a better option to decline treatment. There is an old adage in cosmetic work that “you don’t regret the patients you turn down, you regret the ones you should have turned down.” From personal experience I find this to be true. As the experience level of the cosmetic dermatology office develops, it will become easier and easier to create a smooth and seamless experience for the prospect who becomes a client who then becomes a patient, and when satisfied with their experience, becomes an advocate for your practice. When careful, purposeful, and consistent staff education and training are combined with a dedicated approach to patient education, it is a natural result for the cosmetic portion of a dermatology practice to flourish.

References 1. Werschler WP, Craze MG. Cosmetic Office Practice – A Novel Perspective. Progressive Clinical Insights January/February 1998;6(1):24–5.

C H AP TER 2

Guidelines for Local Anesthesia in Use of Injectable Fillers Mariano Busso Private practice, South Florida

Anticipation of – and treatment for – pain remains an important consideration for physicians preparing to administer injectable dermal fillers. Historically, anesthesia protocols constituted the “pre-treatment” part of the injecting regimen. Recently, some physicians have started to combine anesthesia, such as lidocaine, with the injectable dermal filler itself. The combined solution of dermal filler and anesthesia is administered together. Both of these categories – mixing and pre-treating – are discussed in this chapter.

Option I: Mixing anesthetic with dermal filler immediately before administration In the relatively short period of the arrival of dermal fillers for aesthetic applications, the conventional anesthetic protocol has been pre-treatment of the area with anesthetic agents. However, some of the dermal fillers lend themselves nicely to a different anesthetic approach, namely mixing the anesthetic with the dermal filler itself, just before treatment. This mixing approach with calcium hydroxylapatite (CaHA – Radiesse) first appeared in the literature in late 2007.1 Anecdotal reports suggest both rapid and widespread adoption by physicians (personal communication, Brian Pilcher, Vice President of Medical Affairs, BioForm Medical, 2009). The mixing itself is fairly straightforward. It requires the injectable dermal filler in one syringe and the lidocaine – or lidocaine plus epinephrine – in another. In the case of Radiesse, the 1.3 mL syringe is connected to a 3.0 mL syringe of anesthetic, using a Rapid Fill LuerLok-to-Luer-Lok adapter (Baxa, Englewood, CO). The dermal filler is introduced into the syringe containing the anesthetic first; then the newly combined Radiesse and lidocaine is pushed back and forth from syringe to syringe (Figure 2.1). Approximately 10 passes are sufficient for homogeneous distribution of Radiesse and anesthetic.2 Injectable Fillers: Principles and Practice. Edited by Derek Jones. © 2010 Blackwell Publishing

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Figure 2.1 Radiesse (1.3 mL) combined with lidocaine (0.1 mL), immediately before

injection.

An article published in 2008 explored in detail possible changes to the calcium hydroxylapatite that might arise when the compound was mixed with lidocaine.2 In setting up the study, researchers examined several lidocaine concentrations to determine the dynamic viscosity, extrusion force, and needle jamming rate of the mixture compared with the commercially available Radiesse. Researchers found that the pH of the Radiesse–lidocaine admixture remains closely equivalent to the pH of the Radiesse alone. The viscosity of the blend is lower than the viscosity of the Radiesse by itself, as is the extrusion force. In addition, the “spreadability” of the dermal filler is improved, making it more malleable after its injection into soft tissue. Nevertheless, the mixing does not appear to compromise the inherent physical properties of the dermal filler. Interestingly enough, the use of this admixture first arose in the context of treatment options for the aging hand. Treatment of the hand had heretofore been considerably constrained by the pain induced by injection of any dermal filler in that area. An alternate approach was conceptualized. Rather than administer anesthetic to the hand, a bolus of the dermal filler plus lidocaine mixture was instead injected directly under the skin. The mixture was then spread throughout the hand using firm massage. The immediate result of this approach – mixing anesthetic with CaHA – was a treatment that is easier to massage and disseminate, less painful to the

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patient than conventional hand injection, and characterized by less swelling and bruising, with minimal post-treatment downtime. Benefits for physicians who choose to mix this dermal filler with lidocaine may include reduction of “confounding edema” that arises from pretreatment infiltration of the lidocaine alone, less need for nerve blocks, and shortened treatment times. The authors opine that mixing the dermal filler with lidocaine “allow larger volumes to be injected in one treatment session, such as those necessary for full facial recontouring.”2 Note Injection of the dermal filler Radiesse mixed with lidocaine received approval by the Food and Drug Administration in the second half of 2009. Although this mixing approach would appear to be applicable to other dermal fillers in addition to calcium hydroxylapatite, some caution is warranted until more information appears in the clinical literature.

Option II: Pre-treatment with anesthetic agents Unless the physician is using the mixed combination of anesthetic and injectable dermal filler, the use of local anesthesia is ordinarily advised. Pre-treatment anesthetic agents include nerve blocks, tissue infiltration, topical anesthetic, and skin cooling. Nerve blocks provide total anesthesia to the area being treated, by anesthetizing the main trunk of a nerve. In tissue infiltration, anesthesia is injected just below the skin in the surrounding area that is to be treated with dermal filler.

Topical anesthetics EMLA Cream, one of the first and most studied topical creams, is a eutectic mixture of local anesthetics, a prilocaine 2.5% and lidocaine 2.5% cream. Onset of action is within 1 hour and duration 1–2 hours after removal of the cream.3 LMX-4 (previously called ELA-Max) is a liposomal delivery system that allows a 4% lidocaine preparation to be rapidly absorbed by the skin. The rapid absorption also results in a rapid dissipation of the drug, with diminishing anesthesia approximately 40–60 min after application.4 Synera (formerly S-Caine Patch) consists of tetracaine and lidocaine mixed 7%:7% in a self-contained patch. The product is designed to look like a child’s bandage and is recommended for children aged 3 years and older. Synera contains a heating element that, when activated, enhances absorption, allowing for rapid anesthesia and some degree of vasodilation.

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Side effects of topicals warrant discussion. EMLA, in particular, is associated with angioedema, contact dermatitis, burning, stinging, and even methemoglobinemia. Although rare, methemoglobinemia is more likely in preterm infants. It is contraindicated in children less than 1 month of age.3 All of these topical agents likely require some time before numbing is complete. In addition, lidocaine tips (“Caine tips”) and mucosal swabs are helpful for numbing the mouth.

Physical aids Physical aids include vibrating, icing, and cooling (Zimmer Chiller). The use of vibration for analgesic purposes is based on the gate control theory. Vibration information is received by vibration receptors (pacinian corpuscles and Meissner’s corpuscles) and is conducted by Aβ nerve fibers which stimulate inhibitory interneurons in the spinal cord. These neurons reduce the amount of pain signal transmitted from thinly myelinated Aδ-fibres and fine unmyelinated C-fibers across the midline of the spinal cord and from there to the brain. Vibrations, icing, and chilling provide a temporary anesthetic condition so that the pain of injection is somewhat mitigated.

Environmental aids Finally, environmental aspects can be modulated so that anxieties of the patient are lessened. These include soothing music and talking softly (“talkesthesia”) with the patient throughout the injection period.

Tips for reducing discomfort Pain is always a consideration by providers and patients alike. These tips can help reduce discomfort of anesthesia as well as injection of dermal filler: • Introduce the needle as slowly as possible • Inject as slowly as possible • Use the thinnest needle gauge possible • Inject through areas that are already numb • Use longer needles if possible, to reduce the likelihood of needle pricks • Warm up anesthetics and injectable fillers to body temperature • Buffer xylocaine, if possible.

General comments about use of local anesthesia using lidocaine solutions Generally speaking, use of 1% or 2% solutions is preferred, due to safety of the decreased milligram per milliliter concentration. Epinephrine may be added to help reduce tissue swelling and bruising. However, side effects of

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its administration include tachycardia and increased anxiety. Before the addition of epinephrine, the physician should determine whether the patient has a known sensitivity to it. In addition, the weight of the patient is a consideration in use of epinephrine. Maximum lidocaine dosing without epinephrine should not exceed 3.5 mg/lb of body weight. Maximum lidocaine dosing with epinephrine should not exceed 2.0 mg/lb of body weight. Use of 1.0 mg/lb reduces the likelihood of untoward lesser adverse events.

Treatment supplies for dermal filler injections The following list of supplies may be helpful for physicians as they develop their protocols for pretreatment anesthesia and dermal injection: • 27G 1¼-inch and ½-inch needles • Nerve block medication – lidocaine 1–2% • Localized infiltration medication – lidocaine 1–2% with 1:100 000 epinephrine • 3 mL syringes and needles for numbing • 30G 1-inch or 27G 1¼- or ½-inch needles for numbing • Crushed ice or gel cool packs • Non-latex gloves • Mirror • 3 × 3 gauze pads • Sharps container • Camera for before and after photos • Signed consent form • White eyeliner pencil for marking • Alcohol pads for cleansing area • Arnica gel or other topical ointment for massaging area (optional).

Distribution of sensory nerves in the mid- and lower face Sensation for the middle and lower thirds of the face is provided by the two branches of the trigeminal nerve (cranial nerve V – Figure 2.2). The infraorbital nerve (V2) exits the infraorbital foramen. It supplies sensations to the middle third of the face, i.e. infraorbital area, nasolabial folds (NLFs), and cutaneous lip. The mental nerve (V3) exits the mental foramen. It supplies sensation to the lower third of the face, i.e. the lower lip, the medial/lateral chin, and parts of the jawline.

An infraorbital block From the author’s clinical perspective, a true infraorbital nerve block is required only when treating the lips. Nevertheless, some physicians

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Figure 2.2 Distribution of sensory nerves in the mid- and lower face.

maintain that an infraorbital nerve block is ordinarily required for midface augmentation, unless the anesthetic is being added to the dermal filler itself (see “Mixing anesthetic with dermal filler immediately before administration” above). The anatomy of the infraorbital nerve is easily located. It exits the foramen along a line between the patient’s pupil and canine tooth, bifurcating almost completely medially, then again down toward the ala, with a third large branch descending almost directly beneath the foramen to just above the oral commissure (Figure 2.3). A 30G, 1¼-inch needle is typically used. Injection is into the buccal mucosal groove, in line with the base of the ala, aiming diagonally up toward the pupil. Aspiration should be deployed to avoid injection of anesthetic intravascularly. With the needle inserted from ½ inch to ¾ inch and with the bevel facing down toward the bone, one microdrop should be injected, followed by a pause, and then additional microdrop injections for a total of 0.5–0.75 mL of lidocaine solution. The area should be massaged before repeating the procedure on the contralateral side. Care must be taken with large volumes of injected lidocaine; they may distort tissues and mask the area to be augmented.

A “mini-block” for treatment of NLF When treating NLF, a total infraorbital block is usually not required. Instead, a “mini-block” can provide enough anesthesia to the area of injection (Figure 2.4). This mini-block limits the length of time that the patient’s

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Figure 2.3 Anesthetic injection route and pathways of the infraorbital nerve.

Figure 2.4 Anesthetic injection routes for “mini-block.”

face will be numbed. This procedure will infiltrate branches of the infraorbital nerve but it is not a true infraorbital block. For the mini-block, either a 27 or 30G 1¼-inch needle is acceptable. Injection of anesthetic may be transcutaneous or through the mucosa. If injecting through the

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mucosa, injection of local anesthetic (0.25 or 0.3 mL) should be above each canine and the second bicuspid of the buccal mucosal groove. The needle should be inserted slightly lateral to the canine (third tooth from midline), with the tip of the needle directed toward the ala. Insertion of the needle should only be approximately 2–3 mm above the canine. No further insertion is recommended. The syringe should be aspirated, so that intravascular anesthetic is avoided. One microdrop can be injected, followed by a momentary stop, and then advancement of needle another millimeter or so, continuing to inject microdrops. The key to painless injection is to inject very slowly. Pain upon injection of local anesthesia is associated with distension of tissues from too-rapid injection.

A mental nerve block A mental nerve block is ordinarily required for lower-third face augmentation, unless the anesthetic is being added to the dermal filler. The mental nerve can be visualized by pulling the lower lip away from the gum (Figure 2.5). The same length and gauges mentioned earlier may be used. Injection is a two-phase process: first, the needle is inserted into the buccal mucosal groove, aiming toward the “papillary” line. One microdrop should be injected, followed by a pause, then a resumption of microdrop injection

Figure 2.5 Anesthetic injection routes and pathways of the mental nerve.

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of 0.5–0.75 mL of anesthetic. When the lateral microdrop injections have been completed, the needle is backed toward the insertion point, and reoriented halfway between the previous injection area and the chin midline, i.e., moving vertically toward the midjowl sulcus. Another 0.25 mL anesthetic can be injected in this area. The injected region should be massaged, and the procedure repeated before dermal filler injections on the contralateral side.

Local tissue infiltration Some of the areas injected in facial contouring applications are not served by either the infraorbital or the mental nerves (Figure 2.6). These areas include the lateral brow, malar and submalar regions, the nasal dorsum, inferior NLF, corners of the mouth, marionette lines, the prejowl and mandibular lines, and areas of scar tissue. Injection is performed in the subdermal layer of the skin to provide anesthesia to the immediate areas of injection. Tissue infiltration is used to provide anesthesia to areas not supplied by infraorbital or mental nerves. Tissue infiltration may also be a substitute for blocks and used to numb any area where filler is to be placed, incorporating blanching properties of epinephrine in the area of potential filler injection. However, the infiltration may also distort the tissue.

Figure 2.6 Areas not served by infraorbital and/or mental nerves may require tissue infiltration.

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Injection of small volumes is preferable, to minimize distortion of the augmentation area. A lidocaine solution containing epinephrine can significantly reduce ecchymoses, edema, and erythema due to the accompanying vasoconstriction. The recommended ratio of lidocaine to epinephrine is 1% : 2% lidocaine, with 1:100 000 epinephrine. Although diluting the epinephrine even further can reduce the risk of these adverse events, patients who are sensitive to epinephrine should still be counseled about potential tachycardia and generalized anxiety. For malar, submalar, prejowl sulcus, inferior mandible, and midface infiltration, a 30G, 1¼-inch needle should be used. For marionette lines, oral commissures, nasal dorsum, and lateral brow, a ½-inch, 27G needle is appropriate. Before injection of anesthetic, areas should be cleaned with alcohol. Ice before anesthetic injection helps minimize bruising potential. Post anesthetic injection, the area should be massaged lightly to help disperse the solution into the tissue.

Conclusion Physicians have a choice of mixing their dermal filler with anesthetic or, if they choose, administering conventional pre-treatment anesthetic agents and then administering injectable dermal filler. Those topical agents can be supplemented with physical and environmental aids to reduce discomfort. The option of combining the dermal filler to be injected with the anesthetic of choice provides physicians the benefit of faster treatment times without sacrificing outcomes. Moreover, patients who feel less pain tend to be more satisfied patients, who in turn tell their friends. The result for the physician is a larger and more satisfied patient base. The result for the patient is higher satisfaction. Both results are equally desirable.

Acknowledgments Some of this material originally appeared in a publication produced by BioForm Medical, Inc. (ML00299-00). The author appreciates the cooperation of BioForm Medical, Inc. in the use of the illustrations in this chapter and the editorial assistance of David J. Howell, PhD, RRT (San Francisco, CA).

References 1. Busso M, Applebaum D. Hand augmentation with Radiesse® (calcium hydroxylapatite). J Dermatol Ther 2007;20:315–17.

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2. Busso M, Voigts R. An investigation of changes in physical properties of injectable calcium hydroxylapatite in a carrier gel when mixed with lidocaine and with lidocaine/epinephrine. Dermatol Surg 2008;34:S16–24. 3. Lacy CF, Armstrong LL, Goldman MP, Lance LL, eds. Drug Information Handbook, 9th edn. Hudson, Ohio: Lexi-Comp Inc., 2001. 4. Britt R. Using EMLA cream before venipuncture. Nursing 2005;35(1):17.

C H APTER 3

Hyaluronic Acids: Basic Science Nowell Solish Dermatologic Surgery University of Toronto, Toronto Canada

Kenneth Beer Esthetic, Surgical and General Dermatology and Department of Dermatology, University of Miami, Florida, USA

Differences in hyaluronic acid fillers have profound consequences for their interactions when injected into the skin and subcutaneous tissues. The literature about fillers is replete with anecdotal evidence and opinions about which hyaluron is better or worse, more or less inclined to bruise, softer, harder, or more durable. The science behind these various claims is not only fascinating but also helpful in understanding the strengths and weaknesses of the various products. This, in turn, may help clinicians select products to achieve optimal patient outcomes. In order to understand the differences between the hyaluronic acid fillers (also known as hyalurons, HAs), it is useful to understand their similarities. All HA molecules are naturally occurring linear polysaccharides which are uniquely conserved throughout species. These polymeric chains are identical in all species. There is no antigenic specificity for species or tissue, and therefore a low potential for allergic reactions, so different sources of HA will produce identically structured polymers. The only difference is that bacterially derived HA chains tend to be shorter than those that are derived from animals. Hyalurons are found in the extracellular matrix of connective tissue, synovial fluid, and other tissues including the ground substance of the dermis, fascia, extracellular matrix of the eye, hyaline cartilage, synovial joint fluid, and many other support structures in the body.1 Structurally, these molecules are polyanionic disaccharide units of glucuronic acid and N-acetylglucosamine2,3 (Figure 3.1). The disaccharide monomer has a molecular weight of approximately 400 Da.2 Monomers

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Figure 3.1 Hyaluronic acid monomeric unit.

are connected by alternating β1–3 and β1–4 bonds.2 When connected these repeating disaccharide units form long linear chains. This is referred to as a polymer. These, in turn, may be crosslinked to form very large macromolecules. When exposed to aqueous solutions, hydrogen bonding between adjacent carboxyl and N-acetyl groups occurs. Hydrogen bonding results in a clear viscous gel which is not only stiff but also retains water. Hyaluronic acid molecules are very hygroscopic and 1 g HA can bind up to 6 L of water.1

Hyaluronic acids as dermal fillers HAs have a very short half-life when injected into human tissues. The half-life in humans is at most only a few days. After injection, naturally occurring hyaluronidase will digest non-crosslinked HAs, resulting in water and carbon dioxide. In order to stabilize these molecules and make them persist, it is necessary to crosslink the chains. There are various methods to crosslink these chains and various degrees of crosslinkage that occur. The method and degree of crosslinking have a significant impact on the physical characteristics of the molecules. The raw HA used by various companies to produce their soft tissue augmentation products is frequently obtained from similar sources. Supplied as a raw powder, this material forms a viscous liquid when exposed to water. However, in order to create a gel that is able to persist once injected, the raw material gel must be modified. It is the method of modification that imparts the various attributes to the different gels and it is essential to understand these differences in order

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to understand what is or is not different between various commercial preparations.

Crosslinking Crosslinking is a must for stabilization of the HA for cosmetic injection. Most companies obtain their HAs from similar sources, usually supplied as a powder of raw HAs. Being hygroscopic they form a viscous structure when exposed to water. This gel starts to resemble the products injected into patients for soft-tissue augmentation as well as for intraarticular injections for arthritis. However, it is still unstable and must be crosslinked to provide stability or it will quickly degrade once injected into a person. To link the HA chains and prevent them from being digested, at the present time, there are three different crosslinkers approved by the Food and Drug Administration (FDA). Restylane, Perlane, and the Juvéderm line use BDDE (1,4-butanediol diglycidyl ether) as the crosslinking agent. Prevelle Silk uses DVS (divinyl sulfone) and Elevess uses BCDI (biscarbodiimide).1,2,4 Each of these chemical agents will provide stability to the HA chains and has its own advantages. However, once these products have done their job, it is essential that they be removed from the finished product, mostly by extensive washing steps built into the manufacturing process. Each of these agents is toxic to tissue in any meaningful concentrations, and their final concentrations are limited to trace amounts by the FDA. The residual concentration of crosslinking molecules is a potential hazard for the safety of the final product and is one factor considered by the FDA and physicians injecting these products. For practical purposes, the amount of crosslinking molecule in many of the HA fillers is virtually non-detectable. As each of the molecules has its own proprietary crosslinking mechanism and each has a different degree of crosslinking, it is important to have some benchmarks against which to measure. Typically, the amount of crosslinking is reported as a percentage or degree. This compares the ratio of disaccharides with crosslinkers present in the formulation. One consequence of increased crosslinking is to increase the viscosity as well as the longevity of the HAs (all other factors remaining equal.2,5,6 This implies that increased crosslinking is optimal for injectable HA products. However, crosslinking the molecules beyond a certain point might make the product less biocompatible and result in a foreign body reaction. However, none of the currently FDA-approved products has passed this point of extensive crosslinking.

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Concentration One of the most important determinants of the degree of correction obtained is the amount of HA concentration, but this is not a straightforward measurement. The concentration of HA (mg/mL) includes both crosslinked HA and free (non-crosslinked) HA. Non-crosslinked HA is added to the various fillers as a lubricant and it helps to make the products flow. However, the non-crosslinked products add nothing to the final correction and a new term, ‘effective HA concentration’ (effective HA (EFA) = total HA – non-crosslinked HA) is a better measure of the HA that will contribute to tissue correction. The concentration of HA has not only important implications for longterm correction but also material bearing on initial reactions once injected. Their hygroscopic nature means that the more concentrated products will tend to imbibe more water and, thus, have more tissue swelling after injection. After a steady-state equilibrium has been reached with the surrounding tissue, more concentrated products will maintain more swelling and have more fullness in the area injected.

Gel hardness Gel hardness is affected primarily by the degree of crosslinking between the chains and the total HA concentration. More heavily crosslinked products tend to be stiffer than less crosslinked products.2,5,6 Gel hardness is measured as different values of G′, the elastic modulus. Every other parameter being equal, gels with low G′ will have less crosslinking and be less stiff than those with higher G′. Products with higher G′ will be stiffer, harder to displace.2,5,6 Again every other parameter being equal, the higher the G′ the more difficult it will be to push the product through a needle. Measuring G′ is typically done by putting a gel between two metal plates. The amount of resistance encountered by the top plate as it slides over the gel correlates with the G′ for that gel (Figure 3.2). Besides HA

Plate 1 HA Plate 2

Fixed

Figure 3.2 Gel Harness is measured by placing the gel between two plates. The bottom plate is fixed and the top plate is moved horizontally. The force required to move the top plate relative to the lower plate results in the G′ (Elastic modulus).

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concentration, other factors will also effect the G′ and these can include the amount of free HA present in a gel and the molecular weight of the raw material used in the formulation, e.g. the more free HA present, the more lubricant the gel and the easier the product will flow.

Particle size HA gels are usually produced in large blocks of material (Figure 3.3). Once the gel blocks are manufactured they have to be reduced in size in order to pass through a syringe and needle. The gel blocks may be reduced by methods that behave as screens, as is done with NASHA particles. These NASHA particles (Restylane and Perlane) are produced so that the final particles are of a similar size with standardized shapes. Particulate gel particles have some interesting physical features. Some will conform and bend when pushed through a needle, and others will become sheared if pushed through a small orifice with sufficient force. One hypothesis holds that the larger particles found in Restylane, and especially in Perlane, have a surface to volume ratio that is resistant to

Figure 3.3 NAHSA™ molecule prior to shearing.

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enzymatic breakdown by hyaluronidase. This implies that larger particles will have longer tissue residence and that they will maintain more of a correction for increased amounts of time. However, contradicting this assertion is the fact that both Restylane and Perlane (which have very different particle sizes) have the same duration of correction in the nasolabial crease. This is believed to be due to the porous nature of the particles which negates the surface area affects. A second way of changing the size of the gel-blocked produced is referred to as homogenization. This method is used for the Juvéderm family of products.2 Homogenization results in particles that are less consistent in their size. The variation in particle size is partially responsible for the lower G′ of the products. This lower G′ has positive effects on the flow characteristics, not only as it passes through the needle orifice but also as it dissects the dermal plane once injected. The increased homogenization products have more consistent injection properties, resulting in better injection characteristics. It should be noted that easier injections may also be obtained by adding free HA but the latter will not result in any meaningful correction or duration. In addition to the method of particle production and free HA, another variable that affects the extrusion force is the viscosity (η′) of the gel particle.2,5,6 A gel that has a higher degree of crosslinking will have a higher viscosity and therefore a higher extrusion force. Higher extrusion force products are more difficult to inject and require more force to get them into the dermal planes. One other variable that affects the physical characteristics of the gel is the cohesivity of the product. This is the parameter that is related to the product’s ability to retain its shape on injection. When a dermal filler is implanted into the skin, the natural elasticity or tension of the skin will tend to deform and flatten out the implant, reducing the initial desired correction. In principle, the “lifting” capabilities of a dermal filler (opposing its deformation) primarily rely in two material properties, namely the elastic (also known as storage) modulus G′ and the cohesivity of the fluid. Of these two parameters G′ can be measured using a standard test protocol on a rheometer.2,5,6 Cohesivity, on the other hand, can be measured with the use of a parallel plate rheometer, by lowering the upper plate at a constant speed against a known mass of the filler, while measuring the normal force opposing its deformation. A higher value of the normal force represents a higher resistance to deformation and a higher cohesivity of the product. Nowadays, some dermal filler products in the market rely on high values of G′ to provide the lift necessary to achieve optimal correction. However, these products require the incorporation of higher amounts of non-crosslinked HA in order to aid the extrusion of the gel through a

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thin needle; as a counteraction the addition of non-crosslinked HA (acting as a lubricant) will result in decreased cohesivity of the product. Thus, it can be inferred that the presence of the non-crosslinked HA surrounding the gel particles will lubricate and therefore facilitate the motion of the gel particles within the material, whereas products with less free HA (i.e. the Juvéderm line of dermal fillers) the gel particles tend to be held together, being harder to deform or pull the material apart (therefore retaining its form or shape under stress), resulting in higher cohesivity. An example of when lifting characteristics are paramount is injections into the cheek and zygomatic arches. These are at the level of the periosteum and their goal is to lift the midface upward and outward. Thus, gels that have better lifting characteristics are better suited for this area and indication than those that are smoother.

Conclusion The plethora of HA gel products that are presently approved or under consideration for approval come with a plethora of product claims: some claim to be smooth, others claim to be the longest lived and still others purport to be ideal at lifting the face. To decipher these claims and understand how to select the correct product for a given indication in a particular individual, it behooves the physician to understand the physical chemical properties that are responsible for the various clinical features observed. The concentration of HA, degree of crosslinking, cohesivity, G′, and particle size all interact to create the unique properties of a particular product. Each of these factors may be determined and compared with those of other products being considered. Once they are understood, one should have a better appreciation of how to use the various HA products to obtain optimal patient outcomes.

References 1. Monheit GD, Coleman KM. Hyaluronic acid fillers. Dermatol Ther 2006;19:141–50. 2. Tezel A, Fredrickson GH. The science of hyaluronic acid dermal fillers. J Cosmet Laser Ther 2008;10(1):35–42. 3. Price RD, Berry MG, Navsaria HA. Hyaluronic acid: the scientific and clinical evidence. J Plast Reconstr Aesthet Surg 2007;60:1110–19. 4. Monheit GD, Prather CL. Juvéderm: a hyaluronic acid dermal filler. J Drugs Dermatol 2007;6:1091–5.

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5. Falcone SJ, Berg RA. Crosslinked hyaluronic acid dermal fillers: a comparison of rheological properties. J Biomed Mater Res A 2008;87:264–71. 6. Collins MN, Birkinshaw C. Physical properties of crosslinked hyaluronic acid hydrogels. J Mater Sci Mater Med 2008;19:3335–43

C H APTER 4

Calcium Hydroxylapatite Microspheres in Facial Augmentation Alastair Carruthers Department of Dermatology and Skin Science, University of British Columbia, Vancouver, Canada

Jean Carruthers Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, Canada

Over the last decade, the popularity of non-invasive procedures in facial rejuvenation – compared with surgical intervention – has risen dramatically. In particular, the number of soft-tissue fillers available has grown exponentially and includes collagen, cross-linked hyaluronic acid (HA), poly-L-lactic acid, and polymethylmethacrylate beads, among others. Calcium hydroxylapatite (CaHA) microspheres (Radiesse; Bioform Medical, Inc., San Mateo, CA) is the latest of these augmenting agents designed to combat the signs of volume loss in the face. Approved in 2006 by the Food and Drug Administration (FDA) for the correction of moderate-to-severe facial folds and wrinkles (nasolabial folds), and for the correction of signs of lipoatrophy associated with human immunodeficiency virus (HIV), CaHA is considered an effective, long-lasting, biocompatible, easy-to-use filling agent with a favorable safety profile and a high level of patient satisfaction.

Properties and mechanism of action An injectable implant, Radiesse is composed of uniform, smooth, synthetic CaHA microspheres (25-45 μm) suspended in an aqueous carboxymethylcellulose gel carrier. CaHA comes in pre-filled 1.5-mL (initial treatment) and 0.3-mL (touch-up applications) syringes for ease of use, is delivered via a fine-gauge needle (usually 27G), and provides immediate correction for facial folds and depressions. After implantation, the carrier gel is gradually absorbed; the remaining synthetic implant acts as a scaffold for new tissue formation, inducing local histiocytic and fibroblastic response and Injectable Fillers: Principles and Practice. Edited by Derek Jones. © 2010 Blackwell Publishing

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(a)

(b)

Figure 4.1 Photomicrograph of beads after implantation showing collagen formation.

stimulating the production of collagen around the CaHA microspheres (Figure 4.1).1 The particles are fixed in place as fibroblasts grow, discouraging migration.2 Over time, the synthetic microspheres, which are identical in composition to the mineral content of human bone and teeth,3 are broken down into calcium and phosphate ions and are excreted.4,5 Injectable CaHA has been shown to be nontoxic, nonirritating, and nonantigentic.6 No calcification or ossification has been observed, and skin testing is not required before treatment.4

Pivotal trials Two pivotal trials led to the FDA approval of CaHA for the treatment of nasolabial folds and HIV-associated lipoatrophy in 2006. In a multicenter, randomized, bilateral, evaluator-blinded trial, Smith and colleagues compared the efficacy and safety of CaHA microspheres versus collagen in 117 patients with moderate-to-severe nasolabial folds.7 Individuals received injections of CaHA on one side of the face, and human collagen (Cosmoplast; Allergan Inc., Irvine, CA) on the other, with up to two touch-ups. At 6 months, evaluators rated nasolabial folds treated with CaHA more improved in 79% of those treated, compared with only 5% in those who received collagen (p < 0.0001), with significantly less volume and fewer injections required. Adverse event (AE) rates and duration were similar for both groups, although the incidence of bruising and edema was slightly higher with CaHA than with collagen. A second, pivotal, open-label, 18-month trial of CaHA in 100 individuals with HIV-associated lipoatrophy demonstrated high levels of efficacy and safety over 18 months.8 All assessable patients were rated as improved or better at all time points through 12 months, as measured by the Global Aesthetic Improvement Scale (GAIS), and 91% were improved or better

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at 18 months. Moreover, patient satisfaction remained high: at 12 months, 100% considered treatment beneficial. Skin-thickness measurements at 12 months remained statistically better than those at baseline, and AEs (ecchymosis, edema, erythema, pain, and pruritis) were mild and generally short in duration.

Clinical experience The use of CaHA has been well documented for the treatment of nasolabial folds3,7,9–13 and HIV-associated lipoatrophy,3,14–17 and has had FDA clearance for the treatment of oral–maxillofacial defects, vocal fold insufficiency, and radiographic tissue marking in the USA for over 20 years.4 In addition, practitioners use CaHA off-label for a variety of aesthetic applications, including nasal contouring, cheek augmentation, and the correction of marionette lines and depressed scars.2,3,8,9,16,18,19 Published reports consistently show a high level of patient and injector satisfaction, with minimal side effects and long-lasting results.

Efficacy In a study of 609 patients who received CaHA in the nasolabial folds, marionette lines, oral commissure, cheeks, chin, lips, and radial lip lines, Jansen and Graivier conducted follow-up patient satisfaction surveys (via self-evaluation of preoperative photographs) at 6 months (155 individuals), and again between 12 and 24 months (112 individuals).11 At 12 months, 89% of those involved stated that they would receive the treatment again. Likewise, Roy and colleagues evaluated 82 individuals injected with CaHA for facial rejuvenation (most commonly in the meilolabial folds); both individuals and physicians reported satisfaction with the look and feel of the implants at 3 and 6 months.20 A multicenter, blinded, randomized trial compared CaHA with two HA derivatives in terms of patient satisfaction (surveys), efficacy (GAIS), and duration of correction in 205 individuals who received treatment in the nasolabial folds.21 Individuals received touch-ups at 4 months and were followed for an additional 12 months after the second injection. More individuals who received CaHA were “satisfied” or “extremely satisfied” than those who received either HA product, and CaHA showed a higher level of efficacy in the treatment of nasolabial folds at 8 months, as measured by the GAIS. Sadick and colleagues investigated the efficacy of CaHA in the nasolabial folds and other areas of the face 6 months after treatment and found that 90% of 41 individuals reported very good or excellent results.13 Average physician ratings of the look and feel of the implant were 4.5 and 4.9, respectively, on a scale of 1 to 5 (1 = unsatisfactory; 5 = excellent).

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(a)

(b)

(c)

(d)

Figure 4.2 Representative photographs of PSR-stained histologic specimens. (a) 4

weeks; (b) 16 weeks; (c) 32 weeks; (d) 78 weeks. Original magnification: a,b, ×40; c,d, ×60.

A 12-month, open-label, prospective trial investigated the efficacy of CaHA in 30 individuals with HIV-associated lipoatrophy;17 29 men and 1 woman received up to two injections given 30 days apart, with assessment 3, 6, and 12 months after the last treatment session. Touch-ups were offered at 6 and 12 months. Efficacy was measured by changes from baseline on the GAIS and in cheek thickness at follow-up. In addition, patients completed satisfaction surveys at every visit. All patients were rated as improved or better on the GAIS at all time points; there were no ratings of no improvement or worse. Likewise, changes from baseline in cheek thickness were statistically significant at all follow-up assessments. At 3, 6, and

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12 months, 100% of patients reported treatment satisfaction at all visits on all measures.

Duration Clinical experience suggests that injectable CaHA provides correction for an average duration of 12 months in the face,4,5,16,22 though some reports suggest a longer duration of 12–18 months2,10,11 (Figure 4.2). In 1000 individuals treated for a variety of facial augmentation procedures (primarily nasolabial folds, marionette lines, prejowl depressions, acne scars, malar eminence enhancement, and generalized soft-tissue defects) over a period of 52 months, Tzikas found that patients experienced at least 80% persistence at 1-year follow-up without retreatment, and the majority returned for follow-up injections between 12 and 18 months.5

Safety of CaHA in facial augmentation CaHA is generally well tolerated. To date, there have been no reports of antibody formation or hypersensitivity. Transient erythema, edema, ecchymosis, pain on injection, and pruritis are the most frequently reported AEs,23 and reports indicate that most side effects are mild, minimal, and transient in nature.5,7,8,10,13,17 Sadick and colleagues investigated the safety of CaHA in 113 patients treated primarily in the nasolabial folds, among other sites;13 75 and 38 patients had single or multiple injection sessions, respectively, with volumes of 1.0–2.0 mL per session, and were followed for 6–12 months after the last treatment. Injections were well tolerated in all patients. There were no allergic reactions, and mild erythema and minimal edema lasting from a few hours to a few days were the most common side effects. Seven patients reported minor, transient AEs (ecchymosis, inflammation, and edema, and two cases of submucosal nodules of the lip that were treated successfully with triamcinolone injections). Tzikas injected 1000 patients with CaHA for a variety of facial aesthetic applications (primarily nasolabial folds and marionette lines) over 52 months.5 Injections were mostly well tolerated. Erythema and ecchymosis were the most commonly reported side effects but were mild and transient, typically resolving within 2 weeks. The incidence of nodules in patients treated for lip augmentation was 5.9%.

Nodules Marmur and colleagues examined punch biopsy samples from human volunteers at 1 and 6 months after injection of CaHA into the dermis

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and found no evidence of granuloma formation, migration, or other foreign-body reactions.1 However, nodules and foreign-body reaction to CaHA in the lips are the most commonly reported complications,3,5,11,13,19,24 including one case of nodule formation from a distant injection site,25 with a 5–8% rate of nodule formation reported in the literature.2 Nodules require treatment with either intralesional steroids or incision and drainage.3,19 Some practitioners believe that lack of experience and poor injection technique may affect the incidence of nodule formation. Jansen and Graivier found nodules in 12.4% of patients treated for lip augmentation and in 3.7% of those treated for radial lip lines.11 However, the incidence decreased to 8.8% by using a smaller injection volume and more conservative threading technique. A 47-month study investigated the safety profile of CaHA for the treatment of nasolabial folds and other areas of the face in 113 patients.13 Two of 14 individuals (15%) who received CaHA in the lips experienced nongranulomatous submucosal nodules; the authors postulate that the higher rate of nodule formation was due to small sample size. In 349 lip augmentation procedures performed over 52 months, Tzikas found an overall incidence of nodule formation of 5.9%, but the incidence declined to less than 2% for the last 100 lips treated.5 The formation of nodules outside of the lips was rare (0.002%) and resulted from an injection technique that was too superficial. However, some practitioners, the author included, prefer to avoid CaHA for lip augmentation.

Radiographic properties Radiopaque in nature, CaHA particles are clearly visible on computed tomography (CT) scans and may be visible in standard radiography. However, there is no indication that CaHA potentially masks abnormal tissues or may be interpreted as tumors on CT scans.26 The authors and colleagues investigated whether the implant presented any confounding radiographic properties that could cause problems in the interpretation of radiographs or CT scans; 58 patients with facial lipoatrophy or pronounced nasolabial folds who had been treated with CaHA underwent radiographic and CT imaging studies over an extended time period (up to 427 days after injection) and with varying amounts of CaHA (from 1.3 mL to 34.1 mL in total). Although CaHA appeared inconsistently on the radiographs (Figure 4.3), the implant was easily visualized on CT scans in almost all patients, with no obscuration of underlying structures and no evidence of migration (Figure 4.4). With proper patient history, the material is therefore easily seen soon after injection and does not compromise the assessment of adjacent structures.

Calcium Hydroxylapatite Microspheres in Facial Augmentation

(a)

33

(b)

Figure 4.3 (a) Radiograph after injection of Radiesse showing no radiopacity resulting from the Radiesse.

(a)

(b)

Figure 4.4 CT Scan of an individual before (a) and 2 weeks after (b) injection of Radiesse into the nasolabial fold. The opacity can be seen in the underlying tissue.

Considerations for facial augmentation with CaHA As with any augmentation procedure, proper patient education and communication are critical in ensuring optimal satisfaction and understanding of the associated risks and benefits. A pre-injection discussion should include a review of past medical history and current prescription or nonprescription medications, counseling about pain or other common side

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effects that may occur with treatment, as well as expected short-term and long-term outcomes. CaHA is contraindicated in individuals with a history of anaphylaxis or the presence of multiple severe allergies and should not be used in those with known hypersensitivity to any of the product components.23 Likewise, treatment should be deferred in any person with active skin inflammation or infection in or near the treatment areas. CaHA has been reported to activate herpes zoster;27 patients with a history of herpesvirus infection may wish to receive prophylactic antiviral therapy.28 The safety of CaHA has not been studied in pregnancy or lactation, or in individuals under the age of 18 years.

Pain management As a result of the size of the needle used (in most cases, 27G), injections of CaHA can be painful and may even deter patients from repeating the procedure. Pain can be alleviated by ice, nerve-block anesthesia, topical anesthesia, or infiltration of small amounts of local anesthetic into the treatment area4,29 and will depend on physician and patient preference, as well as site of implantation. For the treatment of HIVassociated lipoatrophy, for example, infraorbital blocks are sometimes used to provide anesthesia extending from the lower lids down through the cheeks to the upper lip.4 In the authors’ experience, however, a combination of topical anesthesia and local infiltration (as described below) provides adequate relief. Regardless of the method used, the treatment area should be marked on the skin before any anesthetic application.4 In addition to using a topical anesthetic 30 min before injection (see Injection techniques below), the author always adds approximately 0.15 mL of 2% lidocaine with 1:100 000 epinephrine, drawn up in a 1-mL Luer-Lok syringe and connected to the CaHA syringe with a Braun fluiddispensing connector (FDC 1000; Braun Medical Inc., Melsungen, Germany). The filler is passed into the lidocaine solution and back into the CaHA syringe about 10 times minimum. The addition of lidocaine to CaHA does not appear to alter the physical properties of the filling agent, although 10 mixing passes are recommended to ensure optimal homogeneity.30 The diluted material is then divided equally between the two syringes.

Injection techniques A 27G, ½- or 1¼ -inch needle is recommended due to the product’s relative viscosity.4,23 Needle jams are more likely to occur with needles smaller than 27G.23 The author uses a wide-bore, 1-inch, 28G needle or, on occasion, a 1½-inch, 25G needle. Before treatment, the injection site is marked with a soft white pencil, and pretreatment photographs are taken. The author pre-

Calcium Hydroxylapatite Microspheres in Facial Augmentation

35

pares the skin with an antiseptic solution, then applies a topical anesthetic (Betacaine; 15% lidocaine, 5% prilocaine in an occlusive base) left on for approximately 30 min. After the skin has been wiped clean, the patient is positioned appropriately so that the volume defects can be seen – usually an upright position with head supported. The skin is tensed, and the needle is gently inserted through the skin bevel down at an approximate 30° angle to the skin,23 with the needle tip positioned at the appropriate depth. Injection techniques and volumes vary according to the size and location of the fold or volume deficit. CaHA can be injected at the subdermal plane, just in the subcutaneous space but superior to the periosteum, or on the periosteum itself.4 It is always the authors’ practice to inject CaHA deeply, either close to the bone or deep in the subcutaneous tissues. An attempt to inject too superficially is likely to produce short- or long-term lumpiness, and deep injections can reduce the incidence of prolonged swelling, particularly in the cheek or midface area. Placement close to the bone usually requires a bolus injection, with massage of the treated area to ensure proper distribution. Depending on the location, CaHA may be injected in a retrograde fashion, using a linear threading, cross-hatching, or fanning technique to deposit transversing threads of material in multiple layers as needed.4,5 In general, it is best to avoid numerous percutaneous punctures or too much motion at the tip of the needle, as both will increase the incidence of bruising. CaHA provides a 1 : 1 correction, with less volume required than collagen or HA filling agents,7,21 particularly when layered with other products,31 and no need for overcorrection.5 Massage is often used after injection to evenly distribute the filler material. In some instances, additional follow-up treatments may be necessary, depending on the size of the defect and the needs of the patient, and some injectors prefer to use smaller amounts in a scheduled sequence of treatment sessions.

Midface injections Signs of aging can be most apparent in the midface, where volume loss initiates the descent of malar fat pads, in turn leading to drooping and increasing prominence of folds and depressions in the lower face (Figure 4.5). Malar and submalar augmentation with a volumizing filler such as CaHA produces a healthier, rounded appearance of youth, and can affect the face as a whole (Figure 4.6); for that reason, cheek augmentation should always be performed first when treating multiple sites on the face in one session.16 Injections are placed in crisscrossing linear threads, with cross-hatching and layering as the needle is withdrawn for structural support (Figure 4.7), and should be avoided above the orbital rim or into the tear troughs.4 Deep (subcutaneous to pre-periosteal) placement of injections can lower the risk of prolonged swelling that can occur

36

(a)

Chapter 4

(b)

Figure 4.5 Woman with marionette lines before (a) and after (b) Radiesse treatment. The replacement of volume in the entire area is apparent in these photographs.

(a) (d)

(b) (e)

(c)

(f)

Figure 4.6 (a–c) Woman with volume loss in the cheeks from the front before (a),

from the side before (b,c); (d–f) similar images of the same patient 2 weeks after volume replacement to the cheeks.

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37

Figure 4.7 Diagram showing the fanning technique for enhancement of the malar/zygomatic area.

in the midface. Extension of the correction laterally and slightly inferiorly along the zygoma may provide better support for crow’s feet and can enhance the overall appearance of the face.16 Some practitioners use the intraoral–supraperiosteal injection approach, which may lessen the need for additional filler in the nasolabial fold and marionette lines, and reduce the incidence of short-term side effects, such as bruising and swelling.4 HIV-associated facial lipoatrophy primarily affects the temporal, infraorbital, submalar, and malar regions, as well as the nasolabial folds (Figure 4.8). Although injections are usually placed deeply in the submalar area using a fanning technique, with additional threads layered into a deeper plane, some practitioners find that extending the filling agent to the malar eminence and periorbital region may result in a more complete correction.4

Lower face As faces lose volume from the malar and medial cheek pads, nasolabial folds begin to deepen. CaHA is particularly beneficial for the treatment of nasolabial folds (Figure 4.9). Deep dermal injections fill the creases, while deeper injections in the subdermal plane using a linear threading and fanning technique can add structural support.4 Using a V formation or injecting the material in a triangular shape, cross-hatching with transversely oriented threads, adds greater support and can lead to a more pleasing aesthetic result.4

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(a)

(b)

Figure 4.8 HIV-positive individual with grade 1–2 facial lipoatrophy before (a) and after (b) correction with 2.6 mL of Radiesse per side.

(a)

(b)

Figure 4.9 Correction of volume loss of the cheeks and nasolabial folds with

Radiesse.

Superficial lines in the oral commissure are best treated with an HA derivative or collagen, although deeper lines can be filled with CaHA. However, this area is more at risk of palpability or nodule formation. Adequate correction involves volume to fill the lines and folds and lift the corners of the mouth. Injections are placed in the deep dermis inferior to the corner of the mouth, extending into the marionette lines, with threads of small amounts (around 0.05 mL) deposited in a fanning and crisscrossing pattern. Marionette lines are difficult to eradicate completely and may need adjunctive therapy with additional fillers (Figure 4.10). To fill, conservative amounts of CaHA are injected subdermally, with HA layered superficially. Some practitioners prefer to schedule multiple sessions using very small amounts of material at each session.4

Calcium Hydroxylapatite Microspheres in Facial Augmentation

(a)

39

(b)

Figure 4.10 Marionette lines before and after correction with Radiesse and a

hyaluronic acid.

(a)

(b)

Figure 4.11 Enhancement of the jawline with Radiesse.

Treatment of marionette lines and the oral commissure should include additional augmentation of the prejowl and perimental area. In the prejowl sulcus, CaHA is deposited in the subdermal plane, taking care to recreate the inferior border of the mandible rather than focusing on simple volume replacement in the body of the mandible (Figure 4.11). For the best results along the chin and jaw, the filler should be injected in increments, followed by gentle massage to help the material blend with the chin and jaw contours.4 An atrophic jawline can be treated with injections placed along the periosteum of the inferior mandible. The marionette and jawline, where the facial artery is superficial, are particularly susceptible to bruising. There are two ways to avoid bruising in this area: inject the chin from the midline or anteriorly (as described above), or insert the material via intraoral–supraperiosteal bolus placement of CaHA (through the oral mucosa). There are definite risks associated with injecting through the oral cavity, with a significant increase in the likelihood of infection. The authors recommend using a prophylactic dose of oral antibiotic 30 min before injecting (1000 mg Keflex or 500 mg Biaxin for individuals who are allergic to penicillin), as well as the use of an antiseptic mouthwash before the

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procedure. The needle can then be inserted through the sulcus and positioned accurately, and the risk of bruising and swelling is dramatically reduced. As there is no percutaneous puncture, the short-term side effects are generally much reduced.

Post-treatment procedures Post-procedure photographs accurately document response to treatment and may be taken immediately after injection and at any follow-up visits. Edema and ecchymosis can be alleviated by gentle compression with an ice-pack for several hours after treatment.5 Advising patients to remain upright for a period of time after treatment and sleeping with their heads elevated may also aid in relieving swelling.4 Patients should avoid excessive sun or heat exposure for approximately 24 hours, or until transient redness or swelling has subsided.21 Follow-up appointments can be scheduled beginning at 2 weeks to assess improvement and address any adverse events. Depending on age, skin elasticity, and depth of deficit, CaHA usually lasts for 10–12 months, and most patients return between 12 and 18 months for follow-up treatment.5

Conclusion CaHA is a durable and versatile injectable filler that has received high marks from practitioners for its durability, versatility, and safety. Approved by the FDA for facial augmentation in 2006, CaHA provides immediate correction of wrinkles and folds, and is particularly useful for filling lines and depressions and replacing volume lost through illness or the aging process. CaHA augmentation lasts for up to a year (or more), and is remarkably popular among patients and physicians alike. With volume enhancement an integral component of any cosmetic practice, the use of CaHA is only likely to increase.

References 1. Marmur ES, Phelps R, Goldberg DJ. Clinical, histologic, and electron microscopic findings after injection of a calcium hdroxylapatite filler. J Cosmet Laser Ther 2004;6:223–6. 2. Goldberg DJ. Calcium Hydroxylapatite. Fillers in cosmetic dermatology. Abingdon: Informa UK Ltd, 2006. 3. Tzikas TL. Evaluation of Radiance FN soft tissue filler for facial soft tissue augmentation. Arch Facial Plast Surg 2004;6:234–9. 4. Graivier MH, Bass LS, Busso M, Jasin ME, Narins RS, Tzikas TL. Calcium hydroxylapatite (Radiesse) for correction of the mid- and lower face: consensus recommendations. Plast Reconstr Surg 2007;120(6 suppl):55S–66S.

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5. Tzikas TL. A 52-month summary of results using calcium hydroxylapatite for facial soft tissue augmentation. Dermatol Surg 2008;34(suppl 1):S9–15. 6. Hubbard W. BioForm Implants: Biocompatibility. Franksville, WI: BioForm, Inc., 2003. 7. Smith S, Busso M, McClaren M, Bass LS. A randomized, bilateral, prospective comparison of calcium hydroxylapatite microspheres versus human-based collagen for the correction of nasolabial folds. Dermatol Surg 2007;33(suppl 2):S112–21. 8. Silvers SL, Eviatar JA, Echavez MI, Pappas AL. Prospective, open-label, 18-month trial of calcium hydroxylapatite (Radiesse) for facial soft-tissue augmentation in patients with human immunodeficiency virus-associated lipoatrophy: one-year durability. Plast Reconstr Surg 2006;118(3 suppl):34S–45S. 9. Cuevas S, Rivas MP, Amini S, Weiss E. Radiesse for aesthetic soft tissue augmentation. Am J Cosmet Surg 2006;23:190–6. 10. Jacovella PF, Peiretti CB, Cunille D, Salzamendi M, Schechtel SA. Long-lasting results with hydroxylapatite (Radiesse) facial filler. Plast Reconstr Surg 2006;118 (3 suppl):15S–21S. 11. Jansen DA, Graivier MH. Evaluation of a calcium hydroxylapatite-based implant (Radiesse) for facial soft tissue augmentation. Plast Reconstr Surg 2006;118 (suppl):22S–30S. 12. Alam M, Yoo SS. Technique for calcium hydroxylapatite injection for correction of nasolabial fold depressions. J Am Acad Dermatol 2007;56:285–9. 13. Sadick NS, Katz BE, Roy D. A multicenter, 47-month study of safety and efficacy of calcium hydroxylapatite for soft tissue augmentation of nasolabial folds and other areas of the face. Dermatol Surg 2007;33(suppl 2):S122–6. 14. Comite SL, Liu JF, Balasubramanian S, Christian MA. Treatment of HIV-associated facial lipoatrophy with Radiance FN (Radiesse). Dermatol Online J 2004;10:2. 15. Roth JS. Restorative approaches for HIV-associated lipoatrophy. PRS Notebook 2005;10:24–8. 16. Busso M, Karlsberg PL. Cheek augmentation and rejuvenation using injectable calcium hydroxylapatite (Radiesse). Cosmet Dermatol 2006;19:583–8. 17. Carruthers A, Carruthers J. Evaluation of injectable calcium hydroxylapatite for the treatment of facial lipoatrophy associated with human immunodeficiency virus. Dermatol Surg 2008;34:1486–99. 18. Flaharty P. Radiance. Facial Plast Surg 2004;20:165–9. 19. Sklar JA, White SM. Radiance FN: A new soft tissue filler. Dermatol Surg 2004; 30:764–8. 20. Roy D, Sadick N, Mangat D. Clinical trial of a novel filler material for soft-tissue augmentation of the face containing synthetic calcium hydroxylapatite microspheres. Dermatol Surg 2006;32:1134–9. 21. Moers-Carpi M, Vogt S, Santos BM, Planas J, Vallve SR, Howell DJ. A multicenter, randomized trial comparing calcium hydroxylapatite to two hyaluronic acids for treatment of nasolabial folds. Dermatol Surg 2007;33(suppl 2):S144–51. 22. Felderman LI. Radiesse for facial rejuvenation. Cosmetic Dermatol 2005;18:823–6. 23. BioForm Medical, Inc. Radiesse® Injectable Implant: Instructions for use. Franksville, WI: BioForm Medical, Inc., 2008. 24. Sankar V, McGuff HS. Foreign body reaction to calcium hydroxylapatite after lip augmentation. J Am Dent Assoc 2007;138:1093–6. 25. Beer KR. Radiesse nodule of the lips from a distant injection site: report of a case and consideration of etiology and management. J Drugs Dermatol 2007;6:846–7. 26. Carruthers A, Liebeskind M, Carruthers J, Forster BB. Radiographic and computed tomographic studies of calcium hydroxylapatite for treatment of HIV-associated facial lipoatrophy and correction of nasolabial folds. Dermatol Surg 2008;34(suppl 1):S78–84.

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27. Sires B, Laukaitis S, Whitehouse P. Radiesse-induced herpes zoster. Ophthal Plast Reconstr Surg 2008;24:218–19. 28. Jones JK. Patient safety considerations regarding dermal filler injections. Plast Surg Nursing 2006;26:156–63. 29. Comite S, Greene A, Cieszynski SA, Zaroovabeli P, Marks K. Minimizing discomfort during the injection of Radiesse with the use of either local anesthetic or ice. Dermatol Online J 2007;13:5. 30. Busso M, Voigts R. An investigation of changes in physical properties of injectable calcium hydroxylapatite in a carrier gel when mixed with lidocaine and with lidocaine/epinephrine. Dermatol Surg 2008;34(suppl 1):S16–23. 31. Godin MS, Majmundar MV, Chrzanowski DS, Dodson KM. Use of Radiesse in combination with Restylane for facial augmentation. Arch Facial Plast Surg 2006;8:92–7.

C H APTER 5

Evolence and Evolence Breeze Jean Carruthers Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, Canada

Alastair Carruthers Department of Dermatology and Skin Science, University of British Columbia, Vancouver, Canada

Injectable bovine collagen (Zyderm; Collagen Corporation, Santa Barbara, CA) was the first soft-tissue augmenting agent approved by the Food and Drug Administration (FDA) for use in humans in 1981.1 Dermal correction with bovine collagen implants is generally of short duration and requires frequent touch-ups after 3–4 months. In addition, hypersensitivity reactions are common, and skin testing is necessary before treatment.2 Human bioengineered collagen (CosmoDerm and CosmoPlast; Inamed Aesthetics, Santa Barbara, CA), the second-generation injectable collagen, was developed to give the same fine texture and quality of injectable product with a great advantage: its human origin meant that skin testing was no longer required. However, bioengineered collagen, similar to its animal-based counterpart, typically lasts for only 3 months before dissipating.3 Evolence and Evolence Breeze (ColBar Life Science Ltd, Herzeliya, Israel) are newly approved, third-generation collagen fillers with enormous potential in the field of facial rejuvenation. Specifically designed with a reduced risk of antigenicity and an increased durability of up to 12 months, this thirdgeneration collagen has a real value in our armamentarium of dermal fillers, delivering good correction with immediate results and minimal down time.

History of injectable collagen implants The first indication that collagen – the most abundant protein in the body – could play an important role in a variety of applications came when Gross and Kirk formed a rigid gel by heating collagen extracted from fresh calf skin in 1958.4 In the late 1960s, investigators purified collagen, identified subtypes in mammals, and discovered that the immunogenicity of the material could be reduced by removing the nonhelical amino acid Injectable Fillers: Principles and Practice. Edited by Derek Jones. © 2010 Blackwell Publishing

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carboxy-terminal telopeptides.5,6 In 1977, Knapp and colleagues demonstrated the first successful dermal implants in rats using human, rabbit, and rat collagen,7 and the first injections of human and bovine collagen were performed shortly thereafter in 28 patients for the correction of acne scars, subcutaneous atrophy, and wrinkling.8 Results demonstrated a 50– 85% correction sustained over 3–18 months. Stegman and Tromovitch assessed bovine collagen for the correction of depressed scars (mainly acne) and found a 50–80% improvement after three to five treatments.9 By 1981, when the US Food and Drug Administration (FDA) approved bovine collagen (Zyderm I) for general use in the nasolabial fold, 728 physician investigators had treated 5109 patients with a high level of safety and efficacy.10 The FDA subsequently approved two other injectable formulations, Zyderm II and Zyplast, in 1983 and 1985, respectively. The initial collagen fillers are xenografts, in that they are derived from a different animal species (bovine), and do meet many of the criteria of the ideal soft-tissue filling agent: ambulatory, reproducible, minimally invasive with few side effects or little down time, and predictable efficacy. Human-derived collagen (CosmoDerm I, CosmoDerm II, and CosmoPlast) was developed to reduce the skin-test requirement or risk of antigenicity, and was approved by the FDA in 2003.11 Vertebrate collagen has a natural triple helical structure. If the three collagen chains are not crosslinked, the injected material will be rapidly removed from the body and the clinical aesthetic effect will be lost. The crosslinking agent in the first two generations of injectable collagen was glutaraldehyde, an electron microscopy fixative. Thus very small amounts of crosslinking were possible and the clinical effect, while excellent, waned unacceptably quickly. Bovine and human collagens typically dissipate after 3 or 4 months.2,3

Evolence/Evolence Breeze Evolence – developed in Haifa, Israel, by ColBar Corporation, now a division of Johnson and Johnson – uses only type I collagen harvested from the porcine Achilles tendon. Type I collagen forms the largest and strongest of fibers, and has been used for heart valve replacements, corneal shields, wound dressings, and surgical meshes for tissue repair.12 Evolence is prepared via a process that includes enzymatic digestion to carefully remove the N-terminus, the locus of major antigenicity between collagens of differing vertebrate origin: pepsin separates the monomeric collagen fibers from the immunogenic telopeptides, which are thus removed to eliminate the risk of xenogenic allergy. The fibers are then polymerized as reconstituted polymeric collagen and crosslinked with a naturally occur-

Evolence and Evolence Breeze

45

Figure 5.1 Glymatrix technology. Pepsin separates collagen fibers from the immunogenic telopeptides ; fibers are polymerized as reconstituted collagen and crosslinked with D-ribose.

1800 EVOLENCE EVOLENCE Breeze Zyplast

Viscosity (pas)

1500 1200 900 600 300 0 0.0

1.0

2.0

3.0 4.0 Shear Rate (rad/s)

5.0

6.0

7.0

Figure 5.2 Viscosity of Evolence, Evolence Breeze and Zyplast is similar when

injected through the appropriate needles.

ring sugar metabolite, D-ribose, via Glymatrix technology to slow the rate of absorption in vivo (Figure 5.1).13 The Glymatrix process of crosslinking is unique to fillers and, as organic sugar produces no toxicity, larger amounts can be used, unlike glutaraldehyde, 1,4-butanediol diglycidyl ether (BDDE), or other cross-linking agents that may be potentially toxic and are used sparingly according to FDA safety parameters. The Glymatrix technology creates a longer-lasting, more robust product, which can provide correction for up to 1 year. Despite this strength, the viscosity of Evolence, Evolence Breeze, and Zyplast is extremely similar when extruded through the appropriate needles (Figure 5.2).

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Duration and clinical efficacy A preclinical trial of Evolence-30 versus bovine collagen (Zyplast) in the nasolabial folds of 12 patients revealed similar efficacy in the first few months, but ultimately a longer-lasting correction; in an average followup of 18 months, Evolence-30 was superior in 9 of 11 patients treated (p = 0.022).14 In a double-blind, randomized, multicenter, within-individual bilateral facial comparison, Narins and colleagues investigated the efficacy, safety, and longevity of Evolence versus hyaluronic acid (HA; Restylane) in 149 patients.15 Individuals were selected with moderate-todeep nasolabial folds on the modified Fitzpatrick wrinkle scale (a score of 2 or more), and up to two injections were used to correct both folds: one with Evolence, the other with Restylane. Patients were followed for 6 months initially, and then for a year for efficacy and safety.13 Skin tests and sequential antibody levels were performed and followed throughout the study. The results from immunoglobulin titers and skin tests indicated no potential for allergic reactions. Data from the initial 6 months of the study indicated no meaningful difference between the Evolence- or Restylane-treated nasolabial folds at any point. Patient evaluation also indicated a 90% improvement over baseline at 6 months on both sides. Out of the 148 individuals followed for 6 months, 145 were followed for efficacy and safety for an additional 6 months, a total of 12 months.13 Filler persistence or a wrinkle severity score of 1 over baseline was maintained at 12 months in 75% of the individuals.

Safety Evolence has been used successfully in Europe for over 5 years as a facial wrinkle and groove filler, with few reported side effects or complications.11 Preclinical studies of Evolence show no evidence of cytotoxicity, delayed dermal contact sensitization, intracutaneous reactivity, systemic toxicity, mutagenicity, or genotoxicity.13,16 A biopsy study in an animal model confirms the good tissue integration and host response with demonstrable evidence of fibroblastic activity and neocollagenesis.17 Intradermal skin testing before the use of Evolence appears unnecessary; multiple studies have found no histopathological signs or clinical symptoms of hypersensitivity.12–15 Shoshani and colleagues investigated the incidence of hypersensitivity of Evolence in a group of 530 patients who received intradermal injections of 0.1 mL Evolence in the left forearm, and a second injection in the right after 2 weeks.12 Clinical assessments and serum anticollagen antibody tests in 519 patients detected no significant erythematous reactions or changes in porcine type I collagen antibodies at any time. Moreover, Evolence is nonhydrophilic and hemostatic, minimizing the incidence of swelling, bruising, and bleeding.14

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Complications As with all fillers, minor adverse events (AEs) associated with Evolence and Evolence Breeze include pain on injection, erythema, edema, ecchymosis, and urticaria.18,19 When injecting Evolence or Evolence Breeze, knowledge of anatomy is crucial; embolism, ulceration, and necrosis can occur with injection in an artery. In addition, Evolence should not be injected into the glabellar region, following restrictions in that area for use of other crosslinked collagen fillers. Clinical experience to date has demonstrated a high level of safety and only minor side effects. A small pilot study using a preparation containing a lower concentration of crosslinked porcine collagen (Evolence-30) in 12 patients revealed no serious side effects.14 A pivotal trial of Evolence and HA (Restylane) in 149 patients with moderate-to-deep nasolabial folds showed similar safety profiles for both products, with no significant AEs (indeed, induration, swelling, bruising, and pain were higher in patients treated with HA).15 A long-term assessment of the same patients (n = 145) noted only mild skin reactions in three individuals (mild erythema in two, and mild nodule formation in one) at 9 and 12 months after injection; no side effects were considered serious or severe, and there were no reports of delayed granuloma or infection.13 Evolence should not be injected into the lips or infraorbital region due to the high incidence of nodule formation. Braun and Braun report on 16 of 20 women injected with Evolence for lip augmentation who experienced multiple lip nodules, many of which required treatment; some nodules were visible in six patients 1 year after injection.20 However, Evolence Breeze can be used in the lips, particularly together with botulinum toxin type A (BTX-A); Landau found only transient lumpiness which disappeared spontaneously by week 4 in 15 women.21 In addition, a recent study by De Boulle and colleagues report a very low incidence of nodules or bumps after the injection of Evolence Breeze in 57 individuals for lip border and volume enhancement.22

Clinical use of Evolence/Evolence Breeze Opaque gels comprising collagen at a concentration of 35 mg/mL are supplied in 0.5- and 1-mL prefilled syringes that can be stored at room temperature; Evolence and Evolence Breeze are third-generation, purified porcine collagens crosslinked with D-ribose and suspended in phosphatebuffered physiological saline. The production processes are slightly different for Evolence and Evolence Breeze, with modified shearing, filtration, and homogenization practices. The modifications to the production line results in a product (Evolence Breeze) that it is softer, lighter, and less

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Figure 5.3 Evolence treatment areas.

(a)

(b)

Figure 5.4 Nasolabial folds and perioral region (a) before and (b) after treatment with Evolence and Evolence Breeze.

viscous, with collagen fibers of shorter lengths, allowing the product to flow through a smaller lumen needle (30G) in a more finely textured consistency.21 Evolence was approved by the FDA in 2008 for the correction of moderate-to-deep facial wrinkles and folds (Figure 5.3), and has been available in Canada, western and eastern Europe, Israel, South Korea, and Russia since 2004. Evolence is used to treat a variety of pronounced rhytids, often in combination with other procedures, such as BTX-A (Figure 5.4), and is ideal for three-dimensional volumizing in the cheeks, malar area, chin, nasolabial folds, and temples (Figure 5.5). Evolence is not indicated for the lips or periorbital regions.

Evolence and Evolence Breeze

(a)

49

(b)

Figure 5.5 Cheek volume (a) before and (b) after augmentation with Evolence.

Figure 5.6 Evolence Breeze treatment

areas.

Evolence Breeze has not been approved by the FDA but is available in Canada and Europe for the treatment of fine-to-moderate wrinkles and folds (Figure 5.6). The lower viscosity of Evolence Breeze makes it ideal for use in the lips (Figure 5.7), superficial lines and scars, and in infraorbital hollows, and it is indicated as a low-volume, intradermal injection for deep, resting, glabellar folds in tandem with BTX-A treatment of the dynamic component of the glabellar frown (Figure 5.8). Evolence and Evolence Breeze are contraindicated in patients with known hypersensitivity reactions to any collagen product, a history of anaphylactic reactions or serious reactions, bleeding disorders, or compromised immune function (e.g. collagen vascular disease).18,19 Neither formulation should be injected into blood vessels, as collagen can initiate

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(a)

(b)

Figure 5.7 The lips (a) before and (b) after augmentation with Evolence Breeze.

(a)

(b)

Figure 5.8 Evolence Breeze is indicated as a low-volume, intradermal injection for deep, resting, glabellar folds in tandem with botulinum type A (BTX-A) treatment. (a) Before and (b) after combination therapy.

platelet aggregation and cause vascular occlusion and localized infarction or embolism. Overfilling intradermal bovine collagen injections in the glabella has been associated with dermal necrosis.18,19 Evolence should not be injected in the infraorbital hollows or the lips due to long-lasting lumps (see “Complications”), although the lower viscosity Evolence Breeze can be useful in those areas.

Injection techniques Evolence contains no lidocaine. For pain relief, we apply topical 15% lidocaine and 5% prilocaine in a petroleum jelly base to a clean face free of make-up for 10–15 min before injection. If required, we use regional and nerve blocks (4% articaine with 1 : 200 000 epinephrine). In most cases, however, we simply add lidocaine (10–20% by volume with 1:100 000 epinephrine) to the Evolence or Evolence Breeze using a sterile

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disposable female-to-female double Luer-Lok. Ten passes of the material back and forth will ensure adequate mixing of the product with the local anesthetic. Slow antegrade injection of the mixed product will reduce any discomfort to easily manageable levels. In our experience, most patients prefer the combination of lidocaine plus Evolence/Evolence Breeze for pain control over the blocks that we used to use when injecting the lips. In accordance with the gate control theory of pain,23 we also use a massager on the chin (the HT-1220 Acuvibe) during injection to minimize pain. As both Evolence and Evolence Breeze differ from their bovine collagen predecessors, the technique of injection is therefore different. Evolence is injected into the deep tissues using the supplied 1-mL syringe with a 27G needle or the Excel needle (27G inside bore, 28G outside bore). The less viscous Evolence Breeze is injected through a 30G needle more superficially. It can be injected into the mid-dermis for lines or into scars to elevate them. The recommended treatment protocol for Evolence is a deep injection using an antero- or retro-grade tunneling technique. We use a linear threading technique with a slow, steady injection and no overcorrection. The slow, continuous flow of the product – which requires less pressure on the plunger than is necessary with HA injections – will produce an even distribution of implant through the area to be corrected. We can use this technique with Evolence Breeze in the lips and infraorbital hollows, but we may also use a very superficial, multiple-stab technique for superficial lines and scars. After and during injection, the implant should be massaged to ensure even correction with no papules or nodules. Lumps should be massaged flat immediately. It is important to note that immediate massage is required to remodel and sculpt the injected area; the product sets quickly but does not move from the injected area, unlike HA. Indeed, the biggest novice mistake is not to massage completely as soon as the nodule or lump is noted. Nodules persisting after 24 hours can be treated with saline injection to break up the collagen fibers, or conservative use of diluted triamcinolone acetamide (2.5% in saline).

Conclusion Evolence and Evolence Breeze are newly approved, third-generation collagen fillers that provide immediate results, which last for up to 12 months and require no skin testing. Evolence is used for the correction of moderate-to-deep nasolabial wrinkles and folds, contour deficiencies, and soft-tissue defects, and has been available in Canada, Europe, Israel, South Korea, and Russia since 2004. Evolence Breeze is also approved by Health

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Canada for the correction of fine-to-moderate wrinkles and folds. Although other filling agents had begun to replace the first two generations of collagen as ideal volumizers, the advent of the more viscous Evolence and Evolence Breeze – longer-lasting collagens delivering good correction, immediate results, and few side effects – has challenged that replacement. Johnson and Johnson in early November 2009 informed its’ customers that it would no longer be distributing Evolence in the US, citing apparent market forces. At the time this book goes to press the product is not available. However, there is always a possibility that he product will be available in the future through a new distributor.

References 1. Sclafani AP, Romo T III. Collagen, human collagen, and fat: The search for a threedimensional soft tissue filler. Facial Plast Surg 2001;17:79–85. 2. Murray CA, Zloty D, Warshawski L. The evolution of soft-tissue fillers in clinical practice. Dermatol Clin 2005;23:343–63. 3. Baumann L. CosmoDerm/CosmoPlast (human bioengineered collagen) for the aging face. Facial Plast Surg 2004;20:125–8. 4. Gross J, Kirk D. The heat precipitation of collagen from neutral salt solutions: Some rate-regulating factors. J Biol Chem 1958;233:355–60. 5. McPherson JM, Ledger PW, Sawamura S, et al. The preparation and physiochemical characterization of an injectable form of reconstituted, glutaraldehyde cross-linked, bovine corium collagen. J Biomed Meter Res 1986;20:79–92. 6. Dzubow LM, Goldman G. Introduction to soft-tissue augmentation: A historical perspective. In: Klein AW (ed.), Tissue Augmentation in Clinical Practice: Procedures and techniques. New York: Marcel Dekker, 1998;1–7. 7. Knapp TR, Luck E, Daniels JR. Behavior of a solubilized collagen as a bioimplant. J Surg Res 1977;23:96–105. 8. Knapp TR, Kaplan EN, Daniels JR. Injectable collagen for soft tissue augmentation. Plast Reconstr Surg 1977;60:398–405. 9. Stegman SJ, Tromovitch TA. Implantation of collagen for depressed scars. J Dermatol Surg Oncol 1980;6:450–3. 10. Watson W, Ray RL, Klein AW, Stegman S. Collagen: A clinical overview. Cutis 1983;31:543–6. 11. Matarasso SL, Sadick NS. Soft tissue augmentation. In: Bolognia J, Jorizzo JL, Rapini RV, Horn T (eds), Dermatology. London: Mosby, Harcourt Health Sciences, 2003: 2439–49. 12. Shoshani D, Markovitz E, Cohen Y, et al. A skin test hypersensitivity study of a cross-linked porcine collagen implant for aesthetic surgery. Dermatol Surg 2007; 33:S152–8. 13. Narins RS, Brandt FS, Lorenc P, et al. Twelve-month persistency of a novel Ribosecross-linked collagen dermal filler. Dermatol Surg 2008;34:S31–9. 14. Monstrey SJ, Pitrau S, Hamdi M, et al. A two stage phase I trial of Evolence collagen for soft tissue contour correction. Plast Reconstr Surg 2007;120:303–11.

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15. Narins RS, Brandt FS, Lorenc ZP, et al. A randomized, multicenter study of the safety and efficacy of Dermicol-P35 and non-animal-stabilized hyaluronic acid gel for the correction of nasolabial folds. Dermatol Surg 2007;33(suppl 2):S213–21. 16. Nir E, Azachi M, Shoshani D, Goldlust A. Long-term in vivo evaluation of the safety and efficacy of a new procine collagen dermal filler cross-linked with ribose. Poster presented at the American Academy of Dermatology 66th Annual Meeting, San Antonio, TX, February, 2008. 17. Pitrau S, Noff M, Blok L, et al. Long term efficacy of a novel ribose-cross-linked collagen dermal filler: a histologic and histomorphometric study in an animal model. Dermatol Surg 2007;53:1–10. 18. ColBar Life Science Ltd. Evolence Instructions for Use. Herzeliya, Israel: ColBar Life Science, 2007. 19. ColBar Life Science Ltd. Evolence Breeze Instructions for Use. Herzeliya, Israel: ColBar Life Science, 2007. 20. Braun M, Braun S. Nodule formation following lip augmentation using porcine collagen-derived filler. J Drugs Dermatol 2008;7:579–81. 21. Landau M. Lip augmentation and rejuvenation using a novel, porcine collagenderived filler. J Drugs Dermatol 2008;7:236–40. 22. De Boulle K, Swingberghe S, Engman M, et al. Lip augmentation and contour correction with a ribose cross-linked collagen dermal filler. J Drugs Dermatol 2009;8 (3 suppl):1–8. 23. Melzack R, Wall PD. Pain mechanisms: A new theory. Science 1965;150:171–9.

C H AP TER 6

Poly-L-Lactic Acid Rebecca Fitzgerald Dermatology Private Practice and David Geffen School of Medicine, University of California, Los Angeles, USA

Danny Vleggaar Centre Dermato-Cosmetique ‘Roseraie’, Geneva, Switzerland

Introduction The purpose of this chapter is to discuss current techniques used with polyL-lactic acid (PLLA) to effectively and safely address changes observed in the aging face. Two simple, yet critically important points should be observed in order to use this product to its best advantage. First, this unique agent is not a filler, but a stimulator of the host’s own collagen which then acts to volumize tissues in a gradual, progressive manner. This mechanism of action has important clinical implications in the manner in which it is used. Biostimulatory agents work through employment of the host response and their biocompatibility is contingent on the ability of the material to perform with an appropriate host response in a specific application.1 As experience has been gained with this product over the last decade, and our techniques adjusted accordingly, we have found it to be a very safe and versatile agent that can be used in a manner that is both predictable and reproducible. Currently recommended preparation and placement techniques will be addressed in detail. The second point is to recognize that changes in different tissue layers of the face within a single individual occur interdependently, as an interlocking three-dimensional puzzle. Therefore, where to place the product to optimize results is enhanced by looking at the face as a whole, rather than focusing on the nasolabial folds or marionette lines, for example, as isolated entities. Seemingly small changes in shape, topography, proportions, balance, and symmetry can have a large impact on the face. This is a large part of the learning curve with this product and for this reason much of this chapter is devoted to analyzing and mapping the face.

Injectable Fillers: Principles and Practice. Edited by Derek Jones. © 2010 Blackwell Publishing

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History Poly-L-lactic acid (PLLA) was first synthesized in the 1950’s and has a long history of safe use in medical applications including suture material, plates, screws, fracture fixation devices and drug delivery systems (figure 6.1). Studies carried out almost a decade ago to evaluate the use of PLLA in the treatment of facial lipoatrophy associated with the human immunodeficiency virus (HIV) showed it to be a safe and effective product capable of replacing significant amounts of volume. Initial reports of a relatively high number of palpable, nonvisible subcutaneous papules in these HIV patients, as well as subsequent isolated case reports of granulomas in the cosmetic population, resulted in early skepticism among physicians.2–4 It should be noted that the early HIV studies were carried out with 3–4 cc dilutions, little or no hydration time, and superficial (as well as large bolus) injections of product in multiple treatment sessions spaced only 2 weeks apart.2 Dramatic decreases in the number of PLLA device related adverse events with adjustments in technique have been documented in the literature over the last decade with safety and efficacy now well established.3 Additionally, granulomatous reactions are now widely recognized to occur with all commercially available filler products. Fortunately this is a rare (and usually self resolving) complication with all agents, as their seemingly unpredictable appearance is still poorly understood.4

Figure 6.1 Historical timeline.

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The currently commercially available formulation of injectable PLLA (Sculptra and Sculptra Aesthetic, Sanofi-Aventis Bridgewater, New Jersey) received Federal Food and Drug Administration (FDA) approval in the United States (US) for the restoration and/or correction of the signs of facial fat loss in patients with HIV associated facial lipoatrophy in 2004. Approval for aesthetic use was gained in 2009, based on the results of a randomized, evaluator-blinded, parallel-group, multicenter study of 233 immunocompetent patients designed at the time of HIV approval using a 5cc dilution, a 2 hour hydration time, and a deep dermal grid pattern injection technique to place product in the nasolabial fold in multiple treatment sessions placed 3 weeks apart. Collagen was used as the comparator in order to adhere to a precedent already familiar to the FDA (from previous filler studies). Although refinements in methodology continue to evolve and it is currently commonplace to use an 8–9 cc dilution, >24 hour hydration time, and subdermal placement, the current aesthetic label reflects this early study design. Particularly useful information from this study is it’s documentation of effects lasting 25 months (the cut off time in the study) with high patient satisfaction (80% at 25 months).5

Mechanism of action of PLLA PLLA is a synthetic polymer of l-lactic acid linked by ester bonds. Polyesters such as PLLA are both biocompatible and biodegradable and are desirable biomaterials because of lack of toxicity in the human host (they degrade to lactic acid which is then metabolized via the citrate cycle).6 The currently commercially available injectable PLLA product (Sculptra, Sculptra Aesthetic, Sanofi-Aventis Bridgewater, New Jersey) is composed of nonpyrogenic mannitol (to enhance lyophilization), sodium carboxymethylcellulose (an emulsifier) and PLLA microparticles. It is supplied as a lyophilized powder in a sterile glass vial which must then be reconstituted with H2O prior to use. A particle size of 40–63 μm in diameter ensures that they are large enough to avoid phagocytosis by dermal macrophages (heterogeneity in size as well as phagocytosis of smaller particles could lead to a more intense inflammatory response) or passage through capillary walls (which could lead to vascular compromise), but small enough to be easily injected by needles as fine as 26G.6 The mechanism of action of injectable PLLA is thought to involve the initiation of a desired subclinical inflammatory tissue response to the polylactides leading to encapsulation of the microparticles and subsequent

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fibroplasia. Over time, the product degrades, the inflammatory response wanes, and the ensuing collagen deposition increases providing a gradual and progressive increase in tissue volume.6 The inflammatory response against an implanted polymeric biomaterial is determined by many factors – some having largely to do with the host, such as the implantation site and the concentration of material; some having largely to do with the implant, such as the physical (shape, size, surface area) and chemical (pH, charge, hydrophilic vs. hydrophobic) properties of the biomaterial.7 As this holds true for both the initial and degraded forms of the product, predictable degradation kinetics is an important factor in ensuring a predictable host response.7 A word about biocompatibility is warranted here, as an understanding of this concept is key to successful use of this product. Although the initial concept of biocompatibility was simply inertness, biomaterials are now used in clinical medicine to purposely harness a desired host response for a specific purpose. Simply put, the effect of a biomaterial on the host is to stimulate an inflammatory/immune response and the response of the host on the biomaterial is to attempt to eliminate or encapsulate the foreign material.7 This is taken into account by the widely accepted “William’s definition” of biocompatibility as the ability of a material to perform with an appropriate host response in a specific application.1 It is critical to note that the mechanism of action of PLLA links biocompatibility of the product to the manner in which it is used i.e., how, where, and how much of the product is used may greatly influence the type and intensity of the host response. Again, a subclinical inflammatory response followed by encapsulation and fibroplasia is the desired end-point for application of this agent as a soft-tissue augmentation device. Understanding the role of the degradation kinetics of the PLLA polymer in it’s ultimate biocompatibility may help explain the importance of avoiding overcorrection in achieving this desired endpoint. PLLA primarily degrades through hydrolysis of ester bonds (although enzymatic metabolism may play a very minor role). The polymer is a very hydrophobic molecule and this hydrolysis is noted to occur in stages. The first and longest stage is hydration of the polymer. The time required is proportional to the molecular weight of the polymerPLLA is a high molecular weight polymer taking months to hydrate.8,9 The final and shortest stage is dissolution into degradation fragmentslargely monomers, dimers, and oligomers of lactic acid. At this final stage the product becomes progressively more hydrophilic and the rate of chain scission, and therefore production of degradation fragments, accelerates.8–11 Phagocytosis of small degradation particles by macrophages and foreign body giant cells then occurs as an expected ‘next step’ in the host response to the biomaterial. This ‘intracellular’ phase of degradation in

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vivo correlates with an observed change in the type and/or intensity of a preexisting inflammatory response which seems to correlate with the concentration of material present.12 While small volumes of material do not reach toxic concentrations in the host, high initial concentrations or rapid sustained release of degradation products may do so. Large volumes of material, both initially, and at this late phase of degradation may lead to an undesired amount of inflammation resulting in an inappropriate host response for the specific application for which it was intended.12 This physiologic response to overcorrection was observed in early orthopedic applications where implants with considerable size were used. Newer processing methods as well as copolymers have addressed these concerns.13 These factors may all play a role in why overcorrection should be avoided with PLLA in the application of soft tissue augmentation. It is interesting to speculate that overcorrection could conceivably cause an adverse event for the life of the product (up to 2 years), perhaps accounting for occasional reports of adverse reactions 12–18 months after treatment. On a positive note, this would also imply that the occurrence of these reactions – both early and late – are preventable by adhering to the currently recommended guidelines for use (designed to avoid overcorrection).

Product preparation and injection technique: optimizing outcomes The manner in which a biostimulatory agent is used determines it’s biocompatibility in a specific application. Experience has taught us that “too much, too soon” with collagen stimulators may lead to overcorrection, where an overabundance of stimulating microparticles may lead to an undesired host reaction in the specific application of these devices in tissue augmentation. It is for this reason that it is recommended that patients are brought to a gradual progressive correction with multiple treatment sessions with these agents. Important technical considerations of which the practitioner should be aware all relate to avoiding overcorrection and include the following.

Product reconstitution Sculptra is composed of PLLA microparticles, nonpyrogenic mannitol, and sodium carboxymethylcellulose, and is supplied as a lyophilized powder. The product insert recommends that Sculptra be reconstituted with 3–5 mL of sterile water for injection and then left to hydrate >2 h

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to disperse the particles. The vial can then be shaken to suspend the microparticles. Lidocaine may be added to the suspension immediately before injection. Much literature now strongly supports a final dilution of at least 5 mL left to hydrate overnight.2–4,6,10 Adequate hydration time avoids the risk of injecting dry microclumps of material which may then hydrate in vivo. Experience over the last several years has shown us that a dilution of 8–9ml provides more product while still maintaining the ability to stimulate a clinically relevant response.

Product amount The amount of product used at any single treatment session should be determined solely and completely by the amount of surface area to be treated at that session using approximately 0.2–0.3 mL/cm. The final volumetric correction is addressed by the number of treatment sessions. The novice injector should be aware that it is initially difficult to resist the temptation to treat to full correction at any one session (although this may be possible with patients needing minimal treatment.) The endpoint is ‘blanketing’ the surface area to be treated at that session. The appropriate volume of product to be used at each session is therefore easily predetermined, i.e. a large atrophic cheek in a male HIV-positive lipoatrophy patient measuring 6 × 8 cm could require as much as an entire vial of product, whereas a 2 × 2 cm cheek hollow in a typical 50-year-old woman may require only 2–4 mL.11

Product placement This can be done with a 1-mL or 3-mL syringe and a 25G (long or short) or 26G (short) needle. Depth of placement varies with location. The product is placed in the subcutaneous layer in the cheeks, preauricular area, nasolabial folds, and lower face using the crosshatch or fanning technique. Superficial placement should be avoided.3,4,6 • Slow injections in a crosshatch pattern facilitate careful control of injection amounts when becoming familiar with the product. • Fanning has the advantage of fewer needle sticks, but the novice injector should be vigilant to avoid multiple deposits at the apex of the fan. • It may be placed as depot injections supraperiosteally along the zygoma, maxilla, canine fossa/pyriform aperture, and mandible. • Be aware that deep subcutaneous or supraperiosteal treatments in the area of the canine fossa/pyriform aperture with bulking agents has led to ischemia and necrosis.14 It is unclear whether this vascular

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compromise is the result of occlusion of a vessel or vascular compression from adjacent swelling. The low viscosity of this product eliminates the risk of compression in this area; however, a reflux maneuver should be done routinely to avoid intravascular injection of product. • Temple injections are placed deeply, under the temporalis fascia. Manufacturer’s instructions are to place 0.05-mL depots in the temple; however, it is common practice among experienced users to place a 0.3–0.6 mL depot in this area, followed by firm pressure and massage to distribute the product ev en l y . If the product has been placed in the correct plane, there should be virtually no resistance to the spread of the product. Again, a routine reflux maneuver before injection of product will eradicate any risk of inadvertent intravascular injection. • Bear in mind that this product is mixed in water, making for a very low viscosity solution when compared with a hyaluronic acid gel. The novice injector must be vigilant to ration the product carefully to avoid inadvertent overcorrection.

Product placement precaution Positional stability of a biostimulatory implant is critical to its safe use. Avoid placement in or through areas of dynamic muscle movement. Frequent reports of ‘lip lumps’ led to recommendations against the use of all collagen-stimulating devices, including polymethylmethacrylate (PMMA), PLLA, and calcium hydroxylapatite, in this area. It is assumed that the perioral muscle movement in this area leads to a clumping of particles, which in turn leads to localized overcorrection and lumps. Injections in the modiolus or depressor anguli oris muscle may behave in a similar fashion. In addition, periorbital supraperiosteal injections approached through the orbicularis oculi muscle have resulted in papules shown to be clumps of product embedded in muscle on histopathology.15 It may be that the path of the needle leaves a tract through which more deeply placed material may be extruded during muscular contraction resulting in clumping in the muscle.

Treat, wait, assess • Remember that this product is not a filler, but a stimulator of the host’s collagen. • Allow time for that response to develop before retreatment. • Wait a minimum of 4 weeks between treatments. • Be aware that, although the majority of the response will be clinically apparent approximately 4 weeks after treatment, it may continue to improve for some time. If there is any question in your mind about the need for an additional treatment, don’t do it. This is especially important

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in young patients who need very little volume. An additional treatment in this case may result in an overvolumized face.

Aftercare Massage after every two to three injections and again at the end of the treatment. Have the patient massage over the next few days using the “rule of 5s” (5 min/5 times daily/5 days). This massage may increase circulation during the initial inflammatory response and has been shown to reduce the incidence of papules.2–4,6,10

Predicting and planning outcomes/Patient selection and preparation Predicting outcomes We have observed what seems to be a common perception that very volume depleted patients are the “optimal candidates” for PLLA treatments. PLLA can certainly be used in these patients with pleasing results, but it will likely require a sizable investment of product, time, and money. Very volume-depleted patients are in fact difficult patients to “fill” regardless of product choice. Keep in mind that with any product, revolumizing is more expensive than recontouring and reshaping. Be aware that this is patient selection at play here, not product choice. In a younger or fuller face, a very pleasing, cost-effective, and durable result can be achieved with a very conservative amount of product. Successfully predicting outcomes for patients depends on many factors; however, a few generalizations can be made: • Very volume depleted faces (usually secondary to HIV lipoatrophy or endurance exercise) often require a lot of product and a lot of treatment sessions to fill, and it is often difficult to sustain the fill without relatively frequent (4 months after the final treatment. Treatment in the deep medial cheek fat pad indirectly effaces the lid cheek junction and the nasolabial fold.

Figure 6.11 A 38 year old: two vials/treatment, two treatments (four vials in total).

Last photograph taken 6 months after final treatment. The patient received no other treatment. Note brow elevation and changing position (increased curl) of upper lip with supraperiosteal treatment above the supraorbital rim and along the medial maxilla.

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Figure 6.12 A 30 year old: two vials/treatment, two treatments (four vials in total).

The patient received no other treatment. Note the brow elevation and change in the perioral area with supraperiosteal injections along the supraorbital rim, zygoma, maxilla, and mandible.

aperture in the canine fossa, and in Ristow’s space (a distinct region for augmentation of the midface lying directly above the central maxilla24) increase the anterior projection of the cheek which then “smoothes out” the skin in the infraorbital area. Interestingly, these injections also seem to “push” the soft tissue forward resulting in increased eversion of the lips. Finally, Figure 6.12 shows a young patient with good skin texture and ample soft tissue, but lacking adequate craniofacial support for the overlying soft-tissue envelope. Note the change in shape and proportions of the face with supraperiosteal treatments. A closer look highlights the subtle, but significant changes achieved in the perioral area with supraperiosteal treatments along the maxilla and mandible. Note the increased upper lip eversion obtained without direct treatment of the lip, and the change in position of the base of the nose.

Facial analysis and mapping A youthful face represents a point in time when a particular set of skeletal proportions is ideal for their soft-tissue envelope.29 We grow into this from infancy and then lose it with age.30 As mentioned previously, although the sequence of changes as we age is somewhat predictable, the pace is not. In addition, the changes in each structural layer of the face do not occur independently, but interdependently, as an interlocking three-

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dimensional puzzle. Subsequently, there is no one algorithm to address facial aging. Facial analysis is a process of observation and palpation/ provocation that allows us to determine the nature and extent of the structural tissue changes aging the face in front of us at that particular point in time, and to then plan a treatment accordingly. It is not a “recipe,” it is a “read.” What you choose to address depends on the extent of the changes noted in each layer and the parity of these changes between layers, i.e. if there is a great deal of disparity, try to blend them all back to a more similar place (i.e. we have likely all experienced at some point the undesirability of putting a pair of young lips on an old face). If there is just a little change in all layers, almost any interventional approach will work. If there is a lot of loss of integrity in multiple layers, then multiple interventions may be needed to obtain optimal results. PLLA is a versatile agent to use to address these changes because it can be used to strengthen the dermis, or to mimic volume elsewhere with “space-occupying” collagen: i.e. it mimics fat if placed in fat, or bone if placed supraperiosteally – allowing the practitioner to tailor the treatment according to the specific aging changes manifested in that individual face.31 Deep supraperiosteal injections are done wherever possible, and subcutaneous injections are carried out where there is no underlying skeletal support as outlined above in the section on technique.

Complications Overall, PLLA injections are associated with low complication rates. As with all injectable procedures, short-term complications such as bruising and edema may occur, but are self-limiting. Careful scrutiny of the available literature reveals the vast majority of complications to be secondary to technical errors in product preparation or placement.4,6,32 Granulomatous reactions, sometimes occurring months to years after administration, have been reported with all currently available commercial devices, including collagen, hyaluronic acid, PLLA, silicone, calcium hydroxyl apatite, polymethylmethacrylate, hydroxyethylmethacrylate, and polyacrylamide gel;32 in fact, this list seems to grow with every newly introduced product. True inflammatory granulomas are rare and unpredictable, and the events leading to their appearance are not yet clearly understood. Fortunately, the rate of clinically detectable granuloma formation is very low (reported to vary between 0.01 and 0.1%) and most resolve with or without treatment.32

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Summary PLLA is a versatile agent that may be used to effectively address facial aging. Its relatively unique mechanism of action allows the product to be used to provide gradual, natural and subtle results. It is now widely recognized by the medical community that volume changes in the skin and soft tissue, as well as in their underlying skeletal support, greatly contribute to the changes observed in the aging face. This appreciation, accompanied by an ever-evolving understanding of the facial aging process (including the relatively early occurrence of changes in the craniofacial platform), focus the use of injectable PLLA basically on two levels (which are most often done in concert with each other): softtissue injections to provide volume, as well as strengthening and support to these tissues, and supraperiosteal placement to address facial contours and ratios.31 Its safety, efficacy, and durability have been consistently demonstrated.2,3,4,6,31,32 Optimizing outcomes, and minimizing adverse events, with this product are not difficult, but do require awareness of and attention to its specific and evolved injection methodology, and are enhanced by a careful facial analysis before treatment. Performed correctly, PLLA injections are associated with low complication rates and high patient satisfaction.

References 1. Williams D. On the mechanisms of biocompatibility. Biomaterials 2008;29: 2941–53. 2. Butterwick K, Lowe NJ. Injectable poly-l-lactic for cosmetic enhancement: Learning from the European experience. J Amer Acad Derm 2009;61(2);281–93. 3. Burgess CM, Lowe NJ. NewFill® for skin augmentation: a new filler or failure? Dermatol Surg 2006;32:1530–32. 4. Lowe NJ. Dispelling the myth: appropriate use of poly-l-lactic acid and clinical considerations. J Eur Acad Dermatol Venereol 2006;20(suppl 1):2–6. 5. Dermik Laboratories. Sculptra Aesthetic Product Information. Bridgewater, NJ: Dermik Laboratories, 2009. 6. Vleggaar D. Facial volumetric correction with injectable poly-l-lactic acid. Dermatol Surg 2005;31 (2):1511–17. 7. Ratner B, Bryant S. Biomaterials: Where we have been and where we are going. Annu Rev Biomed Eng 2004;6:41–75. 8. Gunatillake PA, Adhikari R. Biodegradable synthetic polymers for tissue engineering. Eur Cells Materials 2003; 5:1–16. 9. Mainil-Varlet P. Rahn B, Gogolewski S. Long-term in vivo degradation and bone reaction to various polyactides One-year results. Biomaterials 1997;18:257–66. 10. Tokiwa Y, Calabia BP. Biodegradability and biodegradation of poly(lactide). Appl Microbio Biotechnol 2006;72:244–51.

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11. Ishii D, Ying TH, Mahara A et al. (2009). In vivo tissue response and degradation behavior of PLLA and stereocomplexed PLA nanofibers. Biomacromolecules. http://pubs.acs.org. Downloaded February 7, 2009. 12. Lam KH, Schakenraad JM, Esselbrugge H, Feijen J, Nieuwenhuis P. The effect of phagocytosis of poly (L-lactic acid) fragments on cellular morphology and viability. J Biomed Mat Res 1993;27:1569–77. 13. Ashammakhi N, Serio W. Reflections on complications to Bioabsorbable osteofixation devices J Cranio Surg 2007;18(5):1242–43. 14. Kinoue K, Sato D, Matsumoto K et al. Arterial embolization and skin necrosis of the nasal ala following injection of dermal fillers. Plast Reconstr Surg 2008; 121:127e–28e. 15. Stewart DB, Morganroth GS, Mooney MA et al. Management of visible granulomas following periorbital injection of poly-l-lactic acid. Ophthomal Plast Reconstr Surg 2007;23:298–301. 16. Mest DR, Humble GM. Retreatment with injectable poly-L-lactic acid for HIVassociated facial lipoatrophy 24-month extension of the Blue Pacific Study. Dermatol Surg 2009;35:350–59. 17. Reszko AE, Sadick NE, Magro CM, Farber J. Late-onset subcutaneous nodules after poly-L-lactic acid injection. Dermatol Surg 2009;35(Suppl 1):380–84. 18. Lemperle G, Rullan PP, Gauthier-Hazan N. Avoiding and treating dermal filler complications. Plast and Reconst Surg 2006;118(suppl 3):92S–107S. 19. Narins RS, Jewell M, Rubin M et al. Clinical conference: Management of rare events following dermal fillers-focal necrosis and angry red bumps. Dermatol Surg 2006;32(3):426–34. 20. Fisher GJ, Quan T, Purohit T, et al. Collagen fragmentation promotes oxidative stress and elevates matrix metalloproteinase-1 in fibroblasts in aged human skin. Am J Pathol. 2009;174(1);101–14. 21. Fisher GJ, Varani J, Voorhees JJ. Looking older: Fibroblast collapse and therapeutic implications. Arch Dermatol. 2008;144(5):666–72. 22. Wang F, Garza LA, Kang S, et al. In vivo stimulation of de novo collagen production caused by cross-linked hyaluronic acid dermal filler injections in photodamaged human skin. Arch Dermatol. 2007;143(2):155–63. 23. Rohrich RJ, Pessa JE. The fat compartments of the face: Anatomyand clinical implications fro consmetic surgery. Plast Reconstr Surg. 2007;119:2219–27. 24. Rohrich RJ, Pessa JE, Ristow B. The youthful cheek and the deep medial fat compartment. Plast Reconstr Surg. 2008;121(6):2107–12. 25. Pessa J. Discussion: The tear trough and lid/cheek junction: anatomy and implications for surgical correction. Plast Reconstr Surg 2009;123:1341–42. 26. Le Louarn CL, Buthiau D, Buis J. Structural aging: The facial recurve concept. Aesthetic Plast Surg. 2007;31:213–18. 27. Shaw RB Jr, Kahn DM. Aging of the midface bony elements: A three-dimensional computed tomographic study. Plast Reconstr Surg. 2007;119:675–81. 28. Pecora NG, McNamara JA. The aging craniofacial complex: A longitudinal cephalometric study from late adolescence to late adulthood. Am J Orthod Dentofacial Orthop. 2008;134(4):496–505. 29. Stuzin JM. Restoring facial shape in face lifting: The role of skeletal support in facial analysis and midface soft-tissue repositioning. Plast Reconstr Surg. 2007; 119(1):362–76. 30. Pessa JE, Zadoo VP, Yuan C, et al. Concertina effect and facialaging: nonlinear aspects of youthfulness and skeletal remodeling, and why, perhaps, infants have jowls. Plast Reconstr Surg. 1999;103(2):635–44.

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31. Fitzgerald R, Vleggaar D. Using Poly-l-lactic acid to mimic volume in multiple tissue layers. J Drugs Derm. 2009;8(s10):s5–14. 32. Lemperle G, Gauthier-Hazan N, Wolters M. Foreign Body Granulomas after all injectable dermal fillers: Part I. Possible causes. Plast Reconstr Surg 2009; 123(6):1842–63.

C H APTER 7

Liquid Injectable Silicone Chad L. Prather Department of Dermatology, Louisiana State University, New Orleans and Dermasurgery Center, Baton Rouge, Louisiana, USA

In the age of minimally invasive aesthetic improvement, practitioners and patients continue to strive for the “ideal filler.” The theoretical ideal filler would be versatile and biocompatible, achieve consistent results, have a natural feel in vivo, remain safe, and be affordable. Furthermore, it would be easy to inject, have minimal side effects, and not require allergy testing. The ideal filler would also achieve some degree of longevity and, arguably, permanence. In the modern era, one existing augmenting agent retains many attributes of the ideal filler: liquid injectable silicone (LIS). LIS is the original, permanent, synthetic, soft-tissue-augmenting agent that may correct a variety of cutaneous and subcutaneous atrophies. It uniquely meets most the ideal filler criteria, including versatility, reliability of results, a natural feel, and an excellent cost–benefit ratio. Although its use has historically met with some controversy, when LIS is appropriately administered with the microdroplet serial puncture technique, patients may obtain enduring correction of scars, rhytids, and depressions, as well as lasting augmentation of lips and other facial contour atrophies and deformities. Yet the permanent nature of LIS in vivo is ambiguous. Although it is an attribute when the filler is placed correctly, it may also be a liability when the product is placed incorrectly, results in undesired augmentation, or serves as a nidus for inflammation and infection. For this reason, silicone and other permanent fillers are much less forgiving than temporary fillers: overcorrection or undesired augmentation will also persist. Hence, experience and precise technique are prerequisites to favorable patient outcomes. Physicians should use LIS only after extensive training in the proper technique, and in the appropriate patient. Candidates for treatment should have clear treatment objectives and sufficient insight into the goal of gradual augmentation over multiple treatment sessions. Patients who desire immediate correction or are uncertain of treatment aims are better treated with shorter-duration, temporary fillers rather than LIS.

Injectable Fillers: Principles and Practice. Edited by Derek Jones. © 2010 Blackwell Publishing

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Figure 7.1 Chemical structure of polydimethylsiloxane with repeating trimethylsiloxane units.

Basic science Silicon (Si) is second only to oxygen as the most abundant element of the earth’s crust.1 It is a relatively inert element that is essential to humans in small amounts. “Silicone” (SI) describes the group of synthetic polymers containing elemental silicon. Polymers in the silicone family may exist in solid (elastomer), liquid, and gel states, with various chemical, physical, mechanical, and thermal properties. Synthetic polymers also vary with regard to purity, sterility, and biocompatibility.2,3 Although various silicone polymers are employed for medical use, polydimethylsiloxane is the liquid injectable silicone used for soft-tissue augmentation. The molecular structure of this colorless, odorless, nonvolatile oil consists of repeating dimethylsiloxane units with terminal trimethylsiloxane ends (Figure 7.1). The viscosity of a given LIS product is dependent on the mean chain length of the dimethylsiloxane molecular units of which it is composed. Longer-chain molecules have a higher viscosity, and individual polymers are formulated to a set viscosity dependent on mean chain length. Silicone viscosity is measured in centistokes (cs), where 1 cs equals the viscosity of water. Practically, those LIS products employed for injection into the human body have a viscosity of 350 cs (similar to mineral oil), 1000 cs (similar to honey), or 5000 cs.3 LIS has not been found to be carcinogenic, and has demonstrated “an enviable record of safety” according to a 1998 National Science Panel investigating its use.4 Importantly, viscosity remains stable after tissue implantation. Pure LIS is not altered in vivo, although small amounts may be phagocytosed and enter the reticuloendothelial system.5,6

Mechanism of action LIS is the original fibroplastic filler, and its mechanism of augmentation is twofold: it causes both the gross displacement of dermal and subcutaneous tissue and the deposition of new collagen via fibroplasia. After a localized inflammatory reaction consisting of neutrophil migration and some degree of macrophage phagocytic activity, fibroblasts deposit a thin-walled

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collagen capsule around the silicone microdroplet.7 This capsule effectively anchors the microdroplet in place and prevents migration. Although the process of fibroplasia is classically conceptualized in wound healing, several filler products, both temporary and permanent, are now known to induce collagen fibroplasia as their mechanism of action for aesthetic improvement.8 Fibroplasia accounts for significant tissue augmentation over time, and the practitioner’s approach to volume enhancement differs when using products such as LIS that work by this mechanism. Rather than attempting to reach the final treatment endpoint in a single session, as is often done with fillers that work mostly by tissue displacement, fibroplastic fillers require smaller amounts of product broken up into several sessions adequately spaced over time. Appropriate spacing of treatment sessions 1–2 months apart allows the fibroplastic process adequate time to occur before subsequent treatment sessions and avoids overcorrection and undesired augmentation.

History Dow Corning (DC) introduced the first commercially available silicone for industrial use during World War II. Soon after, however, reports of its use for soft-tissue augmentation began to surface in Japan, Germany, and Switzerland. The US medical experience with silicone began in the 1950s, when physicians and nonphysicians alike began injecting silicone oil into the human body for soft-tissue augmentation.9 Large boluses of silicone were found to result in migration of the product along tissue planes to distant body sites, which led some injectors to add known tissue irritants, such as vegetable fatty acids, to the silicone products in the hope of producing implant-site fibrous reactions to limit product migration. However, granulomatous reactions at implantation sites of the adulterated products frequently occurred. Over the subsequent decades, the widespread use of various silicone oils for augmentation continued, unfortunately without common standards with regard to sterility, purity, injection protocol, injection site, or injection volume. The silicones intended for industrial and medical device use were later joined by products that were to be investigated for soft-tissue augmentation, yet no controlled product source existed. In 1965, DC gained US Food and Drug Administration (FDA) approval for investigation of a sterilized, highly purified silicone oil specifically intended for soft-tissue augmentation. Over 1300 patients were treated, with only 1 report of a severe complication in a patient treated with a large volume of silicone in a single injection. However, study protocol was not rigorously

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controlled with respect to patient eligibility, injection technique, or treatment volume and interval, and DC stopped investigation due to poor study control and inability to prevent product misuse. Before the introduction of bovine collagen in the early 1980s, liquid silicone was indeed the most popular injectable filler due to its natural texture and long-lasting results. But continued reports of complications, such as granuloma formation and migration, brought mounting negative publicity and the passage of a 1975 Nevada law criminalizing the use of injectable silicone in that state. Nationwide, its use declined as collagen quickly became the filler of choice. Although the FDA banned the use of LIS for cosmetic implantation in the early 1990s, its legal use as a filler was restored in 1997 with the passage of the US Modernization Act, which reaffirmed the physician’s right to employ approved medical devices in an off-label manner.10 That same year, Silikon-1000 (Alcon, Fort Worth, TX), a 1000 cs, highly purified silicone, was approved for intraocular retinal detachment. Thus, with an approved product on the US market, LIS could be legally used off-label for soft-tissue augmentation. The FDA has since affirmed that off-label injection of approved products is legal as long as it is based on the unique needs of the patient and is not advertised or marketed for that purpose.3,5 In 2001 and 2003, the FDA also agreed to allow limited clinical studies investigating the use of approved LIS for the cosmetic improvement of nasolabial folds, labiomental folds, mid-malar depressions, and HIVassociated facial lipoatrophy. These studies are currently ongoing.11

Controversy Although the efficacy of LIS is seldom challenged, the past few decades have seen debate about its safety, with both critics and advocates basing their positions largely on anecdotal data rather than rigorously controlled trials.12 Well-controlled, long-term studies of LIS for soft-tissue augmentation have, until recently, been lacking, and the number of patients who have historically experienced treatment success versus the number who have experienced significant complications is simply unknown. A further difficulty in historically analyzing the safety of “silicone” as an augmenting agent is that, outside of the modern, FDA-approved products available since 1997, an unknown number of products claiming to be silicone have likely been adulterated, impure, or other substances altogether. Although highly purified, 350 cs and 1000 cs products intended for injection into the human body were not introduced until the late 1960s and 1990s respectively, various substances masquerading as “silicone” have been injected for the past 60 years, at times with significant

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complications.13–16 Even products labeled as “medical-grade” silicone have not historically been regulated or authenticated. A 1989 analysis of six “medical-grade” silicone oils commonly used for injection revealed six different products of variable viscosity, each with significant amounts of elemental impurities and low-molecular-weight adulterants.17 Critics argue that LIS in an inherently unpredictable implant, fraught with potential complications. Several anecdotal reports and series of complications such as cellulitis, nodules, granulomatous reactions, and migration have been described,13–15 although variables such as product purity, volume, and injection technique could not be established with certainty. Furthermore, complications have been reported to occur as long as 36 years after treatment.16 Migration of product to other areas of the body may occur when large boluses of LIS are injected, but this has never been reported when using the microdroplet serial puncture technique.18,19 Advocates, on the other hand, maintain that the product is extremely safe and beneficial when three tenets of treatment are strictly adhered to: (1) only FDA-approved products intended for injection into the human body should be used; (2) the microdroplet serial puncture technique must be exclusively employed; and (3) a protocol must be followed involving limited per-session injection volumes, spaced over multiple injection sessions, with adequate intersession spacing. Several authors have published excellent safety records after prolonged LIS use. Balkin reported long-term follow-up over 41 years using LIS as a soft-tissue substitute for plantar fat loss in over 1500 patients, with 25 000 recorded silicone injections. He found that the host response to injections consisted of a “banal and stable fibrous tissue formation”.7,20 Advocates such as Orentreich, Carruthers, and Jones have also published multiple reports of their extensive and successful experience with LIS, and reiterate that the three principles of product purity, appropriate technique, and proper protocol are imperative for success.11,21–23 Duffy, who has written extensively on the subject, gathers that LIS has been used for softtissue augmentation worldwide for at least 40 years, and in at least 200 000 patients in the USA.24,25 He pragmatically cautions that, although pure LIS may be a superior filler for the permanent correction of certain defects, physicians who use it must realize that its misuse, or the use of other materials masquerading as LIS, have created “a pervasive climate of distrust and a veritable minefield of extraordinarily unpleasant medicolegal possibilities.” Such perceptions reiterate the importance of ongoing trials as they replace anecdotal reports with rigorously controlled data. Despite 60 years of use, only within the past 8 years have well-controlled trials, with the newer generation of standardized, highly purified products injected according to strict protocol, begun. These studies have so far demonstrated an excellent profile of safety and efficacy. The ongoing

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collection of objective data and longer-term follow-up are necessary to provide clarity into the true risks and benefits of soft-tissue augmentation with the modern silicones.

Indications and patient selection Although there are currently no FDA-approved cosmetic indications for LIS, it has been effectively employed off-label for the augmentation nasolabial folds (Figure 7.2), labiomental folds, mid-malar depressions, lip atrophy26 (Figures 7.3 and 7.4), hemifacial atrophy, acne and other atrophic scarring27 (Figure 7.5), age-related atrophy of the hands, corns and calluses of the feet, and healed diabetic neuropathic foot ulcers.20 It is most practical for the correction of HIV facial lipoatrophy and some acne scarring (Figures 7.6 and 7.7). Many of the above atrophies are also well served by modern, temporary fillers, but, with HIV lipoatrophy,

(a)

(b)

Figure 7.2 (a) Pre- and (b) post-treatment of marionette lines and nasolabial folds.

(Courtesy of Doris Hexsel.)

(a)

(b)

Figure 7.3 (a) Pre- and (b) post-treatment of lip and vertical lip rhytids. (Courtesy of

Doris Hexsel.)

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(b)

Figure 7.4 (a) Pre- and (b) post-treatment of atrophic lip scarring.(Courtesy of Doris

Hexsel.)

(a)

(b)

Figure 7.5 Long-term correction of facial acne scarring with LIS. (a) Pre-treatment and (b) 30-year follow-up. (Courtesy of Jay G. Barnett and Channing R. Barnett.)

(a)

(b)

Figure 7.6 (a) Pre- and (b) post-treatment of HIV-associated facial lipoatrophy: 22 mL

of LIS were injected over 12 monthly sessions. (Courtesy of Derek Jones.)

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(b)

Figure 7.7 (a) Pre- and (b) post-treatment of HIV-associated facial lipoatrophy:

12.5 mL of LIS were injected over 8 monthly treatments (photograph b was taken 6 months after the last silicone injection). (Courtesy of Derek Jones.)

LIS retains several advantages over other fillers for patients requiring a significant degree of durable correction. In HIV-related facial lipoatrophy, LIS presents a highly cost-effective, durable, natural feeling, efficacious treatment option that results in sustained improvement to help combat the social and professional stigmas routinely experienced with this condition. For these reasons, LIS remains an incredibly useful filler in the experienced injector’s armamentarium. In contrast, LIS is specifically contraindicated for injection into the breasts, eyelids, bound-down scars, or an actively inflamed site, and its safety has not been studied in pregnant women. Nor should it be injected into patients with dental carries, chronic bacterial sinusitis, or other active bacterial infection, or in those who may predisposed to facial trauma through contact sports due to an increased risk for chronic infection associated with an implant in such patients. In addition, LIS is not a substitute for surgical re-draping, chemical or mechanical resurfacing, or improvement of dynamic rhytids with botulinum toxin. Rather, the ideal patient is one with appropriate insight into the permanent and off-label nature of LIS, a realistic attitude regarding achievable results, in good physical health, and compliant with recommendations. Those who seek immediate correction or temporary augmentation are best served by temporary fillers. Serious consideration by both the physician and the patient must be given to the longevity of results obtained with LIS. Although permanent fillers such as LIS might reflexively seem preferred to temporary fillers due to their longevity, one must contemplate the possibility that both societal and personal aesthetic goals may change over time. Furthermore, an undesirable outcome will be unlikely to diminish with time and may be difficult to correct.

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Figure 7.8 Silikon-1000. (Courtesy of

Derek Jones.)

Figure 7.9 Instrumentation. (Courtesy of Derek Jones.)

Instrumentation Although 350 cs LIS is approved in Europe, in the USA the most appropriate LIS for off-label soft-tissue augmentation is Silikon-1000 (Alcon, Fort Worth, TX) (Figure 7.8). Adatosil 5000 cs (Bausch & Lomb, Rochester, NY) may also be used off-label, but proves to be rather viscous as a softtissue filler; 0.5 mL LIS is drawn through a 16G Nokor needle into a 1-mL Becton Dickinson (BD) Luer-Lok syringe using sterile technique (Figure 7.9). As molecules from the rubber stopper of the syringe could theoretically contaminate the LIS after a long exposure period, LIS should be drawn into the injecting syringe immediately before treatment, and should never be stored in the syringe. LIS is most easily injected through a 27G, ½-inch Kendall Monoject aluminum-hubbed needle. Plastichubbed needles tend to pop off with the higher injection pressures needed for injection through smaller gauge needles. To increase injector comfort, ½-inch inner diameter rubber electrical bushings purchased from a hardware store may be autoclaved and placed over the barrel of the syringe to cushion the physician’s second and third finger during

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Figure 7.10 Assembled

instrumentation. (Courtesy of Derek Jones.)

Figure 7.11 Patient marking: the

patient should be marked in both the smiling and the resting positions. (Courtesy of Derek Jones.)

injection (Figure 7.10). A BD 3/10 mL insulin syringe, similar to that often used for botulinum toxin, may also be used for injection of LIS, but these syringes must be backloaded.28

Patient preparation As with all fillers, patients should avoid aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), and anticoagulants for 7–10 days before injection. Perhaps more than with any other minimally invasive procedure, a thorough discussion about the risks, benefits, and alternative treatments to LIS should occur and be documented before injecting LIS. Patients must understand that LIS is a permanent filler and that it is being used off-label. Written informed consent must be obtained. Furthermore, high-quality pre-treatment photographs should be taken. Make-up is removed, and the skin is washed with an antibacterial cleanser and prepped with a povidone–iodine antiseptic or other surgical preparatory solution. Areas to be injected are outlined under good lighting with the patient in a sitting position, using a fine-tip marking pen (Figure 7.11). Target areas for volume restoration should be marked in both the smiling and the resting position, as these often change remarkably with facial activity. When treating HIV facial lipoatrophy, mid-malar depressions

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often become slightly elevated on smiling, and overcorrection of this area may result in a “chipmunk” appearance when the patient smiles. A topical anesthetic such as lidocaine or other topical amide mixture is then placed on the treatment area and wiped off after 30 min with clean gauze.

Injection technique Although temporary fillers may be injected by varied techniques, LIS should be injected only by the microdroplet serial puncture technique originally described by Orentreich.5 Other injection techniques risk undesirable consequences, including pooling or beading of silicone macrodroplets in the injection tract and possible migration via escape from the anchoring fibroplastic capsules. A microdroplet is defined as 0.005–0.01 mL of product, an amount that possesses a very large surface area compared with volume. A larger surface area:volume ratio effectively allows the microdroplet to be anchored into place by the ensuing fibroplasia that occurs around it. With larger macrodroplets, defined as >0.01 mL, encapsulation may not be sufficient to prevent product migration. A larger surface area:volume ratio also allows for a greater amount of fibroplasia – and thus augmentation – per unit volume, since a given volume of LIS dispersed into many microdroplets provides a greater total surface area than would be provided by fewer, larger droplets. Maximizing the total surface area of injected product effectively maximizes the degree of augmentation. Injections are made into the immediate subdermal plane or deeper. Often, as the needle enters the subdermal plane, there is a slight give in the tissue resistance to the needle. Intradermal injection should be diligently avoided, because it may result in dermal erythema and ridging (Figure 7.12). Care should be taken to make sure that the needle is in the subdermal plane before depressing the plunger. Furthermore, the injector’s thumb should be removed from the plunger before removing the needle. Injections should be placed at 2- to 5-mm intervals along the skin

Figure 7.12 Dermal erythema and

ridging secondary to intradermal injection. (Courtesy of Derek Jones.)

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surface at the optimal angle for penetration and deposition into the subdermal plane. The optimal angle varies with the intended depth of LIS placement. For areas where deeper placement is desired, a more oblique (approaching perpendicular to the skin surface) angle of insertion is best, whereas a more acute (approaching parallel to the skin surface) angle of insertion works best for more superficial deposition. As a rule, multiple passes over the same treatment area in a single session should be avoided, although experienced injectors may sometimes make a second pass at a different subcutaneous level. Importantly, greater correction should be accomplished over a longer period of time rather than with a larger per-session volume. Per session treatment volumes should be limited to 0.5 mL for smaller surface areas such as the nasolabial fold, and no more than 2.0 mL for larger surface areas such as facial lipoatrophy. Such per-session volumes allow around 100–200 individual injections with microdroplet deposition at 2- to 5-mm intervals, allowing a large treatment area to be covered in a single session if necessary. Moreover, injection sessions should be spaced at least 1 month apart, or longer, to allow for a limited fibrous tissue reaction to occur around each silicone microdroplet. As with all fillers working mainly by fibroplasia, intentional overcorrection immediately after injection should be avoided. As optimal correction approaches, treatment intervals should be extended to allow complete deposition of fibrous tissue before the next injection. Intervals on the order of every 2–6 months are appropriate in the late treatment period in order to allow for delayed fibroplasia, during which continued treatment could result in overcorrection.

Side and effects and managing complications The immediate injection-related side effects commonly seen with all fillers occur with LIS as well. The mild pain of needle insertion is usually well controlled with pretreatment topical lidocaine anesthetics. Occasionally, pre-treatment with oral analgesics (i.e. 0.5 mg alprazolam and two tablets of acetaminophen/hydrocodone 5/500 mg) 1 hour before treatment may be necessary in the pain-intolerant patient. Post-injection edema and erythema are common, usually mild, and resolve within a few days. The transient edema may even be representative of what optimal correction may look like after several treatments. Ecchymosis, when it occurs, also usually resolves within a few days. When injected with the appropriate technique, LIS is remarkably similar in texture and sensation to natural soft tissue. However, when larger cumulative volumes are employed, such as in HIV facial lipoatrophy, the treated area may occasionally feel slightly rubbery and firmer than natural

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soft tissue. Migration of LIS is an often-mentioned and undesired side effect of LIS. Using small volumes over multiple treatment sessions with the microdroplet technique avoids this problem, because microdroplets of silicone are anchored to the surrounding soft tissue by fibroplasia. However, LIS may track along tissue planes in the path of least resistance when injected in large boluses all at once. Skin dyschromia is a rare side effect of LIS, occurring most often when LIS is inadvertently injected into the dermis. When the inflammatory response to LIS extends into the dermis, postinflammatory erythema, postinflammatory hyperpigmentation, and telangiectasias may occur. Often, dermal ridging occurs in conjunction with the dyschromia. Erythema and telangiectasia may be treated with a pulsed dye laser or intense pulsed light device. Hyperpigmentation may be treated with hydroquinone and sun protection. And dermal ridging may improve with intralesional steroid injection, but the response is often incomplete and the problem persistent. A more concerning potential adverse event to LIS is granuloma formation, presenting as edematous, inflamed, indurated nodules or plaques in the subcutis or dermis. Such reactions have been described with LIS as well as a variety of other permanent or longer-lasting fillers such as polymethylmethacrylate and polylactic acid.21 These reactions are thought to be immune mediated, yet the basis of the immune mechanism remains unclear. It has been postulated that granulomatous reactions may be a result of infection at a distant site, as granulomatous reactions to LIS have been noted with acute bacterial dental abscesses or sinusitis to resolve upon treatment of the infection. Another leading, and perhaps complementary, theory is that bacterial biofilm formation around the LIS microdroplet may serve as a nidus for a chronic infection and resultant inflammatory host response.29 Biofilms may occur if bacterial organisms are introduced upon filler injection or seed the filler later during bacteremic episodes, and once present may remain dormant for months or years on foreign body surfaces such as implanted LIS. Biofilms may serve as a target of a delayed immune response by the patient when organisms convert back to a planktonic state, explaining the potential for granuloma formation years after LIS injection. In theory, immune restoration in HIV might also then predispose the patient to granuloma formation years later,25 but this has not been frequently observed by experienced injectors.21,27 It is estimated that some fraction of 1% of patients correctly treated with injectable grade LIS may eventually develop such granulomatous reactions.5 Should granulomatous reactions develop, they may be treated with high concentrations of intralesional triamcinolone (20– 40 mg/mL) at 2- to 4-week intervals. However, based on the biofilm hypothesis, institution of a full-dose, broad-spectrum antibiotic such as

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minocycline once or twice daily should also occur. Isotretinoin, etanercept, and topical imiquimod have also been used successfully to treat LIS granulomas.30–33 Ultimately, however, granulomas that fail to resolve may require surgical removal.

Summary In an era of expanding soft-tissue augmenting agents, liquid injectable silicone remains a unique and effective filler when appropriately employed by experienced injectors using the microdroplet serial puncture technique. Although LIS is effective for the correction of a variety of facial atrophies and deformities, currently its greatest application is for the permanent correction of HIV-associated facial lipoatrophy. Although LIS has generated controversy in the past, the modern, highly purified silicone oils studied in controlled clinical settings have so far proven to be extremely safe agents that warrant distinction from their predecessors. Yet, as with any procedure, complications may still occur, and may be more difficult to treat due to the permanent nature of the product. For this reason, LIS should be considered only in appropriate patients who have had full disclosure as to the off-label nature of its use and adequate informed consent. When all criteria are met, LIS may be one of the most cost-effective and natural fillers available, and continued studies are ongoing to further examine both long-term safety and efficacy.

References 1. Turekian KK, Wedepohl KH. (Distribution of the elements in some major units of the earth’s crust. Bull Geol Soc Am 1961;72:175–92. 2. Spanoudis S, Koski G. Sci.polymers. Available at www.plasnet.com.au/ index.php?option=com_content&view=article&id=89:polymer-faq&catid=118: FAQ&Itemid=258 (accessed January 31, 2009). 3. Orentreich DS, Jones DH. Liquid injectable silicone. In: Carruthers J, Carruthers A (eds), Soft Tissue Augmentation, 1st edn. New York: Elsevier, 2005: 77–91. 4. Diamond B, Hulka B, Kerkvliet N, Tugwell P. Summary of report of national science panel: silicone breast implants in relation to connective tissue diseases and immunologic dysfunction, 1998. Available at: www.fjc.gov/BREIMLIT/SCIENCE/ summary.htm (accessed January 31, 2009). 5. Orentreich DS. Liquid injectable silicone: techniques for soft tissue augmentation. Clinics Plast Surg 2000;27:595–612. 6. Selmanowitz VJ, Orentreich N. Medical grade fluid silicone: a monographic review. J Dermatol Surg Oncol 1977;3:597–611. 7. Wallace WD, Balkin SW, Kaplan L, Nelson SD. The histological host response of liquid silicone injections for prevention of pressure-related ulcers of the foot: a 38year study. J Am Pod Med Assocn 2004;94, 550-557.

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8. Carruthers J, Carruthers A, Mandy SH, Lowe NJ, Prather CL, Jones DH. Fillers working by fibroplasia. In: Carruthers J, Carruthers A (eds), Soft Tissue Augmentation, 2nd edn. New York: Elsevier, 2008: 90–100. 9. Klein AW. Skin filling: collagen and other injectables of the skin. Dermatol Clinics 2001;19:491–508. 10. Food and Drug Administration. Physicians to stop injecting silicone for cosmetic treatment of wrinkles, Press Release P92-5, 1992. Available at: www.fda.gov/bbs/ topics/NEWS/NEW00267.html (accessed January 31, 2009). 11. Jones DH, Carruthers A, Orentreich D, et al. Highly purified 1000-cSt silicone oil for treatment of human immunodeficiency virus-associated facial lipoatrophy: an open pilot trial. Dermatol Surg 2004;30:1279–86. 12. Duffy DM. (2002) The silicone conundrum: a battle of anecdotes. Dermatologic Surgery 28, 590. 13. Delage C, Shane JJ, Johnson FB. Mammary silicone granuloma: Migration of silicone fluid to abdominal wall and inguinal region. Arch Dermatol 1973;108(1): 105–7. 14. Baselga E, Pujol R. Indurated plaques and persistent ulcers in an HIV-1 seropositive man. Arch Dermatol 1994;130:785–9. 15. Rapaport MJ, Vinnik C, Zarem H. Injectable silicone: cause of facial nodules, cellulitis, ulceration, and migration. Aesthet Plast Surg 1996;20:267–76. 16. Rapaport MR. Silicone injections revisited. Dermatol Surg 2002;28:594–5. 17. Parel JM. Silicone oils: physiochemical properties. In: Glaser BM, Michels RG (eds), Retina, Vol 3. St Louis, MI: Mosby, 1989: 261–77. 18. Duffy DM. Liquid silicone for soft tissue augmentation. Dermatol Surg 2005;31(11 Pt 2):1530–51. 19. Price EA, Schueler H, Perper JA. Massive systemic silicone embolism: a case report and review of literature. Am J Forensic Med Pathol 2006;27(2):97–102. 20. Balkin SW. Injectable silicone and the foot: a 41-year clinical and histologic history. Dermatol Surg 2005;31(11 Pt 2):1555–9. 21. Jones D. HIV facial lipoatrophy: causes and treatment options. Dermatol Surg 2005;31(11 Pt 2):1519–29. 22. Jones DH. Injectable silicone for facial lipoatrophy. Cosmet Dermatol 2002; 15:13–15. 23. Orentreich D, Leone AS. A case of HIV-associated facial lipoatrophy treated with 1000-cs liquid injectable silicone. Dermatol Surg 2004;30:548–51. 24. Duffy DM. Tissue injectable liquid silicone: new perspectives. In: Klein AW (ed.), Augmentation in Clinical Practice: Procedures and techniques. New York: Marcel Dekker, 1998: 237–63. 25. Duffy DM. Liquid silicone for soft tissue augmentation: histological, clinical, and molecular perspectives. In: Klein A (ed.), Tissue Augmentation in Clinical Practice, 2nd edn. New York: Taylor & Francis, 2006: 141–237. 26. Fulton JE Jr, Porumb S, Caruso JC, Shitabata PK. Lip augmentation with liquid silicone. Dermatol Surg 2005;31(11 Pt 2):1577–86. 27. Barnett JG, Barnett CR. Treatment of acne scars with liquid silicone injections: 30-year perspective. Dermatol Surg 2005;31(11 Pt 2):1542–9. 28. Benedetto AV, Lewis AT. Injecting 1000 centistoke liquid silicone with ease and precision. Dermatol Surg 2003;29:211–14. 29. Christensen L. Normal and pathologic tissue reactions to soft tissue gel fillers. Dermatol Surg 2007;33:S168–75. 30. Desai AM, Browning J, Rosen T. Etanercept therapy for silicone granuloma. J Drugs Dermatol 2006;5:894–6.

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31. Baumann LS, Halem ML. Lip silicone granulomatous foreign body reaction treated with aldara (imiquimod 5%). Dermatol Surg 2003;29:429–32. 32. Lloret P, Espana A, Leache A, et al. Successful treatment of granulomatous reactions secondary to injection of esthetic implants. Dermatol Surg 2005;31:486–90. 33. Pasternack FR, Fox LP, Engler DE. Silicone granulomas treated with etanercept. Arch Dermatol 2005;141:13–15.

C H APTER 8

Hydrogel Polymers Naissan O. Wesley Skin Care and Laser Physicians of Beverly Hills, Los Angeles, USA

History and science Hydrogel polymers are hydrophilic substances that are made up of polyacrylamide subunits.1 Acrylamide is a highly water-soluble vinyl monomer formed from the hydration of acrylonitrile. As a monomer, acrylamide has been shown to be neurotoxic and teratogenic.2,3 However, when the monomers are crosslinked to the polymer form, the potential neurotoxicity and teratogenicity effects cease.3 Most commercial uses of acrylamide are available in the form of polymers. Polyacrylamide can hold between 300 and 400 times its weight in water and has been used for many years in medical applications, drug delivery, intraocular lenses and soft contact lenses, water purification, paper processing, mining and mineral processing, food packaging, and agriculture.3,4 Their use for aesthetic procedures was first reported in 2001. Soft-tissue hydrogel polymer fillers are gels that are permanent, nonbiodegradable, and hydrophilic.1 They have a high degree of elasticity. With regard to Bio-Alcamid, its oxidizability is