April 2020 HSC Section 4 - Plastic and Reconstructive Problems

AcademyU ®

| www.entnet.org/hsc

Your Otolaryngology Education Source

Plastic and Reconstructive Problems

Home Study Course

Hsc Home Study Course

Section 4 April 2020

© 2020 American Academy of Otolaryngology–Head and Neck Surgery Foundation The global leader in optimizing quality ear, nose, and throat patient care.

THE HOME STUDY COURSE IN OTOLARYNGOLOGY -- HEAD AND NECK SURGERY

SECTION 4

Plastic and Reconstructive Problems

April 2020

SECTION FACULTY:

Andrea Jarchow Garcia, MD** P. Daniel Ward, MD, MS, FACS** Jaime Andrews, MD, FACS C.W. David Chang, MD Waleed Ezzat, MD Laura E. Hetzler, MD Rahul Seth, MD Charles R. Woodard, MD

American Academy of Otolaryngology - Head and Neck Surgery Foundation

Section 4 suggested exam deadline: June 9, 2020 Expiration Date: August 6, 2020; CME credit not available after that date

The Home Study Course (HSC) is designed to provide relevant and timely clinical information for physicians in training and current practitioners in otolaryngology−head and neck surgery. The course, spanning four sections, allows participants the opportunity to explore current and cutting- edge perspectives within each of the core specialty areas of otolaryngology. The Selected Recent Material represents primary fundamentals, evidence-based research, and state of the art technologies in plastic and reconstructive problems. The scientific literature included in this activity forms the basis of the assessment examination. The number and length of articles selected are limited by editorial production schedules and copyright permission issues and should not be considered an exhaustive compilation of knowledge of plastic and reconstructive problems. The Additional Reference Material is provided as an educational supplement to guide individual learning. This material is not included in the course examination and reprints are not provided. Needs Assessment AAO-HNSF’s education activities are designed to improve healthcare provider competence through lifelong learning. The Foundation focuses its education activities on the needs of providers within the specialized scope of practice of otolaryngologists. Emphasis is placed on practice gaps and education needs identified within eight subspecialties. The Home Study Course selects content that addresses these gaps and needs within all subspecialties. Target Audience The primary audience for this activity is physicians and physicians-in-training who specialize in otolaryngology−head and neck surgery.

Outcome Objectives The participant who has successfully completed this section should be able to:

1. Discuss some of the issues with current autologous fat grafting. 2. Review the 10-Item Standardized Cosmesis and Health Nasal Outcomes Survey. 3. Explain pain control after septoplasty and rhinoplasty. 4. Discuss ablative and nonablative lasers in facial plastic surgery. 5. Describe the complications associated with nonsurgical rhinoplasty.

6. Review the role of ATX-101 in submental fat reduction. 7. Implement an algorithmic approach to blepharoplasty.

8. Discuss different options available for treatment of androgenetic alopecia. 9. Restate the role of a bioabsorbable nasal implant for nasal valve collapse. 10. Explain different treatment options for keloids and hypertrophic scars. 11. Integrate new tools and techniques in nasal reconstruction. 12. Review the effects of facial paralysis and options for treatment. 13. Discuss the treatment of facial fractures, septal perforations, craniofacial deformities, and vascular malformations.

Medium Used The Home Study Course is available in electronic or print format. The activity includes a review of outcome objectives, selected scientific literature, and a self-assessment examination. Method of Physician Participation in the Learning Process The physician learner will read the selected scientific literature, reflect on what they have read, and complete the self-assessment exam. After completing this section, participants should have a greater understanding of plastic and reconstructive problems as they affect the head and neck area, as well as useful information for clinical application. Accreditation Statement The American Academy of Otolaryngology—Head and Neck Surgery Foundation (AAO-HNSF) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Credit Designation The AAO-HNSF designates this enduring material for a maximum of 40.0 AMA PRA Category 1 Credit(s) ™. Physicians should claim credit commensurate with the extent of their participation in the activity. ALL PARTICIPANTS must achieve a post-test score of 70% or higher for a passing completion to be recorded and a transcript to be produced. Residents’ results will be provided to the Training Program Director. PHYSICIANS ONLY : a post-test score of 70% or higher is required to receive Credit for this activity. Two retest opportunities will automatically be available if a minimum of 70% is not achieved. Disclosure The American Academy of Otolaryngology−Head and Neck Surgery/Foundation (AAO-HNS/F) supports fair and unbiased participation of our volunteers in Academy/Foundation activities. All individuals who may be in a position to control an activity’s content must disclose all relevant financial relationships or disclose that no relevant financial relationships exist. All relevant financial relationships with commercial interests 1 that directly impact and/or might conflict with Academy/Foundation activities must be disclosed. Any real or potential conflicts of interest 2 must be identified, managed, and disclosed to the learners. In addition, disclosure must be made of presentations on drugs or devices or uses of drugs or devices that have not been approved by the Food and Drug Administration. This policy is intended to openly identify any potential conflict so that participants in an activity are able to form their own judgments about the presentation. [1] A “Commercial interest” is any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. 2 “Conflict of interest” is defined as any real or potential situation that has competing professional or personal interests that would make it difficult to be unbiased. Conflicts of interest occur when an individual has an opportunity to affect education content about products or services of a commercial interest with which they have a financial relationship. A conflict of interest depends on the situation and not on the character of the individual. Estimated time to complete this activity: 40.0 hours

2020 Section 4 PLASTIC AND RECONSTRUCTIVE PROBLEMS

** Co-Chairs: Andrea Jarchow Garcia, MD, Assistant Professor, Department of Otolaryngology-Head and Neck Surgery, University of North Carolina-Chapel Hill, Chapel Hill, NC; Private practice, Dilworth Facial Plastic Surgery, Charlotte, NC. Disclosure: No relationships to disclose. P. Daniel Ward, MD, MS, FACS, Ward MD Facial Plastic Surgery , Form Med Spas ; Adjunct Associate Professor, Department of Otolaryngology-Head & Neck Surgery, University of Utah School of Medicine, Salt Lake City, UT. Disclosure: Leadership: FormRx; Honoraria: Candela; Galderma.

Faculty: Jaime Andrews, MD, FACS, Chief of Otolaryngology – Head and Neck Surgery, Blanchfield Army

Community Hospital, Fort Campbell, KY. Disclosure: No relationships to disclose.

C. W. David Chang, MD, FACS, Associate Professor of Clinical Otolaryngology, Department of Otolaryngology—Head and Neck Surgery, University of Missouri, Columbia, MO. Disclosure: Research: Genentech Research: GSK Waleed H. Ezzat, MD, FACS , Director, Division of Facial Plastic and Reconstructive Surgery, Assistant Professor, Department of Otolaryngology – Head and Neck Surgery, Boston University School of Medicine, Boston, MA. Disclosure: No relationships to disclose. Laura E. Hetzler, MD, Associate Professor and Residency Program Director, Director, Division of Facial Plastic and Reconstructive Surgery, Department of Otolaryngology – Head and Neck Surgery, Louisiana State University, Health Sciences Center, New Orleans, LA. Disclosure: No relationships to disclose. Rahul Seth, MD, Associate Professor , Otolaryngology- Head and Neck Surgery Department, University of California, San Francisco, San Francisco, CA. Disclosure: Research: Bard Davol Charles R. Woodard, MD, Associate Professor & Director, Facial Plastic & Reconstructive Surgery, Program Director-Otolaryngology Residency, Department of Head and Neck Surgery & Communication Sciences, Duke University School of Medicine, Durham, NC. Disclosure: No relationships to disclose.

Planner(s): Linda Lee, AAO─HNSF Education Program Manager Stephanie Wilson, Stephanie Wilson Consulting, LLC; Production Manager Jeffrey Simons, MD, AAO-HNSF Education Steering Committee Chair Richard V. Smith, MD, AAO-HNSF Education

No relationships to disclose No relationships to disclose

No relationships to disclose

Expert Witness: various legal

Steering Committee, Past Chair

firms

Scott B. Roofe, MD, chair, AAO-HNSF Facial Plastic &

No relationships to disclose

Reconstructive Surgery Education Committee

This 2019-20 Home Study Course Section 4 does not include discussion of any drugs and devices that have not been approved by the United States Food and Drug Administration.

Disclaimer The information contained in this activity represents the views of those who created it and does not necessarily represent the official view or recommendations of the American Academy of Otolaryngology – Head and Neck Surgery Foundation. June 9, 2020: Section 4 suggested exam submission deadline. August 6, 2020, midnight EST: deadline for all 2019-20 HSC exams and evaluations to be submitted.

EVIDENCE BASED MEDICINE The AAO-HNSF Education Advisory Committee approved the assignment of the appropriate level of evidence to support each clinical and/or scientific journal reference used to authenticate a continuing medical education activity. Noted at the end of each reference, the level of evidence is displayed in this format: [EBM Level 3] .

Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2001) Level 1

Randomized 1 controlled trials 2 or a systematic review 3 (meta-analysis 4 ) of randomized controlled trials 5 . Prospective (cohort 6 or outcomes) study 7 with an internal control group or a systematic review of prospective, controlled trials. Retrospective (case-control 8 ) study 9 with an internal control group or a systematic review of retrospective, controlled trials. Case series 10 without an internal control group (retrospective reviews; uncontrolled cohort or outcome studies).

Level 2

Level 3

Level 4

Expert opinion without explicit critical appraisal, or recommendation based on physiology/bench research.

Level 5

Two additional ratings to be used for articles that do not fall into the above scale. Articles that are informational only can be rated N/A , and articles that are a review of an article can be rated as Review. All definitions adapted from Glossary of Terms, Evidence Based Emergency Medicine at New York Academy of Medicine at www.ebem.org . 1 A technique which gives every patient an equal chance of being assigned to any particular arm of a controlled clinical trial. 2 Any study which compares two groups by virtue of different therapies or exposures fulfills this definition. 3 A formal review of a focused clinical question based on a comprehensive search strategy and structure critical appraisal. 4 A review of a focused clinical question following rigorous methodological criteria and employing statistical techniques to combine data from independently performed studies on that question. 5 A controlled clinical trial in which the study groups are created through randomizations. 6 This design follows a group of patients, called a “cohort”, over time to determine general outcomes as well as outcomes of different subgroups. 7 Any study done forward in time. This is particularly important in studies on therapy, prognosis or harm, where retrospective studies make hidden biases very likely. 8 This might be considered a randomized controlled trial played backwards. People who get sick or have a bad outcome are identified and “matched” with people who did better. Then, the effects of the therapy or harmful

exposure which might have been administered at the start of the trial are evaluated. 9 Any study in which the outcomes have already occurred before the study has begun. 10 This includes single case reports and published case series.

OUTLINE

April 2020

SECTION 4: PLASTIC AND RECONSTRUCTIVE PROBLEMS

I.

Cosmetic A. Tissue grafting and related topics for cosmetic applications B. Cosmetic rhinoplasty C. Laser therapy for rejuvenation D. Injectables and chemodenervation

E. Blepharoplasty F. Hair restoration

II.

Reconstruction A. Functional rhinoplasty B. Treatment of hypertrophic scars and keloids

C. Flaps and grafts D. Facial paralysis E. Facial fractures F. Septal perforation repair Congenital A. Craniofacial deformities B. Vascular malformations C. Cleft rhinoplasty

III.

TABLE OF CONTENTS Selected Recent Materials - Reproduced in this Study Guide

April 2020, Section 4: PLASTIC AND RECONSTRUCTIVE PROBLEMS

Additional Reference Material........................................................................................................ i - iii

I. COSMETIC A. Tissue grafting and related topics for cosmetic applications

Brooker JE, Rubin JP, Marra KG. The future of facial fat grafting. J Craniofac Surg . 2019; 30(3):644- 651. EBM level 5....................................................................................................................................1-8

Summary : The authors note current disadvantages to autologous fat grafting, notably the high long-term resorption rate in transplanted volume augmentation. The authors point to “near future” techniques for uses and preparations of fat for rejuvenation.

Sclafani AP, Azzi J. Platelet preparations for use in facial rejuvenation and wound healing: a critical review of current literature. Aesthetic Plast Surg . 2015; 39(4):495-505. EBM level 5......................9-19

Summary : A scoping-style review of publications about platelet preparations (such as platelet-rich plasma and platelet-rich fibrin matrix) summarizes findings of in vitro, animal, and human studies. The quality of studies was not assessed. There is some evidence for the beneficial use of platelet preparations for cosmetic applications. B. Cosmetic rhinoplasty Moubayed SP, Ioannidis JPA, Saltychev M, Most SP. The 10-Item Standardized Cosmesis and Health Nasal Outcomes Survey (SCHNOS) for functional and cosmetic rhinoplasty. JAMA Facial Plast Surg . 2018; 20(1):37-42. EBM level N/A....................................................................................................20-25

Summary : This is a new validated patient reported outcome measure for standardizing preoperative assessment of patients undergoing rhinoplasty.

Sclafani AP, Kim M, Kjaer K, et al. Postoperative pain and analgesic requirements after septoplasty and rhinoplasty. Laryngoscope . 2019; 129(9):2020-2025. EBM level 2..........................................26-31

Summary : Surgeons may be able to reduce the number of opioid tablets prescribed for pain control following septoplasty or rhinoplasty.

C. Laser therapy for rejuvenation Britt CJ, Marcus B. Energy-based facial rejuvenation: advances in diagnosis and treatment. JAMA Facial Plast Surg . 2017; 19(1):64-71. EBM level 3a........................................................................32-39 Summary : A review of the medical literature on the varying lasers (ablative and nonablative) currently in use and conditions treated by these lasers for facial resurfacing. The article is a bit long, but filled with a lot of good information.

Sanniec K, Afrooz PN, Burns AJ. Long-term assessment of perioral rhytide correction with erbium:YAG laser resurfacing. Plast Reconstr Surg . 2019; 143(1):64-74. EBM level 4................40-50

Summary : The authors describe their long-term outcomes in patients receiving erbium:YAG rejuvenation of the perioral region. This is more a case-series, but the value lies in the in-depth explanation of the physics of the erbium:YAG laser and the authors’ preferred technique.

D. Injectables and chemodenervation Bertossi D, Giampaoli G, Verner I, et al. Complications and management after a nonsurgical rhinoplasty: a literature review. Dermatol Ther . 2019; 32(4):e12978. EBM level N/A...................51-58

Summary : Early recognition of minor and major complications in nonsurgical (filler) rhinoplasty is important.

Glogau RG, Glaser DA, Callender VD, et al. A double-blind, placebo-controlled, phase 3b study of ATX-101 for reduction of mild or extreme submental fat. Dermatol Surg . 2019; 45(12):1531-1541. EBM level 1.........................................................................................................................................59-69

Summary : ATX-101 (Kybella) was well tolerated and efficacious at reducing mild to extreme submental fat.

E. Blepharoplasty Zoumalan CI, Roostaeian J. Simplifying blepharoplasty. Plast Reconstr Surg . 2016; 137(1):196e- 213e. EBM level 5...............................................................................................................................70-87

Summary : The authors describe an algorithm for approaching upper and lower lid blepharoplasty. Indications and complications are discussed.

F. Hair restoration Adil A, Godwin M. The effectiveness of treatments for androgenetic alopecia: a systematic review and meta-analysis. J Am Acad Dermatol . 2017; 77(1):136-141. EBM level 1.......................................88-98 Summary : The only treatments recognized by the FDA for androgenetic alopecia (AGA) are minoxidil and finasteride (both FDA-approved) and low-level laser light therapy (FDA-cleared). This study is a systematic review of randomized controlled trials. This meta-analysis suggests that minoxidil, finasteride, and low-level laser light therapy are effective for promoting hair growth in men with AGA, and that minoxidil is effective in women with AGA.

Mao G, Zhang G, Fan W. Platelet-rich plasma for treating androgenic alopecia: a systematic review. Aesthetic Plast Surg . 2019; 43(5):1326-1336. EBM level 3............................................................99-109

Summary: Androgenic alopecia (AGA) is the most common type of hair loss, and infiltration of subcutaneous platelet-rich plasma (PRP) has been suggested to improve AGA. While numerous heterogenous studies evaluate the efficacy of PRP to treat AGA, the authors evaluated the body of literature effectively. Most studies were with small sample size and were non-RCT. Results suggest PRP may be effective in treating AGA.

II. RECONSTRUCTION

A. Functional rhinoplasty Sidle DM, Stolovitzky P, Ow RA, et al. Twelve-month outcomes of a bioabsorbable implant for in- office treatment of dynamic nasal valve collapse. Laryngoscope . 2019 Jun 28. doi: 10.1002/lary.28151. [Epub ahead of print]. EBM level 2b..............................................................................................110-115 Summary : The authors performed a case series of 166 patients who were treated with a bioabsorbable nasal sidewall implant with or without concurrent inferior turbinate reduction. Twelve-month data demonstrates improvement in NOSE scores. The study is an update of a previous publication that demonstrated 6-month post-procedure data. Disclosure: some authors served as consultants and/or received research funding from Spirox, the parent company of Latera, prior to purchase by Stryker. Stolovitzky P, Senior B, Ow RA, et al. Assessment of bioabsorbable implant treatment for nasal valve collapse compared to a sham group: a randomized control trial. Int Forum Allergy Rhinol . 2019; 9(8):850-856. EBM level 1.............................................................................................................116-122 Summary : The authors performed a single-blinded, randomized sham-controlled trial of a bioabsorbable nasal sidewall implant to improve nasal airway obstruction secondary to nasal valve collapse. One- month and 3-month outcomes (NOSE and VAS) are provided, showing improvement in both arms, but greater improvement in the implant arm. Disclosure: some authors served as consultants and/or received research funding from Spirox, the parent company of Latera, prior to purchase by Stryker. B. Treatment of hypertrophic scars and keloids Khan FA, Drucker NA, Larson SD, et al. Pediatric earlobe keloids: outcomes and patterns of recurrence. J Pediatr Surg . 2019 Jul 24; doi: 10.1016/j.jpedsurg.2019.07.006. [Epub ahead of print]. EBM level 4.....................................................................................................................................123-126

Summary : This manuscript describes outcomes after treatment of pediatric keloids. This study has a 2-year follow-up and reports similar recurrence rates across all treatment modalities.

Siotos C, Uzosike AC, Hong H, et al. Keloid excision and adjuvant treatments: a network meta- analysis. Ann Plast Surg . 2019; 83(2):154-162. EBM level 3a....................................................127-135

Summary : This meta-analysis covers 14 studies with 994 patients comparing outcomes of keloid treatment. All subjects included excision but varied on adjuvant treatment method, if any. Patients with radiation as an adjuvant therapy fared best, though this did not reach statistical significance. C. Flaps and grafts Abdelwahab M, Kandathil CK, Most SP, Spataro EA. Utility of indocyanine green angiography to identify clinical factors associated with perfusion of paramedian forehead flaps during nasal reconstruction surgery. JAMA Facial Plast Surg . 2019; 21(3):206-212. EBM level N/A...........136-142

Summary : Indocyanine green angiography is an effective method to quantify relative neovascularization perfusion in forehead flaps.

Salibian AH, Menick FJ, Talley J. Microvascular reconstruction of the nose with the radial forearm flap: a 17-year experience in 47 patients. Plast Reconstr Surg . 2019; 144(1):199-210. EBM level 4...............................................................................................................................................143-154

Summary : The radial forearm free flap is a useful tool in total nasal reconstruction.

D. Facial paralysis Joseph AW, Kim JC. Management of flaccid facial paralysis of less than two years’ duration. Otolaryngol Clin North Am . 2018; 51(6):1093-1105. EBM level 4..............................................155-167 Summary : This article nicely outlines an algorithm for management of facial paralysis of less than 2 years’ duration. The authors refine an organized approach to treatment planning based on key clinical findings. Nellis JC, Ishii M, Byrne PJ, et al. Association among facial paralysis, depression, and quality of life in facial plastic surgery patients. JAMA Facial Plast Surg . 2017; 19(3):190-196. EBM level 2b.............................................................................................................................................168-174 Summary : This is a controlled prospective observational study looking at the correlation between depression, quality of life, and facial paralysis. Presence of facial paralysis as well as an increased severity of facial paralysis were found to correlate with a higher incidence of depression and lower quality of life when compared to controls. E. Facial fractures Dedhia RD, Morisada MV, Tollefson TT, Strong EB. Contemporary management of frontal sinus fractures. Curr Opin Otolaryngol Head Neck Surg . 2019; 27(4):253-260. EBM level 5.............175-182 Summary : Previously, treatment of mandible subcondylar fractures favored closed management. However, recent treatment trends suggest open reduction and fixation may provide better functional outcomes. This review of the topic additionally describes surgical technique. F. Septal perforation repair Ozturan O, Yenigun A, Senturk E, et al. Endoscopic endonasal repair of septal perforation with interpositional auricular cartilage grafting via a mucosal regeneration technique. Otolaryngol Head Neck Surg . 2016; 155(4):714-717. EBM level 4............................................................................187-190 Summary : The authors sought to demonstrate the efficacy of septal perforation repair closure by placing a interpositional auricular cartilage graft between septal mucosa without use of mucosal advancement flaps. Complete closure was achieved in > 80% of patients, and partial closure in > 15% of patients using this technique. All septal perforations were less than 20 mm. A. Craniofacial deformities Chen JT, Schmid DB, Israel JS, Siebert JW. A 26-year experience with microsurgical reconstruction of hemifacial atrophy and linear scleroderma. Plast Reconstr Surg . 2018; 142(5):1275-1283. EBM level 4...............................................................................................................................................191-199 Summary : The authors review their treatment strategy for facial reconstruction in patients with Parry Romberg syndrome. While the study has little objective data, in the authors’ experience, they have found free-tissue transfer provides greater longevity and may stabilize the disease process. Summary : Treatment of frontal sinus fractures has been evolving. Management may involve greater use of observation and minimally invasive procedures. Strohl AM, Kellman RM. Current management of subcondylar fractures of the mandible, including endoscopic repair. Facial Plast Surg Clin North Am . 2017; 25(4):577-580. EBM level 5..........183-186

III. CONGENITAL

Schultz KP, Dong E, Truong TA, Maricevich RS. Parry Romberg syndrome. Clin Plast Surg . 2019; 46(2):231-237. EBM level 5...........................................................................................................200-206

Summary : This article summarizes the clinical features and treatment options of Parry Romberg syndrome. Treatment options depend upon risk, severity, and potential course of the disease.

B. Vascular malformations Morgan P, Keller R, Patel K. Evidence-based management of vascular malformations. Facial Plast Surg . 2016; 32(2):162-176. EBM level 3a.....................................................................................207-221 Summary : A review of the literature presenting the current evidence-based practices of the treatment of various vascular malformations. While this is a longer article, it is filled with excellent information and is a quick read.

Waner M, O TM. Multidisciplinary approach to the management of lymphatic malformations of the head and neck. Otolaryngol Clin North Am . 2018; 51(1):159-172. EBM level 5........................222-235

Summary : There is a paucity of new information on lymphatic malformations within the last 2 years, and this high-quality review has a lot of great information.

C. Cleft rhinoplasty Allori AC, Mulliken JB. Evidence-based medicine: secondary correction of cleft lip nasal deformity. Plast Reconstr Surg . 2017; 140(1):166e-176e. EBM level 5.........................................................236-246 Summary : The authors nicely delineate the composite structural abnormalities that lead to primary and secondary nasal deformities. Though the article is indeed experiential, it classifies acceptable intermediate interventions while acknowledging that “less is more” in these patients prior to definitive repair. Zhang RS, Lin LO, Hoppe IC, et al. Nasal obstruction in children with cleft lip and palate: results of a cross-sectional study utilizing the NOSE scale. Cleft Palate Craniofac J . 2019; 56(2):177-186. EBM level 3b.............................................................................................................................................247-256 Summary : This is a retrospective cross-sectional study looking at the incidence of nasal obstruction in the cleft population, stratifying based on surgical and presurgical interventions, such as NAM, and postsurgical management, such as nasal stents. The functional findings demonstrate a nice review of the stigmatic cleft deformity and predict that those with the worse scores, Veau 3 and CL+A, can degenerate further after speech surgery.

APRIL 2020 SECTION 4 ADDITIONAL REFERENCES

Albathi M, Oyer S, Ishii LE, et al. Early nerve grafting for facial paralysis after cerebellopontine angle tumor resection with preserved facial nerve continuity. JAMA Facial Plast Surg . 2016; 18(1):54-60.

Al-Haddab M, Abduljabbar A, Al-Somaily A. The sterility of partially used hyaluronic acid fillers after long storage. Dermatol Surg . 2017; 43(7):967-970.

Antell DE, May JM, Bonnano MJ, Lee NY. A comparison of the full and short-scar face-lift incision techniques in multiple sets of identical twins. Plast Reconstr Surg . 2016; 137(6):1707-1714.

Aşiran Serdar Z, Aktaş Karabay E, Tatliparmak A, Aksoy B. Efficacy of high-intensity focused ultrasound in facial and neck rejuvenation. J Cosmet Dermatol . 202; 19(2):353-358.

Banyard DA, Bourgeois JM, Widgerow AD, Evans GR. Regenerative biomaterials: a review. Plast Reconstr Surg . 2015; 135(6):1740-1748.

Baugh RF, Basura GJ, Ishii LE, et al. Clinical practice guideline: Bell’s palsy. Otolaryngol Head Neck Surg . 2013; 149(3 Suppl):S1-S27.

Beleznay K, Carruthers JD, Humphrey S, Jones D. Avoiding and treating blindness from fillers: a review of the world literature. Dermatol Surg . 2015; 41(10):1097-1117.

Britt CJ, Marcus B. Energy-based facial rejuvenation: advances in diagnosis and treatment. JAMA Facial Plast Surg . 2017; 19(1):64-71.

Cabin JA, Massry GG, Azizzadeh B. Botulinum toxin in the management of facial paralysis. Curr Opin Otolaryngol Head Neck Surg . 2015; 23(4):272-280.

Daniali LN, Rezzadeh K, Shell C, et al. Classification of newborn ear malformations and their treatment with the EarWell Infant Ear Correction System. Plast Reconstr Surg . 2017; 139(3):681-691.

Delaney SW. Treatment strategies for frontal sinus anterior table fractures and contour deformities. J Plast Reconstr Aesthet Surg . 2016; 69(8):1037-1045.

Dixon H, Datema FR. A new endoscopic technique to close big nasal septal perforations: prospective evaluation of the double meat hook technique in 19 consecutive cases. Clin Otolaryngol . 2018; 43(2):710-714.

Doerr TD. Evidence-based facial fracture management. Facial Plast Surg Clin North Am . 2015; 23(3):335-345.

Doft MA, Goodkind AB, Diamond S, et al. The newborn butterfly project: a shortened treatment protocol for ear molding. Plast Reconstr Surg . 2015; 135(3):577e-583e.

El-Domyati M, Abdel-Wabab H, Hossam A. Combining microneedling with other minimally invasive procedures for facial rejuvenation: a split-face comparative study. Int J Dermatol . 2018; 57(11):1324- 1334.

i

Ezzat WH, Liu SW. Comparative study of functional nasal reconstruction using structural reinforcement. JAMA Facial Plast Surg . 2017; 19(4):318-322.

Fabi S, Sundaram H. The potential of topical and injectable growth factors and cytokines for skin rejuvenation. Facial Plast Surg . 2014; 30(2):157-171.

Floyd EM, Ho S, Patel P, et al. Systematic review and meta-analysis of studies evaluating functional rhinoplasty outcomes with the NOSE score. Otolaryngol Head Neck Surg . 2017; 156(5):809-815.

Guy WM, Pattisapu P, Ongkasuwan J, Brissett AE. Creation of a head and neck keloid quality of life questionnaire. Laryngoscope. 2015; 125(12):2672-2676.

Guyuron B, Seyed Forootan NS, Katira K. The super-high SMAS facelift technique with tailor tack plication. Aesthetic Plast Surg . 2018; 42(6):1531-1539.

Hahn S, Holds JB, Couch SM. Upper lid blepharoplasty. Facial Plast Surg Clin North Am . 2016; 24(2):119-127.

Hashem AM, Couto RA, Waltzman JT, et al. Evidence-based medicine: a graded approach to lower lid blepharoplasty. Plast Reconstr Surg. 2017; 139(1):139e-150e.

Jacono AA, Malone MH, Talei B. Three-dimensional analysis of long-term midface volume change after vertical vector deep-plane rhytidectomy. Aesthet Surg J. 2015; 35(5):491-503.

Joseph AW, Ishii L, Joseph SS, et al. Prevalence of body dysmorphic disorder and surgeon diagnostic accuracy in facial plastic and oculoplastic surgery clinics. JAMA Facial Plast Surg. 2017; 19(4):269- 274.

Kandinov A, Mutchnick S, Nangia V, et al. Analysis of factors associated with rhytidectomy malpractice litigation cases. JAMA Facial Plast Surg . 2017; 19(4):255-259.

Kenworthy W, Langridge B, Patel N, Waterhouse N. Use of platelet preparations in facial rejuvenation and wound healing remains unproven. Aesthetic Plast Surg . 2016; 40(2):329-330.

Killion EA, Hyman CH, Hatef DA, et al. A systematic examination of the effect of tissue glues on rhytidectomy complications. Aesthet Surg J . 2015; 35(3):229-234.

Lee LN, Quatela O, Bhattacharyya N. Postoperative revisits and readmissions after facelift surgery. Laryngoscope . 2018; 128(12):2714-2717.

Patel SA, Liu JJ, Murakami CS, et al. Complication rates in delayed reconstruction of the head and neck after Mohs micrographic surgery. JAMA Facial Plast Surg . 2016; 18(5):340-346.

Pawar SS, Koch CA, Murakami C. Treatment of prominent ears and otoplasty: a contemporary review. JAMA Facial Plast Surg . 2015; 17(6):449-454.

Reilly MJ, Tomsic JA, Fernandez SJ, Davison SP. Effect of facial rejuvenation surgery on perceived attractiveness, femininity, and personality. JAMA Facial Plast Surg . 2015; 17(3):202-207.

Rohrich RJ, Dauwe PB, Pulikkottil BJ, Pezeshk RA. The importance of the anterior septal angle in the open dorsal approach to rhinoplasty. Plast Reconstr Surg . 2017; 139(3):604-612.

ii

Scheuer JF 3rd, Sieber DA, Pezeshk RA, et al. Anatomy of the facial danger zones: maximizing safety during soft-tissue filler injections. Plast Reconstr Surg . 2017; 139(1):50e-58e.

Spataro E, Piccirillo JF, Kallogjeri D, et al. Revision rates and risk factors of 175 842 patients undergoing septorhinoplasty. JAMA Facial Plast Surg . 2016; 18(3):212-219.

Surowitz J, Lee MK, Most SP. Anterior septal reconstruction for treatment of severe caudal septal deviation: clinical severity and outcomes. Otolaryngol Head Neck Surg . 2015; 153(1):27-33.

van Leeuwen MC, Stokmans SC, Bulstra AE, et al. High-dose-rate brachytherapy for the treatment of recalcitrant keloids: a unique, effective treatment protocol. Plast Reconstr Surg. 2014; 134(3):527-534.

Verhiel S, Piatkowski de Grzymala A, van der Hulst R. Mechanism of action, efficacy, and adverse events of calcium antagonists in hypertrophic scars and keloids: a systematic review. Dermatol Surg . 2015; 41(12):1343-1350.

Wee JH, Mun SJ, Na WS, et al. Autologous vs irradiated homologous costal cartilage as graft material in rhinoplasty. JAMA Facial Plast Surg . 2017; 19(3):183-188.

Wilson AJ, Chang B, Taglienti AJ, et al. A quantitative analysis of onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA: a randomized, double-blind, prospective clinical trial of comparative dynamic strain reduction. Plast Reconstr Surg . 2016; 137(5):1424-1433.

Wu DC, Fitzpatrick RE. Facial rejuvenation via the sequential combined use of multiple laser modalities: safety and efficacy. Lasers Surg Med . 2016; 48(6):577-583.

Yeung A, Hassouneh B, Kim DW. Outcome of nasal valve obstruction after functional and aesthetic- functional rhinoplasty. JAMA Facial Plast Surg . 2016; 18(2):128-134.

iii

Reprinted by permission of J Craniofac Surg. 2019; 30(3):644-651.

O RIGINAL A RTICLE

The Future of Facial Fat Grafting

Jack E. Brooker, MD, J. Peter Rubin, MD, yz and Kacey G. Marra, PhD yz

magnetic resonance imaging (MRI) to track the fate of facial fat grafts found that 49% of the original graft resorbed in the first 3 months, increasing to 55% by the first 6 months. 9 The first demon- stration of long-term survival in fat grafting was reported in the mid- 1990s when Coleman reported his trials in the nasolabial fold. 10,11 Unlike previous authors, Coleman did not extract the fat from the donor area at high negative pressure, break up the adipose tissue, or implant into the recipient area at high positive pressure. Instead fat was transferred in ‘‘parcels’’ such that cells had their own nutritional source upon implantation. 10 This fat grafting procedure is now used in a wide range of clinical scenarios including aesthetic surgery, cranio- facial abnormalities, posttumor resection reconstruction and trauma reconstruction. 8 Additionally, fat grafting has been used for the surgical correction of a number of congenital craniofacial anomalies, including hemifacial microsomia and Parry-Romberg syndrome. 12,13 Although initially seen as an autologous filler, interest soon grew in the apparent regenerative effects of engrafted lipoaspirate on overly- ing skin. 14,15 Tissue overlying the grafts appeared to improve in the first year postoperatively; pore size decreased, wrinkles softened, skin pigmentation changes regressed. 14 As a result the use of fat grafting has also been reported in scar resolution secondary to acne and burns. 1,16 Rigotti et al contend that radiation scarring is due to anoxia and poor vascularity and contend that tissue healing in refractory scars relies on the stem-cell populationwithin the graft secreting angiogenic factors which leads to microvascularization and oxygenation. 17 There are several key advantages which render fat grafting attractive to plastic and reconstructive surgeons. Autologous fat grafting is versa- tile, lacks immunogenicity and is readily available in most patients. 18 Patient satisfaction has generally been high with fat grafting, even when multiple procedures are required. 19 Complications are also relatively low compared to prosthetics and fillers and include hema- toma, ecchymosis, and resorption. 19 Resorption remains a major challenge even with Coleman’s improved method for harvesting and grafting; retention rates during the 1990s ranged from 20% to 90% while more recent studies report that resorption rates still vary from 20% to 60%. 8 The sheer unreliability of long-term retention is itself a significant drawback to the use of facial fat grafting. Adipose tissue is derived from the mesoderm with cellular components including endothelial cells, mesenchymal stem cells, fibroblasts, macrophages, pericytes and muscle cells which, after lipoaspiration, can be broken down (usually with collagenase) and separated by centrifuge. 20 Adipose-derived stem cells (ASCs) are mesenchymal stem cells (MSC) with many properties similar to bone-marrow-derived stem cells (BMSC) and bear the relevant immunologic cell surface markers (CD105, CD73, CD29, CD44, CD90) (25). 21 The ASCs are multipotent, like BMSCs, and can differentiate into multiple cell lines. 22 The ASCs are capable of differentiating into mesenchymal phenotypes. 22 These include mesenchymal tissue such as chondrocytes and osteocytes as well as nonmesenchymal cell phenotypes; cardiomyocytes, neurons, and endothelial cells have all been reported. 22–25 NEAR FUTURE APPLICATIONS Nanofat Grafting It has been suggested that stromal cells and preadipocytes represent the surviving population of cells in a graft as their

Abstract: Fat grafting was first described in the early 20th century but for many years remained a relatively underused technique due to the unreliability of long-term volume expansion. Significant improvements in reliability have been made in the last 2 decades and there is a large body of literature pertaining to extraction, processing and injection methods to obtain more lasting effects. However, volume loss and graft resorption remain a major challenge in the long term and lead to unpredictability in results. Enriching adipose graft with stromal vascular fraction, ex vivo cultured adipose stem cells and platelet-derived growth factor among others is one method under active investigation which may assist graft survival through a range of mechanisms including increased angiogenesis. Breaking adipose graft into smaller fragments such that engrafted cells have greater access to donor-site oxygenation and nutrition is another method which in theory may promote survival. Presently, adipose grafting in the face is usually for the addition of volume to fill defects. However, the stem-cell containing fraction of adipose graft- ing (stromal vascular fraction) appears to exert a rejuvenating effect on overlying skin and soft tissue when administered alone. The application of these low-volume injections represents a significant shift in thinking away from mere volume expansion. These techni- ques have been tested in a range of animal models and some human studies. In this review, the authors provide a broad overview of present research and highlight both limitations in previous research and current areas of investigation. A utologous fat grafting has been has been practiced for over 100 years, having first been described for the use of tuberculo- sis-induced changes to facial contours. 1 The growth of fat grafting in the area of facial reconstruction was at first slow but over time gathered new applications. The use of fat grafting in the obliteration of frontal sinus described in the 1950s remains the gold standard today. 2– 4 In the 1980s and early 1990s, the use of fat grafts in cosmetic filling was described by multiple surgeons 5–7 ; however, results often dem- onstrated a high degree of resorption and their reports garnered relatively little attention at the time. 8 One 5-year study utilizing From the Department of Plastic Surgery; y Department of Plastic Surgery, Department of Bioengineering, McGowan Institute of Regenerative Medicine; and z Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA. Received August 29, 2018. Accepted for publication September 22, 2018. Address correspondence and reprint requests to Kacey G. Marra, PhD, Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15213; E-mail: marrak@upmc.edu Key Words: Adipose, craniofacial, fat, graft, stem cell ( J Craniofac Surg 2019;30: 644–651)

The authors report no conflicts of interest. Copyright # 2019 by Mutaz B. Habal, MD ISSN: 1049-2275 DOI: 10.1097/SCS.0000000000005274

The Journal of Craniofacial Surgery

Volume 30, Number 3, May 2019

1

The Journal of Craniofacial Surgery

Volume 30, Number 3, May 2019

Future of Facial Fat Grafting

metabolic rates are lower than mature adipose cells rendering them more resistant to the burden of hypoxia which follows grafting. 27 Consequently, the concept of nanofat grafting is rapidly developing. Tonnard et al described their results in 2013. Their study involved the complete emulsification of abdominal fat such that no viable adipocytes were evident. This strategy is not intended for volume augmentation, but rather to both mechanically concentrate the ASCs and also create a more flowable graft material that can be applied with a narrow gauge injection cannula or needle. Emulsifi- cation was achieved by passing fat between two 10cc syringes connected by a luer-lok followed by filtration through a nylon cloth. The effluent collected was considered the ‘‘nanofat’’ sample. Nonmulsified fat was also used as a control (referred to as microfat if taken via a small multiport cannula with sharp 1-mm side-holes or macrofat if taken via a standard 3-mm cannula). Histologic staining confirmed the presence of viable adipocytes in macrofat and microfat samples and the absence of these in the nanofat sample. The stromal vascular fraction (SVF) was separated from the lipoas- pirates and cultured for 7 days after which CD34 positive cells were identified. Neither the morphology (fibroblast in nature) nor the CD43 positive cells to SVF ratio differed significantly between nanofat, microfat, and macrofat lipoaspirates. A further 10 days in an adipogenic medium yielded cells which were round and lipid filled (again no difference was seen between the 3 lipoaspirate types either in quantity or quality). Grafting occurred in 67 patients, of which the greatest facial indication was perioral skin rejuvenation, followed by glabellar skin and dark lower eyelids. 28 Three patients with images were selected by Tonnard et al which are displayed in Figure 1. Uyulmaz and colleagues published their experience in a total of 52 patients with scars (n ¼ 40), discoloration (n ¼ 6), and wrinkles (n ¼ 6) treated with nanofat injections. The processing method was

FIGURE 2. Top row shows a 52-year female with irregular, hyperpigmented lesion of the cheek before (A) and 4 months after nanofat injection (B). Bottom row shows a 49-year-old patient with periorbital hyperpigmentation before (A) and 1 month after nanofat injection (B). 29 Adapted from ‘‘Nanofat Grafting for Scar Treatment and Skin Quality Improvement’’ by S Uyulmaz et al, 2018, Aesthetic Surgery Journal , 38, p. 424-425. Copyright 2018 by the American Society for Aesthetic Plastic Surgery.

the same as that described by Tonnard et al. The average volume of injected lipoaspirate was 4.6 mL. Pre- and postoperative photo- graphs were judged by a panel of 3 physicians; a plastic surgeon, a general surgeon and a dermatologist who graded their outcomes independently as good, satisfactory or no change. In 66% of patients they judged the outcome to be good, with only 7% receiving a ‘‘no change’’ rating. Scars were judged to be highly improved (88% receiving a ‘‘good’’ grading) while wrinkles and discoloration had more equivocal results though as noted above, the sample sizes of these last 2 categories were small. 29 Selected patient images before and after nanofat injection are shown in Figure 2. Nanofat grafting represents a shift in thinking as regards the application of fat grafting. 28 Traditional grafting relies on the volume which can be achieved through the implantation of mature adipose tissue. Long-term viability relies on the maintenance of this tissue vitality though the preservation of tissue architecture and the insertion of small ‘‘packets’’ to ensure vascularization and preser- vation of volume and consistency. Nanofat grafting relies on none of this, but instead utilizes the stem-cell population within the SVF to achieve rejuvenation of native tissue, resolution of scars, and reversal of aging signs. In the regulatory framework, this mechani- cal processing is still considered minimal manipulation and falls under the umbrella of a surgical procedure. Facial fat grafting has traditionally been utilized to augment volume in the various compartments of the face. 11,30 In youth, adipose tissue in the face is abundant, diffuse, and balanced; however, as the face ages, there is increasing imbalance which develops in volume; some compartments become hypertrophied while others become atrophied. 30 The SVF is the product of lipoaspirate after collagenase degra- dation. This leads to 2 distinct phases; a floating mature adipocyte fraction and a lower, aqueous fraction containing cellular compo- nents. 31 Separation of the aqueous component of the degradation product yields a heterogenous mixture of cells including ASC, endothelial precursor cells, macrophages, smooth muscle cells, lymphocytes, pericytes, and preadipocytes. 31 Stromal Vascular Fraction-Enriched Fat Grafting

FIGURE 1. Sun damaged skin in a 41-year-old female (top row), bulging and pigmentation of the lower eye-lids in a 36-year-old female and perioral rhytides in a 61-year-old female. Left-hand images show preinjection state and right- hand images show state 7 months after nanofat injection. 26 Adapted from ‘‘Nanofat grafting: basic research and clinical applications’’ by P. Tonnard et al, 2013, Plastic and Reconstructive Surgery 132, p. 1023-1024. Copyright 2013 by the American Society of Plastic Surgeons.

# 2019 Mutaz B. Habal, MD

2

The Journal of Craniofacial Surgery

Volume 30, Number 3, May 2019

Brooker et al

Given the ASC and stromal stem-cell population, it was theo- rized that SVF enrichment of adipose tissue grafts may improve graft volume retention. A number of animal studies, some of which are summarized in Table 1, compared graft retention rates of adipose/SVF grafts to adipose grafts alone and overwhelmingly reported superior rates in the adipose/SVF cohorts. Matsumoto et al published one of the earliest studies using an immunodeficient mouse recipient model for human adipose grafts. 32 It was found that the addition of SVF significantly improved graft retention rates and through immunofluorescent tagging of the SVF cells, they were able to later identify them between mature ASC in the connective tissue and some expressed Von Willebrand factor, suggesting increased angiogenesis was one part of their mechanism of action. 32 Another study by Paik et al used a similar model but employed varying doses of cells ranging from 0 (control) to 10 million and found that graft retention rates at higher doses of SVF were poorer which the authors hypothesized was due to increased metabolic demand from the increased loading of stem cells which compete for nutrients with the adipocytes in the postgraft period. 33 Rasmussen et al included 13 animal studies for SVF-enriched adipose grafting in their review and found a 0.65- to 2.5-fold improvement in volume retention compared to adipose grafting alone after a mean of 13 weeks. 34 Human studies have been reported using SVF-enriched grafts to the face. In their review, Toyserkani et al included 3 studies of SVF- enriched facial fat grafting, summarized in Table 2, all of which led to significant increases in volume retention compared to fat grafting alone. 35 In their meta-analysis, Zhou et al included 4 studies using SVF-enriched fat grafting to the face and found a significant overall increase in volume retention in the SVF-enriched group (71%) compared to the unenriched group (52%). 36 They also found that the number of reoperations was reduced from 24.2% to 10.6%. 36 Gontijo-de-Amorim et al published a prospective comparative study of 30 patients with hemifacial soft tissue volume loss from tumor excision, Parry-Romberg syndrome, and trauma. 37 Fifteen patients received standard autologous fat grafting while the remain- ing 15 received grafting enriched with SVF. At 12 months a subset of 5 patients from each group underwent volumetric analysis by computed tomography (CT) and all had aesthetic outcomes judged by independent surgeons at 1 to 2 years. 37 Example patient images (both with Parry-Romberg syndrome) prior to grafting and 2 years after grafting are shown in Figure 3, with the top patient receiving only un-enriched grafting and the bottom patient receiving SVF- enriched grafting. Patients receiving SVF-enriched grafting were judged to have an ‘‘excellent’’ outcome by the independent surgeon panel in 82.5% of patients while those receiving graft only were judged ‘‘excellent’’ in 47.6% of patients. The CT volumetric analysis showed a volume loss of 24% in the un-enriched control group and 9.6% in the enriched group. Flow cytometry identified an average of 16,000 mesenchymal stem cells in each of 25 SVF pellets analyzed. 37 Facial rejuvenation has also been examined using SVF-enriched grafts. Charles de Sa´ et al harvested abdominal fat from 6 facelift patients and extracted SVF from the lipoaspirate. 38 Patients received SVF-enriched fat to the right preauricular area while expanded ASC in culture (number of passages unknown) was administered to the left preauricular area. Skin biopsies were assessed 3 months after grafting using histologic and electron microscopy analysis. 38 Important considerations for the use of ASC enriched fat grafts are the regulatory constraints, especially in the United States and European Union, and the added cost of the procedure versus fat grafting alone. Unlike mechanical emulsification, deliberate sepa- ration of SVF is considered ‘‘greater than minimal’’ manipulation in many regions and the cell product has a higher regulatory burden.

Cultured ASC-Enriched Fat Grafting The ASCs represent a more homogenous population of cells compared to SVF after culturing. 48,49 A number of animal studies specifically examined ASC enrichment have been reported. For example, Zhang et al harvested adipose from donor rats and extracted the SVF before culturing in fetal bovine serum. 42 The ASCs were isolated and expanded to passage 4, mixed with adipose grafts and injected into recipient rats. CD34 staining was greater at 14 days in the ASC-enriched grafts and volume retention was greater at 3 months than nonenriched grafts. 50 Piccinno et al utilized a rabbit model and harvested SVF from animals from which they then isolated ASC via 4 sequential passages. 43 These ASCs were mixed with hyaluronic acid and autologous adipose grafts and implanted. The ASC-enriched grafts showed greater vascularity and reduced necrosis at 14 days and after 3 months; ASC-enriched grafts also showed significantly greater volume retention. 43 Mose- ley et al published one of the few studies in mice comparing both cultured ASC and fresh ASC-enriched grafts in mice. Both were reported to be superior in volumetric retention and qualitative appearance (abundance of adipocytes and lower fibrosis than con- trols) and the transgenic ASCs were still present upon immunohis- tochemical staining at 6 months. 44 Rasmussen et al reviewed 11 animal studies using cultured ASC with 8 reporting significant improvement in volume retention over adipose grafting alone. 34 In general, the studies reported greater vascularity and decreased necrosis cysts on histology in the ASC-enriched grafts. 34 Human studies with ex vivo expanded ASC are less numerous than those for SVF-enriched adipose grafts; however, a number do exist. Kølle et al performed the first randomized controlled trial whereby patients underwent 2 separate liposuction procedures, 1 to harvest adipose for injection, and the other for isolation of ASCs. 54 The 2nd aspiration was split into 2, with 20 million ASCs added to 1 half only. The ASC-enriched and un-enriched grafts were then randomly injected into the posterior part of the right and left upper arm. Volume was measured by MRI at the time of engraftment and 121 days later where the ASC-enriched graft was found to have a retention of 80.9% versus 16.3% for the un-enriched graft. 54 Koh et al applied this to the face in 5 subjects with Parry- Romberg syndrome, with 5 further subjects receiving microfat injections only as controls. 55 Donor fat was obtained from abdomi- nal lipoaspirates and cultured for 14 days whereupon microfat in the experimental group was enriched with 1 10 7 cells. Patients under- went CT volumetric analysis at 6 months which showed a 2.51-fold fat uptake rate in the experimental versus control group. Figure 4 shows the front-on views taken preoperatively, 6 months postoper- atively, and 12 postoperatively showing long-term retention though no control group images were included by Koh et al. At present at least 1 human trail examining the utility of ex vivo expanded ASC in facial fat grafting is currently underway with no results posted at the time of writing (NCT03258164). Barriers to clinical application of this technology include not only the time and resource intensive process of ex vivo expansion of primary stem cells but also regulatory hurdles as well. Currently, human cell based therapies are allowed to be marketed only with FDA approval unless they meet certain stringent parameters including minimal manipulation, something which all ex vivo expanded cultures have undergone. 64 At present a significant amount of rigorous evidence from controlled trials will be required before this technology can be effectively marketed. More radical utilization of ASC has been reported in the repair of osseous craniofacial defects. Multiple in vivo studies in rats, rabbits, and mice have been reported some of which are summarized in Table 1. These studies have shown inconsistent results, with some showing considerable efficacy using implantable matrices seeded

# 2019 Mutaz B. Habal, MD

3