[Skip to Content]
[Skip to Content Landing]

Effectiveness of Low Doses of Hyaluronidase to Remove Hyaluronic Acid Filler NodulesA Randomized Clinical Trial

Educational Objective:
To learn from this pilot study that titrating hyaluronidase dosing enables potential sculpting of asymmetrical filler sites.
1 Credit CME
Key Points

Question  Can low doses of hyaluronidase safely and effectively dissolve hyaluronic acid filler nodules?

Findings  In this randomized clinical trial of 9 women and 72 injection sites, small unit doses of hyaluronidase allowed removal of minute quantities of filler without removing the entire implant.

Meaning  Minor asymmetries after filler can be corrected by the injector in a manner convenient for patients.


Importance  Although hyaluronidase is known to remove hyaluronic acid fillers, use of low doses has not been well studied.

Objective  To assess the effectiveness and dose-related effect of small quantities of hyaluronidase to treat hyaluronic acid filler nodules.

Design, Setting, and Participants  Split-arm, parallel-group, randomized clinical trial at an urban academic center. Participants were 9 healthy women. Recruitment and follow-up occurred from February 2013 to March 2014; data analysis occurred from February to July 2016.

Interventions  Each participant received aliquots (buttons) of either of 2 types of hyaluronic acid fillers into bilateral upper inner arms, respectively. At 1, 2, and 3 weeks each button was treated with a constant volume (0.1 mL) of variable-dose hyaluronidase (1.5, 3.0, or 9.0 U per 0.1 mL) or saline control.

Main Outcomes and Measures  Both a blinded dermatologist and the participant independently assessed detectability.

Results  Seventy-two treatment sites on 9 women (mean [SD] age, 45.8 [15.7] years) received all interventions and were analyzed. There was a significant difference in physician rater assessment between saline and hyaluronidase at 4 weeks (visual detection: mean difference = 1.15; 95% CI, 0.46-1.80; P < .001; palpability: mean difference = 1.22; 95% CI, 0.61-1.83; P < .001) and 4 months (visual detection: mean difference = 0.77; 95% CI, 0.33-1.26; P = .001; palpability: mean difference = 0.82; 95% CI, 0.38-1.25; P < .001) that was mirrored by participant self-assessment at 4 weeks (visual detection: mean difference = 0.87; 95% CI, 0.26-1.48; P = .006; palpability: mean difference = 1.59; 95% CI, 1.41-1.77; P < .001) and 4 months (visual detection: mean difference = 1.31; 95% CI, 1.09-1.53; P < .001; palpability: mean difference = 1.52; 95% CI, 1.03-2.01; P < .001), and hyaluronidase was associated with greater resolution of buttons compared with normal saline. The 9.0-unit hyaluronidase injection sites were significantly less palpable than the 1.5-unit sites at both 4 weeks (mean difference = 0.50; 95% CI, 0.01-.99; P = .045) and 4 months (mean difference = 0.47; 95% CI, 0.14-0.81; P = .007). Dose dependence was more notable for Restylane-L.

Conclusions and Relevance  Although very small doses of hyaluronidase can remove hyaluronic acid fillers from patient skin, slightly higher doses often result in more rapid resolution.

Trial Registration  clinicaltrials.gov Identifier: NCT01722916

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 CME Credit™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

Article Information

Accepted for Publication: December 12, 2017.

Corresponding Author: Murad Alam, MD, Department of Dermatology, Feinberg School of Medicine, Northwestern University, 676 N St Clair St, Ste 1600, Chicago, IL 60611 (m-alam@northwestern.edu).

Published Online: April 25, 2018. doi:10.1001/jamadermatol.2018.0515

Author Contributions: Dr Alam had full access to the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Alam, Hughart, Geisler, West, Poon.

Acquisition, analysis, or interpretation of data: Alam, Geisler, Paghdal, Maisel, Weil, Veledar, Poon.

Drafting of the manuscript: Alam, Hughart, Geisler, Poon.

Critical revision of the manuscript for important intellectual content: Alam, Paghdal, Maisel, Weil, West, Veledar, Poon.

Statistical analysis: Maisel, Weil, Veledar.

Obtained funding: Alam.

Administrative, technical, or material support: Hughart, Paghdal, Maisel, West.

Study supervision: Alam, Hughart.

Conflict of Interest Disclosures: Dr Alam is employed at Northwestern University. Dr Alam has been a consultant for Amway and Leo Pharma, both unrelated to this research. Grants: Northwestern University has a clinical trials unit that receives grants from very many corporate and governmental entities to perform clinical research. Dr Alam has been principal investigator on studies funded in part by Allergan, Medicis, Bioform, and Ulthera. In all cases, grants and gifts in kind have been provided to Northwestern University and not Dr Alam directly, and Dr Alam has not received any salary support from these grants. Dr Alam receives royalties from Elsevier for technical books he has edited. No other disclosures are reported.

Funding/Support: This study was supported by departmental research funds, Department of Dermatology, Northwestern University.

Role of the Funder/Sponsor: Northwestern University had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Khan  TT, Woodward  JA.  Retained dermal filler in the upper eyelid masquerading as periorbital edema.  Dermatol Surg. 2015;41(10):1182-1184.PubMedGoogle ScholarCrossref
Cohen  JL, Biesman  BS, Dayan  SH,  et al.  Treatment of hyaluronic acid filler-induced impending necrosis with hyaluronidase: consensus recommendations.  Aesthet Surg J. 2015;35(7):844-849.PubMedGoogle ScholarCrossref
Rzany  B, Becker-Wegerich  P, Bachmann  F, Erdmann  R, Wollina  U.  Hyaluronidase in the correction of hyaluronic acid-based fillers: a review and a recommendation for use.  J Cosmet Dermatol. 2009;8(4):317-323.PubMedGoogle ScholarCrossref
Sclafani  AP, Fagien  S.  Treatment of injectable soft tissue filler complications.  Dermatol Surg. 2009;35(suppl 2):1672-1680.PubMedGoogle ScholarCrossref
Cox  SE.  Clinical experience with filler complications.  Dermatol Surg. 2009;35(suppl 2):1661-1666.PubMedGoogle ScholarCrossref
Narins  RS, Coleman  WP  III, Glogau  RG.  Recommendations and treatment options for nodules and other filler complications.  Dermatol Surg. 2009;35(suppl 2):1667-1671.PubMedGoogle ScholarCrossref
Grunebaum  LD, Bogdan Allemann  I, Dayan  S, Mandy  S, Baumann  L.  The risk of alar necrosis associated with dermal filler injection.  Dermatol Surg. 2009;35(suppl 2):1635-1640.PubMedGoogle ScholarCrossref
DeLorenzi  C.  Transarterial degradation of hyaluronic acid filler by hyaluronidase.  Dermatol Surg. 2014;40(8):832-841.PubMedGoogle ScholarCrossref
Dayan  SH, Arkins  JP, Mathison  CC.  Management of impending necrosis associated with soft tissue filler injections.  J Drugs Dermatol. 2011;10(9):1007-1012.PubMedGoogle Scholar
Dayan  SH, Arkins  JP, Somenek  M.  Restylane persisting in lower eyelids for 5 years.  J Cosmet Dermatol. 2012;11(3):237-238.PubMedGoogle ScholarCrossref
McGuire  LK, Hale  EK, Godwin  LS.  Post-filler vascular occlusion: a cautionary tale and emphasis for early intervention.  J Drugs Dermatol. 2013;12(10):1181-1183.PubMedGoogle Scholar
Park  KY, Son  IP, Li  K, Seo  SJ, Hong  CK.  Reticulated erythema after nasolabial fold injection with hyaluronic acid: the importance of immediate attention.  Dermatol Surg. 2011;37(11):1697-1699.PubMedGoogle ScholarCrossref
Lee  A, Grummer  SE, Kriegel  D, Marmur  E.  Hyaluronidase.  Dermatol Surg. 2010;36(7):1071-1077.PubMedGoogle ScholarCrossref
Hirsch  RJ, Brody  HJ, Carruthers  JD.  Hyaluronidase in the office: a necessity for every dermasurgeon that injects hyaluronic acid.  J Cosmet Laser Ther. 2007;9(3):182-185.PubMedGoogle ScholarCrossref
Glaich  AS, Cohen  JL, Goldberg  LH.  Injection necrosis of the glabella: protocol for prevention and treatment after use of dermal fillers.  Dermatol Surg. 2006;32(2):276-281.PubMedGoogle Scholar
Carruthers  J, Fagien  S, Dolman  P.  Retro or peribulbar injection techniques to reverse visual loss after filler injections.  Dermatol Surg. 2015;41(suppl 1):S354-S357.PubMedGoogle ScholarCrossref
Goodman  GJ, Clague  MD.  A rethink on hyaluronidase injection, intraarterial injection, and blindness: is there another option for treatment of retinal artery embolism caused by intraarterial injection of hyaluronic acid?  Dermatol Surg. 2016;42(4):547-549.PubMedGoogle ScholarCrossref
Beleznay  K, Carruthers  JD, Carruthers  A, Mummert  ME, Humphrey  S.  Delayed-onset nodules secondary to a smooth cohesive 20 mg/mL hyaluronic acid filler: cause and management.  Dermatol Surg. 2015;41(8):929-939.PubMedGoogle ScholarCrossref
Park  S, Park  KY, Yeo  IK,  et al.  Investigation of the degradation-retarding effect caused by the low swelling capacity of a novel hyaluronic acid filler developed by solid-phase crosslinking technology.  Ann Dermatol. 2014;26(3):357-362.PubMedGoogle ScholarCrossref
Vartanian  AJ, Frankel  AS, Rubin  MG.  Injected hyaluronidase reduces Restylane-mediated cutaneous augmentation.  Arch Facial Plast Surg. 2005;7(4):231-237.PubMedGoogle ScholarCrossref
Menon  H, Thomas  M, D’silva  J.  Low dose of hyaluronidase to treat over correction by HA filler—a case report.  J Plast Reconstr Aesthet Surg. 2010;63(4):e416-e417.PubMedGoogle ScholarCrossref
Sall  I, Ferard  G.  Comparison of the sensitivity of 11 crosslinked hyaluronic acid gels to bovine testis hyaluronidase.  Polym Degrad Stab. 2007;92:915-919.Google ScholarCrossref
Jones  D, Tezel  A, Borrel  M.  In vitro resistance to degradation of hyaluronic acid dermal fillers by ovine testicular hyaluronidase.  Dermatol Surg. 2010;36:804-809.Google ScholarCrossref
Landau  M.  Hyaluronidase caveats in treating filler complications.  Dermatol Surg. 2015;41(suppl 1):S347-S353.PubMedGoogle ScholarCrossref
Flynn  TC, Thompson  DH, Hyun  SH.  Molecular weight analyses and enzymatic degradation profiles of the soft-tissue fillers Belotero Balance, Restylane, and Juvéderm Ultra.  Plast Reconstr Surg. 2013;132(4)(suppl 2):22S-32S.PubMedGoogle ScholarCrossref
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right

Name Your Search

Save Search
With a personal account, you can:
  • Track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience

Lookup An Activity


My Saved Searches

You currently have no searches saved.

With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
State Requirements