. 2023 May 15;43(6):NP438-NP448.

doi: 10.1093/asj/sjad028.

Making Sense of Late Tissue Nodules Associated With Hyaluronic Acid Injections

Greg J Goodman¹, Cara B McDonald², Adrian Lim³, Catherine E Porter⁴, Anand K Deva⁵, Mark Magnusson⁶, Anita Patel⁷, Sarah Hart⁸, Peter Callan⁹, Alice Rudd¹⁰, Stefania Roberts¹¹, Katy Wallace¹², Philip Bekhor¹³, Michael Clague¹⁴, Linda Williams¹⁵, Niamh Corduff¹⁶, Nina Wines¹⁷, Firas Al-Niaimi¹⁸, Sabrina G Fabi¹⁹, Howard M Studniberg²⁰, Saxon Smith²¹, Angelo Tsirbas²², Sean Arendse²³, Antoinette Ciconte²⁴, Terence Poon²⁰

Affiliations

¹ Honorary professor at the University College of London, London, United Kingdom.
² Dermatologist, St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia.
³ Practicing dermatologist, Department of Dermatology, Royal North Shore Hospital, St Leonards, New South Wales, Australia.
⁴ Cosmetic physician in private practice in Sydney, New South Wales, Australia.
⁵ Professor, Department of Plastic and Reconstructive Surgery, Macquarie University, Sydney, Australia.
⁶ Associate professor, Department of Plastic and Reconstructive Surgery, Griffiths University Southport, Queensland, Australia.
⁷ Dermatologist in Private practice in Bondi Junction, New South Wales, Australia.
⁸ Aesthetic physician in private practice in Auckland, the North Island, New Zealand.
⁹ Specialist plastic surgeon in private practice in Geelong, Victoria, Australia.
¹⁰ Dermatologist, Department of Dermatology, Alfred Hospital Prahran Victoria, Victoria, Australia.
¹¹ Aesthetic physician in private practice in Melbourne, Victoria, Australia.
¹² Nurse practitioner at a private dermatology practice in South Yarra, Victoria, Australia.
¹³ Dermatologist, Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia.
¹⁴ Cosmetic nurse in private practice in South Yarra, Victoria, Australia.
¹⁵ Cosmetic physician in private practice in East Brisbane, Queensland, Australia.
¹⁶ Plastic surgeon in private practice in Geelong, Victoria, Australia.
¹⁷ Principal dermatologist in private practice in Sydney, New South Wales, Australia.
¹⁸ Dermatologist, Department of Dermatology, Aalborg University, Aalborg, Denmark.
¹⁹ Dermatologist, Department of Dermatology, University of California San Diego, La Jolla, CA, USA.
²⁰ Dermatologist in private practice in Sydney, New South Wales, Australia.
²¹ Dermatologist at the Sydney Clinical School, ANU Medical School, College of Health and Medicine, Australian National University, Canberra, ACT, Australia.
²² Oculoplastic surgeon in Sydney, New South Wales, Australia.
²³ Cosmetic physician in private practice in Melbourne, Victoria, Australia.
²⁴ Dermatologist at Eastern Health Hospital, Box Hill and Canterbury, Victoria, Australia.

PMID: 36759325
PMCID: PMC10184938
DOI: 10.1093/asj/sjad028

Making Sense of Late Tissue Nodules Associated With Hyaluronic Acid Injections

Greg J Goodman et al. Aesthet Surg J. 2023.

. 2023 May 15;43(6):NP438-NP448.

doi: 10.1093/asj/sjad028.

Authors

Affiliations

¹ Honorary professor at the University College of London, London, United Kingdom.
² Dermatologist, St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia.
³ Practicing dermatologist, Department of Dermatology, Royal North Shore Hospital, St Leonards, New South Wales, Australia.
⁴ Cosmetic physician in private practice in Sydney, New South Wales, Australia.
⁵ Professor, Department of Plastic and Reconstructive Surgery, Macquarie University, Sydney, Australia.
⁶ Associate professor, Department of Plastic and Reconstructive Surgery, Griffiths University Southport, Queensland, Australia.
⁷ Dermatologist in Private practice in Bondi Junction, New South Wales, Australia.
⁸ Aesthetic physician in private practice in Auckland, the North Island, New Zealand.
⁹ Specialist plastic surgeon in private practice in Geelong, Victoria, Australia.
¹⁰ Dermatologist, Department of Dermatology, Alfred Hospital Prahran Victoria, Victoria, Australia.
¹¹ Aesthetic physician in private practice in Melbourne, Victoria, Australia.
¹² Nurse practitioner at a private dermatology practice in South Yarra, Victoria, Australia.
¹³ Dermatologist, Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia.
¹⁴ Cosmetic nurse in private practice in South Yarra, Victoria, Australia.
¹⁵ Cosmetic physician in private practice in East Brisbane, Queensland, Australia.
¹⁶ Plastic surgeon in private practice in Geelong, Victoria, Australia.
¹⁷ Principal dermatologist in private practice in Sydney, New South Wales, Australia.
¹⁸ Dermatologist, Department of Dermatology, Aalborg University, Aalborg, Denmark.
¹⁹ Dermatologist, Department of Dermatology, University of California San Diego, La Jolla, CA, USA.
²⁰ Dermatologist in private practice in Sydney, New South Wales, Australia.
²¹ Dermatologist at the Sydney Clinical School, ANU Medical School, College of Health and Medicine, Australian National University, Canberra, ACT, Australia.
²² Oculoplastic surgeon in Sydney, New South Wales, Australia.
²³ Cosmetic physician in private practice in Melbourne, Victoria, Australia.
²⁴ Dermatologist at Eastern Health Hospital, Box Hill and Canterbury, Victoria, Australia.

PMID: 36759325
PMCID: PMC10184938
DOI: 10.1093/asj/sjad028

Abstract

Background: The pathogenesis of delayed-onset tissue nodules (DTNs) due to hyaluronic acid (HA) injections is uncertain.

Objectives: To formulate a rational theory for DTN development and their avoidance and treatment.

Methods: A multidisciplinary and multicountry DTN consensus panel was established, with 20 questions posed and consensus sought. Consensus was set at 75% agreement.

Results: Consensus was reached in 16 of 20 questions regarding the pathogenesis of DTNs, forming the basis for a classification and treatment guide.

Conclusions: The group believes that filler, pathogens, and inflammation are all involved in DTNs and that DTNs most likely are infection initiated with a variable immune response. Injected filler may incorporate surface bacteria, either a commensal or a true pathogen, if the skin barrier is altered. The initially high molecular weight HA filler is degraded to low molecular weight HA (LMWHA) at the edge of the filler. Commensals positioned within the filler bolus may be well tolerated until the filler is degraded and the commensal becomes visible to the immune system. LMWHA is particularly inflammatory in the presence of any local bacteria. Commensals may still be tolerated unless the immune system is generally heightened by viremia or vaccination. Systemic pathogenic bacteremia may also interact with the filler peripheral LMWHA, activating Toll-like receptors that induce DTN formation. Given this scenario, attention to practitioner and patient hygiene and early systemic infection treatment deserve attention. Classification and treatment systems were devised by considering each of the 3 factors-filler, inflammation, and infection-separately.

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Figures

**Figure 1.**
Inflammatory nodule showing filler by the blue rectangle (blue amorphous material) surrounded by chronic inflammatory cells comprising epithelial cells, macrophages, lymphocytes (black rectangle), and giant cells (yellow rectangle).

**Figure 2.**
Day of implantation. All fillers are high molecular weight hyaluronic acid (HMWHA) at time of implantation. HMWHA is anti-inflammatory even in the presence of implanted bacteria. Illustration created by and published with permission from Beth Croce.

**Figure 3.**
Delay to nodule development: Scenario 1. As the filler ages, it is degraded by reactive oxygen species (ROS) and native hyaluronidases (Hyal). The bacteria implanted with the filler may be destroyed immediately or become sequestered within the filler and become visible after a delay at the periphery of the filler as the filler is degraded or by growth of the bacterial colony. There the bacteria may interact with the immune system in an environment of proinflammatory degraded hyaluronic acid fragments. Illustration created by and published with permission from Beth Croce. HMWHA, high molecular weight hyaluronic acid; LMWHA, low molecular weight hyaluronic acid.

**Figure 4.**
Delay to nodule development: Scenario 2. The high molecular weight hyaluronic acid (HMWHA) filler ages and degrades to low molecular weight hyaluronic acid (LMWHA). Viremia or bacteremia may seed to the periphery of filler where this LMWHA degradation zone exists. LMWHA in the presence of viremia or bacteremia will exert a variable upregulation of the immune system, dependent on the virulence of the systemic infection. A viremia may just generally upregulate immune surveillance allowing “recognition” of previously tolerated implanted bacteremia. Illustration created by and published with permission from Beth Croce.

**Figure 5.**
Overview of inflammation in delayed hyaluronic acid filler nodules. (1) Over time, high molecular weight hyaluronic acid (HMWHA) fillers degrade to low molecular weight hyaluronic acid (LMWHA). (2) In the presence of pathogens, either implanted or systemic, LMWHA is inflammatory. (3) This inflammation induces reactive oxygen species (ROS) which hasten dissolution of the filler HMWHA and further degrade LMWHA into macrophage digestible fragments. (4) These small fragments of LMWHA attract macrophages to the zone of degradation for endocytosis of these fragments and final destruction by endocellular lysosomes. Illustration created by and published with permission from Beth Croce.

**Figure 6.**
Migration of product over time resulting in visible product or swelling, as in this typical example seen in the tear trough of a 56-year-old female.

**Figure 7.**
Multiple nodules affecting lips, cheeks, and tear trough of a 48-year-old female.

**Figure 8.**
Hot inflammatory nodule following a systemic illness in a 54-year-old female.

**Figure 9.**
Acute infection producing an abscess following procedure in a 48-year-old female.

See this image and copyright information in PMC

References

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Making Sense of Late Tissue Nodules Associated With Hyaluronic Acid Injections

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Making Sense of Late Tissue Nodules Associated With Hyaluronic Acid Injections

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