Clinic Rev Allerg Immunol DOI 10.1007/s12016-012-8348-5 Late-Onset Inflammatory Adverse Reactions Related to Soft Tissue Filler Injections Jaume Alijotas-Reig & Maria Teresa Fernández-Figueras & Lluís Puig # Springer Science+Business Media New York 2013 Abstract An ever-increasing number of persons seek medi- immunogenic or that complications are very uncommon, un- cal solutions to improve the appearance of their aging skin or wanted side effects do occur with all compounds used. for aesthetic and cosmetic indications in diverse pathological Implanted, injected, and blood-contact biomaterials trigger a conditions, such as malformations, trauma, cancer, and ortho- wide variety of adverse reactions, including inflammation, pedic, urological, or ophthalmological conditions. Currently, thrombosis, and excessive fibrosis. Usually, these adverse physicians have many different types of dermal and subder- reactions are associated with the accumulation of large numb- mal fillers, such as non-permanent, permanent, reversible, or ers of mononuclear cells. The adverse reactions related to non-reversible materials. Despite the claims of manufacturers fillers comprise a broad range of manifestations, which may and different authors that fillers are non-toxic and non- appear early or late and range from local to systemic. Clini- cians should be aware of them since the patient often denies the antecedent of injection or is unaware of the material The contents of the manuscript have not been previously published and employed. Most of these adverse effects seem to have an are not being considered by any other journal elsewhere at this time. All authors agree with the contents of the article and also having their immunological basis, the fillers acting more as adjuvants than names included in the list of authors. All authors have contributed in as direct T-cell activators, on a background of genetic predis- the conception, acquisition, and interpretation of data, and revision of position. Their treatment has not been the subject of well- the manuscript. JAR and LP drafted the paper, and MFF built tables designed studies; management of both acute and systemic and figures. The authors also state that they do not have any commercial or any reactions is often difficult, and requires anti-inflammatory other type of interest that may have influenced the drawing up and the and occasionally immunosuppressive therapy. The clinical, results of this paper. pathological, and therapeutic aspects of inflammatory and J. Alijotas-Reig immune-mediated late-onset adverse reactions related to soft Ageing and Systemic Autoimmune Diseases Research Unit, tissue filler injections are thoroughly reviewed herein. Service of Internal Medicine-I, Aging Basic Research Unit, Molecular Biology and Biochemistry Research Centre . ’ Keywords Acrylamides Adverse reactions ASIA for Nanomedicine (CIBBIM-Nanomedicine), Vall d Hebron . University Hospital, Barcelona, Spain Dermal fillers Granuloma Hyaluronic acid Methacrylate . Treatment J. Alijotas-Reig : M. T. Fernández-Figueras : L. Puig Department of Medicine, Universitat Autonoma, Barcelona, Spain M. T. Fernández-Figueras Introduction Pathology Department, Trias i Pujol University Hospital, Barcelona, Spain An ever-increasing number of persons seek medical solutions for their aging skin for purely aesthetic and cosmetic indica- L. Puig Dermatology Department, Sant Pau University Hospital, tions or for diverse medical conditions. Only for aesthetic Barcelona, Spain reasons, more than 10 million fillers have been injected in the USA in 2009 according to the American Society of Aesthetic * J. Alijotas-Reig ( ) and Plastic Surgery [1]. Currently, physicians have many dif- Josep Ma. de Segarra, 2-F, 08190 Sant Cugat del Vallés, Barcelona, Spain ferent types of dermal and subdermal fillers, which may be e-mail: [email protected] classified according to their origin and average persistence in Clinic Rev Allerg Immunol Table 1 Non-biological and biological dermal fillers Expected Microscopic features permanence Calcium hydroxylapatite (CaHA) Up to 6 months Clumping, migration, or granulomatous reaction containing basophilic round structures. Filler may persist longer than ordinary Carboxymethyl cellulose + polyethylene oxide Up to 12–18 months ND Hydroxyethyl methacrylate/ethyl methacrylate Very long Granulomatous reaction with many giant cells engulfing polygonal translucent structures Paraffin Permanent Foreign-body granulomatous reaction containing abundant vacuoles of large size Polyacrylamide hydrogel (PAAG) Very long Foreign body and palisading granulomatous reaction surrounding a large pool of basophilic foamy material with mucinous appearance Poly-alkyl-imide Very long Irregular encapsulation, dystrophic calcification, acute inflammation in relation to pools of alcian-blue-positive basophilic mucinous material Polydimethyl siloxilane (silicone oil) Permanent Clumping, migration, chronic inflammation, or granulomatous reaction with pseudoxanthomatous containing translucent particles of birefringent silicone Poly-L-lactic acid Up to 2 years Granulomatous reaction with multinucleated giant cells containing translucent spiculated polarizable aggregates Polymethylmethacrylate (PMMA) Up to 5 years Granulomatous reaction containing translucent medium-sized Polyethyl methacrylate (pHEMA-EMA) + hyaluronic round structures acid Poly-tetrafluoroethylene (PTFE)/expanded PTFE Permanent Migration. Acute inflammation with granulation tissue suggesting infection Polyvinylhydroxide microspheres in polyacrilamide gel Up to 9 months Granulomatous reaction containing translucent microspheres Polyvinil-pirrolydone + silicon Permanent Granulomatous reaction. Translucent yellowish spiculated or “popcorn”-shaped aggregates of particles Biological fillers Expected Microscopic features permanence Alginate 3 to 12 months Severe granulomatous reaction. The filler may not be visible or appear as large basophilic oval particles (0.1–0.12 mm) Collagen Up to 12 months Non-specific inflammation, foreign body reaction, or granuloma annulare-like reaction. Occasional necrosis. Characteristics of non-human collagen polarization differ from those of human collagen allowing its identification Dextranomeres + hyaluronic acid Up to 12 months Granulomatous foreign-body reaction surrounding spherical particles of dextrans, sometimes immersed in a hyaluronic acid mucinous background. In cases of delayed inflammatory reaction, only a non-specific chronic inflammation is observed Fat More than 2 years Fat necrosis, fibrosis, and dystrophic calcification Hyaluronic acid in different forms Up to 12 m Granulomatous reactions surrounding bluish translucent mucinous material corresponding to hyaluronic acid tissue [2, 3]. Besides, an increasing number of new dermal reversibility of their adverse effects. Over the last 10 years, fillers are currently available (Table 1). The properties of an different clinical profiles [7, 8] as well as suggestive histopath- ideal filler—mainly to be safe (neither allergenic nor immuno- ological patterns have been described [13, 14], and some genic), non-carcinogenic, non-teratogenic, and non-migratory authors have proposed a grading system classification of —are not entirely accomplished by any of the available materi- foreign body reactions induced by injected fillers into als. Even though manufacturers and different authors claim that four categories [15]. Implanted and injected biomaterials fillers are non-immunogenic or that complications are very trigger a wide variety of adverse reactions, including uncommon [4, 5], unwanted side effects do occur with all the inflammation, thrombosis, and fibrosis. Usually, these compounds used [6–14]. Thus, two notions are lacking in the adverse reactions are associated with the rapid accumu- commonly used classifications of fillers: long-term safety and lation of large numbers of mononuclear cells [16]. Clinic Rev Allerg Immunol Fig. 1 Normal and pathological cell responses after foreign material injections in humans. a Normal events after filler injection. b Pathological events in late-onset inflamma- tory adverse reactions after fill- er injection In this review, we will discuss the main clinical and classified according to their origin and average persistence pathological features of local and systemic late-onset ad- in tissue—resorbable, non-resorbable, or temporary, semi- verse reactions, including the histopathologic findings, permanent, and permanent [2, 3]. immunopathogenic basis, and therapeutic schedules related A non-comprehensive list of fillers ever used in soft to soft-tissue dermal filler injections. tissue augmentation is provided in Table 1, with detailed reference of their composition, brand names, permanence, source, types of adverse reactions reported, and histopatho- Search Strategy and Selection Criteria logical clues to their identification. A comprehensive MEDLINE, PubMed, and Google Scholar electronic database search was performed (2000–January Late-Onset, Immune-Mediated Adverse Reactions 2012), which was restricted to papers published in English, Related to Fillers using the relevant key words: dermal fillers, soft tissue filler, injectable filler, tissue augmentation, hyaluronic acid, collagen, Immune-Mediated Delayed Local Reactions poly-L-lactic acid, hydroxylapatite, methacrylate, silicone, pol- yalkylimide, polyacrylamide, biofilm, granuloma, ASIA, auto- Non-permanent Fillers immune diseases, adverse reactions, and treatment. Selected articles published before