Conflict of interest None declared.
Early granulomatous foreign body reactions to a novel alginate dermal filler: the system’s failure?
Article first published online: 20 SEP 2011
© 2011 The Authors. Journal of the European Academy of Dermatology and Venereology © 2011 European Academy of Dermatology and Venereology
Journal of the European Academy of Dermatology and Venereology
Volume 27, Issue 1, pages 121–123, January 2013
How to Cite
Schuller-Petrović, S., Pavlović, M.D., Schuller, S.S., Schuller-Lukić, B. and Neuhold, N. (2013), Early granulomatous foreign body reactions to a novel alginate dermal filler: the system’s failure?. Journal of the European Academy of Dermatology and Venereology, 27: 121–123. doi: 10.1111/j.1468-3083.2011.04264.x
Funding sources None declared.
- Issue published online: 18 DEC 2012
- Article first published online: 20 SEP 2011
- Received: 15 May 2011; Accepted: 25 August 2011
Background Cutaneous granulomas after a soft filler injection represent one of the worst scenarios for both patient and injector.
Objectives To present clinical and histopathological features of granulomatous nodular reactions induced by a new alginate-based dermal filler (Novabel®), and put it in context of the process of injectable soft tissue fillers approval and promotion in the EU.
Methods A case series of four patients injected with Novabel® for volume restoration of the face and hands, who developed severe foreign body reactions.
Results Four patients injected with Novabel® into tear troughs and/or dorsa of hands developed severe granulomatous reactions within months after injections. As we injected with the new filler into a total of 10 patients, a high incidence of 40% of the disfiguring adverse effect was observed. The inadequate response of manufacturer to our reporting the side-effects along with the available data on registration process of dermal fillers confirmed that the area is not well-regulated.
Conclusions The status of dermal fillers as class III medical devices, and the process of their approval and marketing in the EU need to be seriously reconsidered to avoid unnecessary and serious adverse reactions.
Injectable soft tissue fillers are now widely used in aesthetic dermatology. According to the statistics from the American Society for Aesthetic Plastic Surgery, the hyaluronic acid based dermal fillers are the second commonest aesthetic procedure in US (up from third in 2008) with over 1.31 million treatments in 2009.1 A new product (Novabel®), an alginate-based temporary filler, was recently approved and promoted to offer several advantages over traditional hyaluronic acid fillers, specifically for the correction of tear trough deformity.2 Alginate, the monovalent salt form of alginic acid, is a non-repeating copolymer that contains two urocanic acids, 1,4 linked beta-d mannuronic and alfa-l guluronic acid. These residues exist in linear polysaccharide chains that can dimerize to form hydrogels at room temperature in the presence of divalent ions such as calcium.3 The most promising biotechnological and biomedical application of alginate resides in its use as a hydrogel for cell immobilization for applications ranging from production of ethanol from yeast cells to transplantation and cell therapy.4 Novabel® was obtained from alginates derived from marine algae and processed by a patented Geleon technology.2,5
From December 2009 through March 2010, we injected 10 patients with Novabel® in one to two sessions and 2–10 mL of total amount of the filler. Four of the 10 patients (40%) developed nodular indurations in some or all of the treated areas within 6 months after the injections.
A healthy 56-year-old woman, with no prior treatment with dermal fillers, was injected with 4 mL of Novabel® into lips and tear troughs, and with 2 mL into cheeks and periorbital region. She returned after 2 months for redness and swelling in the right infraorbital area. A month later, she presented with further swelling and palpable hard nodules in both infraorbital regions (Fig. 1a). Subcutaneous hypoechogenic structures surrounded with a hyperechogenic border were seen by ultrasound (Fig. 1b).
A 43-year-old healthy woman, with no history of prior dermal fillers injections, and receiving no medication was injected with 5 mL of Novabel® in tear troughs, cheeks and upper lips. Three months later, she presented with bilateral hard nodules in her tear troughs which are still present.
A total of 5 mL of Novabel® were injected into back of both hands of a healthy 63-year-old woman. As a result of insufficient correction, 2 weeks later, she was re-injected with additional 2 mL. Four months later, she presented multiple hard nodules on dorsa of her hands (Fig. 2a) which were visualized as hypoechogenic encapsulated structures up to 6 mm in diameter (Fig. 2b). Several nodules were excised and examined histologically. Histology revealed extensive subcutaneous granuloma formation around spherical exogenous basophilic material (Fig. 2c,d). The large oval particles measured 0.1–0.12 mm. The patient uneventfully underwent autologous fat transfer to both hands 4 years prior to these injections.
A 48-year-old woman was treated with 2 mL of Novabel® into both tear troughs. Five months later, she noted hard palpable nodules in the treated areas. She was seen 9 months after injections when ultrasound examination was performed disclosing similar hypoechogenic structures rimmed by a hyperechogenic border. Being almost 2 cm long, the structure probably represents the whole amount of the injected product. This was her first filler.
Granulomatous foreign body reactions are potentially serious side-effects of all injectable soft tissue fillers including those resorbable with no organ or tissue specificity like hyaluronic acid.6–9 Although alginates are considered relatively non-immunogenic, they do induce a host immune response. Experiments in sheep confirmed that calcium alginates injected subcutaneously induce a mild foreign body reaction with a capsule formation around the injected material.10 Protein contamination may be one of factors responsible for enhanced immunogenicity of alginate implants.11 The cross-linking agents usually used in alginate preparations are divalent cations, mostly Ca2+ and Ba2+. Data on both in Novabel® have not been declared. Earlier reports showed that calcium alginate gel exhibits enhanced immunogenicity and poor bioresorbability, which may lead to adverse tissue interactions and poor wound-healing properties.12
A manufacturer of the Novabel® (Biocompatibles Inc, a partner of Merz) gained the CE Mark approval for it in March 2009.13 An unpublished, multicentre phase III clinical trial of Novabel® injection into nasolabial folds was performed on 154 patients with excellent efficacy and safety outcomes.2 Despite the fact that the study had been performed on nasolabial folds only, the filler was recommended for use in other areas including tear troughs and cheeks.2 Upon our report of the first patient with the inflamed nodular indurations, the manufacturer responded that they had not had any data on such side-effects and, if our patients had it, it might have been a result of our suboptimal injection technique. In light of our long and rich experience with various soft tissue fillers over almost two decades (more than 3000 injections) and completed training specifically for Novabel®, it was the least acceptable explanation.7,8 Only 2 months later, in July 2010, the product was removed from the market, and on 12 August 2010 a Medical Device Alert was issued in UK (REF: MDA/2010/064) (http://www.mhra.gov.uk/Publications/Safetywarnings/MedicalDeviceAlerts/CON090979?tabName=Problem). The manufacturer has received reports of adverse reactions to the filler including redness, bruising, pain, swelling and histologically confirmed granuloma. They have also received reports of nodules and indurations in the infra-orbital area.
In Europe, dermal fillers are classified as medical devices, and their registration and approval should follow procedures outlined in the Guidelines on Medical Devices as published in the MEDDEV. 2.7.1 Rev.3 of December 2009 (http://ec.europa.eu/consumers/sectors/medical-devices/files/meddev/2_7_1rev_3_en.pdf ). According to Annex X Section 1.1a of Directive 93/42/EEC, in the case of implantable devices and devices in class III, clinical investigations shall be performed unless it is duly justified to rely on existing clinical data. Being a new type of dermal fillers, Novabel® should have been thoroughly clinically tested. As most of the reactions appeared in the infraorbital region, it may be possible that they were not appreciated if clinical investigation was performed solely in the nasolabial folds. It is well known that tear troughs are the most demanding region of the face for soft tissue augmentation.14 However, the product was marketed for use not limited to this region of face. The occurrence of granulomatous reactions on the dorsa of hands argues against the injection site as a major factor in adverse reactions to Novabel.
Notified bodies play a key role in the assessment and verification of clinical evaluations provided by medical device manufacturers to support demonstration of conformity of a device with the essential requirements of the relevant EU directive. Thus, manufacturer should be obliged to clearly state the indication(s) that should be backed by data from clinical studies. Host immune system responds to any filler by a weak granulomatous reaction, and under some circumstances, the filler may provoke significant pathology that strengthens the need for a stricter regulation of their approval.15,16 The fact that Novabel® was withdrawn from the market after only half a year since its introduction on the EU market, puts in question the reliability of the current process of injectable soft tissue filler approval.
- 1American Society for Aesthetic Plastic Surgery. Cosmetic Surgery National Data Bank 2009 Statistics. [WWW document] 2009. URL http://www.surgery.org/sites/default/files/2009stats.pdf (last accessed: 7 February 2011).
- 2Novabel reshapes the face of aesthetic medicine. The European Aesthetic Guide, Merz Supplement, January 2010; 1–8..
- 5Merz Aesthetics. What is Novabel®? [WWW document]. URL http://www.novabel.co.uk/index.php?option=com_content&view=article&id=4&Itemid=100&phpMyAdmin=56bb66d61a13bd22bda0953f17d8489b (last accessed: 7 February 2011).
- 6Complications of soft tissue augmentation. J Drugs Dermatol 2008; 7: 841–845., .
- 13Biocompatibles. CE mark approval for cosmetic dermal filler bead. [WWW document] 2009. URL http://www.biocompatibles.com/media/press-releases/2009/19-03-2009.aspx (last accessed: 8 February 2010).