Introduction

Medical devices comprise a large, heterogeneous group of approximately 1.5 million products which, by definition, serve the diagnosis, therapy, and prevention of human diseases. They are subject to national guidelines and are divided into four categories via the European Medical Devices Regulation (MDR)—depending on the risk assessment for the vulnerability of the human body during their use [1]. Articles belonging to category 1 pose a low risk, with a low degree of invasiveness, for temporary use. Category IIa includes products with moderate risk potential and moderate invasiveness. Category IIb medical devices, on the other hand, carry increased risk and have a systemic effect when used long-term. The highest risk category III is assigned to products that are highly invasive, intervene directly in the heart or cardiovascular or nervous system, or are implantable. As examples, but to be checked in individual cases, possible medical devices in the individual categories are listed in Table 1. Outside Europe, other classifications apply. Information on their ingredients is not required by law. The prevalence of contact allergies to medical devices or their ingredients is therefore unknown. Due to increasing reports of contact allergies to medical devices, a declaration obligation is therefore required [2].

Table 1 Categories of the European Medical Device Regulation (adapted from [1])
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Medical devices for diabetics

The development and introduction of continuous glucose monitoring systems, insulin pumps and flash glucose meters means a significant increase in quality of life and safety for insulin-dependent diabetics. The respective products are usually applied to the upper arm or abdomen using sensor or application needles in the subcutaneous tissue over several (7–14) days [3]. Thus, the demands on the adhesive properties of the fixative patch are very high. Polymers of acrylates are frequently used as adhesives, which are considered largely inert but always contain traces of monomers. Both the continuous occlusive adhesion of the patch materials and the close skin contact during friction/physical movement may additionally promote the formation of acrylate monomers [4]. Acrylate monomers are potent contact allergens. In addition, the repeated tearing of the adhesive surfaces when changing the plasters results in a disturbed skin barrier as well as irritative eczema, on the basis of which sensitization to contact allergens can develop [3,4,5].

Shortly after the introduction of new diabetic devices, reports of contact allergies in the application area increased. The release of potential contact allergens can occur from the adhesives of the skin patches as well as from the fixing layer of the housing on the patch, the housing and its adhesive, metal and chip components, the adhesive layer of the sensor needle as well as the components of the needle itself. It was not until elaborate chemical methods, in particular gas chromatography coupled with mass spectroscopy, were increasingly used to obtain information about the triggering contact allergens [5, 6].

Manufacturers of diabetic medical devices try to avoid potential or already known contact allergens when developing new generations of the devices by applying new technologies, for example, by fixing the casing by thermal methods or changing the materials used. They are not required to declare this change in composition. Optionally, additional contact allergens are introduced with new adhesives or housings, which may result in a broader spectrum of sensitization of affected patients with possible restrictions in the use of further products. Acrylate compounds are widely used, not only in medical products such as adhesives and dental materials, but they are also present in ultraviolet light (UV)-curing varnishes, plastics, printer inks, etc. [7].

Isobornyl acrylate (IBOA) is among the most frequently observed contact allergens in diabetic devices. In addition to its use in the automotive industry, particularly due to the weather resistance of IBOA-containing automotive paints, it is used in the plastics/plastics industry due to its durability and flexibility. In contrast to other acrylate compounds, only a few cross-reactions to other acrylates have been described so far.

IBOA was/is present in the FreestyleLibre 1® (Abbott Diabetes Care, Alameda, CA, USA) (Fig. 1), Enlite Sensor® (Medtronic, Fridley, MN, USA), the tubeless insulin pump Omnipod Pump® (Insulet Corporation, Billerica, MA, USA), the Paradigm MiniMed Quick-Set® and Paradigm MiniMed Sure-T® (Medtronic, Fridley, MN, USA) insulin infusion sets, the Accu® Check Insight Flec insulin infusion set (Roche Diabetes Care, Indianapolis, IN, USA), Medtrum A 6 TouchCare® (Medtrum Technologies, Shanghai, China), and Ypsopump® (Ypsomed, Burgdorf, Switzerland) [5, 6]. The Dexcom G6® (Dexcom Inc., San Diego, CA, USA) initially did not appear to contain IBOA, but low concentrations of IBOA could be detected by now [8]. However, many IBOA-sensitized patients tolerate the Dexcom G6®.

Fig. 1
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Contact dermatitis to FreeStyleLibre 1®

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As far as currently known, the Eversense XL CGM system (Roche, Basel, Switzerland) with implantable sensor and the FreeStyleLibre 2 Sensor® are IBOA-free [6, 9, 10].

In the course, after modification of the fixation patch, a monoacrylate [2,2’-methylenebis(6-tert-butyl-4-methylpenol)-monoacrylate] was described as another contact allergen in the use of the Dexcom G 6® [11] as well as N,N-dimethylacrylamide in the Freestyle Libre 2® [12].

Rosin as well as modified rosin compounds (e.g., methyl abietate or its oxidation product methyl dehydroabietate) should also be considered as a cause of contact dermatitis both on the glucose sensors themselves (e.g., in the FreeStyle Libre 1®, Dexcom G6®) or the distance patches, such as hydrocolloid patches [13].

It is recommended to read the epicutaneous test with the suspected contact allergens after 48, 72 and 168 h. Suggestions for epicutaneous testing series for diabetic devices exist, but are not feasible everywhere due to national regulations regarding the manufacturability/testability of allergens [7].

Medical adhesives

Rosin and abietic acid are known triggers of contact allergies to medical adhesives. The hydroperoxides of abietic acid, which are components of rosin, have a clear sensitizing potential [14]. Foti et al. were able to show that acrylic acid can also be a triggering contact allergen in ECG electrodes [15].

D‑limonene is mostly used as a fragrance, solvent and degreaser, but also in the production of resins, rubber products, polymers and medical adhesives. It is also partly a component of rosin [14]. In contact with air, limonene hydroperoxides are formed, which are potent contact allergens. Dendooven et al. were able to show that D‑limonene and/or related ingredients are possible triggers of contact eczema to the patch product in patients who are exposed to low-allergen patch materials, most of which are rosin-free. Via gas chromatography coupled with mass spectroscopy, D‑limonene was detected as a constituent in these patches [14].

Isocyanates are required for the manufacture of paints, adhesives, coatings and polyurethane foams. They could also be detected unbound in polyurethane-containing medical devices for diabetics and wound dressings, respectively [16]. Contact sensitization to isocyanates was seen in this study particularly to 4,4’-methylene diphenyl diisocyanate (MDI), less frequently to 2,4-toluene diisocyanate, possibly via cross-reactions to MDI, as well as isophorone diisocyanate.

Despite proven contact sensitization to MDI, MDI-containing medical devices can be tolerated in part because the manifestation of contact dermatitis depends not only on the allergen content of the product (ppm) but also on the intensity of contact sensitization and the duration of application to the skin [16].

Traces of formaldehyde, detectable in self-adhesive bandages/bandages and other wound dressings, can also induce contact dermatitis in previously sensitized patients [17, 18].

Furthermore, acrylates in plasters and self-adhesive bandages are also optional contact allergens [19].

Gloves

Contact allergies to medical protective gloves (Fig. 2) are very often due to the vulcanization accelerators used in their manufacture, such as thiurams, dithiocarbamates, thiazoles, thioureas, and guanidines [20,21,22]. In the case of persistent contact dermatitis of the hands, despite the use of appropriate protective gloves, contamination of the reusable glove with the triggering contact allergen may be the recurrent trigger. In a case of a clearly sensitized patient with hand eczema, traces of isothiazolinones were detected in new, unused nitrile gloves and discussed as a possible allergen source [23]. If the contact eczema persists despite the use of “contact allergen-free” gloves, both the declaration of the glove and its permeability with regard to potential/known contact allergens must be questioned [23, 24].

Fig. 2
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Protective gloves. © Africa Studio/Fotolia

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Blood pressure cuffs

Contact allergies to blood pressure cuffs have hardly been published so far, especially since their use is usually short-term. In the course of prolonged blood pressure monitoring, a 14-year-old with type 1 diabetes, sensitized to IBOA by his initially used glucose sensor, developed a contact allergy to the cuff. Chemical analysis of the various cuff components revealed that the adhesive used to attach the feeding tube to the cuff, as well as the cuff itself, contained IBOA. Two other acrylate compounds (lauryl acrylate [synonym dodecyl acrylate] and 2‑phenoxyethyl acrylate [PEA]) were also detected. PEA was positive in the epicutaneous test; no test substance was available for lauryl acrylate [25].

FFP2 masks, surgical mouth–nose protection

Contact allergies to mouth–nose masks (Fig. 3) mostly concern the elastic straps used to fix them to the ears. Contact dermatitis very rarely occurs in the area of the face. In this case, the metal wire over the nose (e.g., nickel sulfate, cobalt chloride), the adhesive for fixing the foam pad over the nose or the pad itself (e.g., methyldibromoglutaronitrile), and possibly formaldehyde, as a possible byproduct of polypropylene (e.g., in the filter) or as contamination from the packaging, may be suspicious triggers [26]. Potential contamination, including volatile contamination with contact allergens, can hardly be determined.

Fig. 3
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FFP2 mask. © PixelboxStockFootage/stock.adobe.com

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The filter of FFP2 (filtering face piece) masks is often made of polypropylene—a polymerized, relatively low-reaction hydrocarbon. Individual cases describe immediate type allergies to mouth–nose protection or FFP2 masks [27, 28]. Goller et al. reported a type 1 allergy to polypropylene in an FFP2 filter mask. In one case, the manufacturer confirmed contamination of the mask with formaldehyde and bronopol [27, 28].

Surgical tissue adhesives

Cyanoacrylates have been used for years, especially in plastic surgery, to seal wounds. The monomers they contain trigger anionic polymerization on contact with various body fluids. If this polymerization proceeds completely, cyanoacrylates are not immunogenic. In case of incomplete polymerization, there is a risk that the remaining monomers act as potent allergens [29]. Contact allergies are usually triggered by n-butyl cyanoacrylate or 2‑octyl cyanoacrylate. Recently, a flare-up reaction to an n-butyl cyanoacrylate-containing adhesive was described decades after its initial application. It initially appeared like a vesicular viral—in the course like a bacterial—superinfection, starting from the suture. A long-lasting, disseminated contact allergic reaction was induced, which only resolved after more than 1 year of immunosuppressive therapy with methotrexate [30].

Traces of formaldehyde may be present in cyanoacrylate-containing adhesives as an impurity [17].

Intrauterine device

Contact dermatitis to intrauterine devices has been described very rarely. Three months after insertion of a copper-containing intrauterine device (IUD), a patient developed systemic contact dermatitis with disseminated dyshidrosiform vesicles. Epicutaneous testing revealed contact sensitization to copper sulfate, thiomersal, and epoxy resin. After removal of the IUD, the symptoms resolved [31].

Endovascular stents

Reports and studies on the potential role of a contact allergic reaction to vascular stents refer to the restenosis rate within the stent or histologically detectable eosinophilic infiltrates. After implantation of a stent, there is an increased risk for restenosis due to various factors: both mechanically and by the technical execution of the implantation, a proinflammatory stimulus can be triggered. In addition to genetic predisposition, comorbidities (especially diabetes mellitus) and nicotine abuse, biological factors such as resistance to the released drugs from the coated stents and hypersensitivity to the implanted materials are optional factors that favor restenting [32].

Pure steel stents as well as gold-coated stents showed a higher restenosis rate than drug-eluting stents (e.g., with paclitaxel, sirolimus, everolimus, zotarolimus). Studies on whether nickel allergic patients have a higher restenosis rate are conflicting [33,34,35]. Prospective studies with large numbers of patients are lacking so far.

Cardiac electronic implants

Cardiac implantable electronic devices (CIED) include pacemakers (PM), implantable defibrillators (ICD), and cardiac resynchronization therapy (CRT) devices [36]. Any local device-associated redness, hyperthermia, or “pacemaker dermatitis” should first be ruled out as an infection. This can occur months to years after implantation and increases with device complexity [36]. Teleangiectatic pressure erythema after pacemaker implantation is a possible differential diagnosis [37]. Allergic reactions to cardiac electronic implants are rare. Published case reports with contact allergy to nickel sulfate, cobalt chloride, or titanium have been described, but some should be questioned because infections have not been ruled out [38, 39]. Titanium is predominantly used as the metal box for the device, as it reduces electromagnetic interactions with the environment. However, the subject of discussion is whether contact allergy to titanium can be reliably detected with the currently available methods/test materials [39]. Sensitization to titanium might be verified by lymphocyte transformation testing if the epicutaneous test is negative [40]. Titanium tetrachloride must be highly diluted with water and rapidly hydrolyzes to insoluble titanium dioxide [39]. In the case of a proven causative contact allergy, a coating film with polytetrafluoroethylene can prevent this reaction in the long term [41].

In case of a suspected contact allergy to a medical device, it is recommended to report the allergy to the manufacturer or, depending on the product, to the Drug Commission of the German Medical Association (“Arzneimittelkommission der deutschen Ärzteschaft”) and, if necessary, to cooperate with physicians/institutions that have possibilities for further diagnostics.

From an allergological point of view, labeling of medical devices is necessary, both for appropriate diagnostics and for targeted counseling of affected individuals. In the case of contact allergies acquired via medical devices, this can have an impact on patients’ private and professional lives.