Adhesives Used for Diabetes Medical Devices

When we talk about medical devices for diabetes treatment, the focus is usually on scientific aspects and clinical efficacy. Safety issues are largely discussed in terms of hypoglycemic events, devices failures, and so on. However, in practice other aspects, like rashes, itching, site reactions, pulling off, falling off, sweating off, losing a transmitter or receiver, issues with transmission at night, bad sensors, bad customer service, alarms silenced if smartphone is on vibrate, and so on are often of concern for patients and diabetologists. One area that does not get much attention involves the adhesives used to attach devices to the human skin.

Medical device companies usually purchase their adhesives from different adhesive manufacturers. Only a limited number of scientific publications in diabetes or diabetes technology related journals have addressed this important “tool.”¹ It seems to be taken for granted that adhesives “work” without any trouble and allow users to live a normal life while having one or more devices attached to the skin. In social media surveys, however, adhesives seem to be an emerging problem where desperate users exchange their experiences about skin side effects such as rashes and itching.

There is a trend for the extension of glucose sensor wearing time of continuous glucose monitoring systems (CGM). Longer wearing time means less injuries of the skin, less hassle for sensor change and lower sensor costs per day. However, longer wearing time of glucose sensors or insulin infusion sets (IIS) means also higher challenges for the adhesive material used. The consequence of longer usage time might be that we see in more patients allergic skin reactions (contact dermatitis). Such issues are known from other patients that need a prolonged supply by adhesives such as, for example, stoma patients or patients with longer postsurgical closure,^2,3 but was also observed with a CGM system.⁴

Beside a longer wearing time of an adhesive, there may be other factors that predispose for developing a type 4 allergy. Definitely, the potency of the sensitizer is most crucial, but also individual aspects such as a non-intact skin barrier of the individual is also most critical for developing a contact allergy. So, atopic dermatitis patients are found to be more susceptible⁵. Furthermore, children were more on risk than adults to develop a contact dermatitis in this study, which may be due to their more fragile skin and hyperreagibility of their immune system⁶. At this time, there are less examinations, if people with diabetes type 1, especially children, have a higher risk to develop type 4 allergies than individuals without an immune disease. In a huge retrospective study, there was found an inverse relationship between allergic contact dermatitis and type 1 diabetes mellitus⁷. This observation supports the findings that there is a lower prevalence of atopy symptoms in children with type 1 diabetes mellitus⁸. So, at this time, we assume that a sensitization potency of the adhesive, a prolonged exposure, a younger age and a reduced skin barrier are the most important factors for developing a contact allergy towards the adhesive.

The tasks required for an adhesive to fulfill represent a high bar. The device has to stick to the skin without falling off, while not inducing any skin reaction during its use or removal. Infusion set and patch pump adhesives are advised to be changed every 2 to 3 days, while CGM systems remain in place for 6 to 7 days and the flash glucose monitoring (FGM) system for 14 days. In practice, many patients use them much longer. To adhere to the skin for this many days is a challenge.

Does the use of an adhesive for long periods of time induce skin reactions in at least a subset of patients? A number of reports about such skin reactions accompanied by photos showed up in the lay press and the internet. Recently a “statistic” in lay journal reported data from 169 FGM patients: 83 reported no skin reactions, 5 can’t use the FGM anymore due to skin reactions, the others report some degree of skin reaction, related to the number of sensors they had used. In the patients’ wish list at the end of the article, a change in the adhesive was most frequently mentioned.

Most experienced diabetologists and diabetes educators observe only a limited number of skin reactions in daily practice. It might appear that manufacturers have successfully improved the quality of the adhesives and reduced such issues. However, lacking a systematic evaluation of such observations that can be reported in a readily accessible manner, this observation might be biased. It should be noted that in the case of IIS glycemic levels rise during the days over which they are used, and some pump wearers change their site daily or every other day to avoid the hyperglycemia associated with extended wear. It is not clear to what extent short term wear of expensive IIS or sensors is due to issues with or issues from adhesives. Such systems have been in use for decades and it appears as if the adhesives have been optimized over time, though some reports about skin reactions exist.^9,10

Do we have reliable data about skin reactions? This requires a more detailed view:

• During the evaluation process required for approval of medical devices, adhesives are tested and skin reactions are registered (as adverse events) in clinical trials. However, only a relatively small number of patients are evaluated in these trials and “sensitive” kids and elderly patients are not sufficiently represented to uncover a statistically significant number of events. Also, these studies usually do not last very long. Contact dermatitis and other type 4 delayed hypersensitivity reactions typically show up only after prolonged use with repeated applications to the skin. Such reactions fail to be detected in relatively short term studies. Sensitive patients will display these skin reactions after several hours.

• In daily life patients tend to apply the given medical device over and over within certain regions of the skin for convenience over years and decades. Such a situation is not studied in clinical studies for market approval. How much attention and documentation is paid to such adverse events in these studies depends on the skills of the personnel performing the study. Dermal adverse events receive little attention in short-term studies.

• After market approval, should the user report skin reactions that occur during daily life to the diabetes team or to the device manufacturer? Depending on the severity of the skin reaction, the diabetes team may suggest using a different site, applying a cortisone cream, or placing another adhesive beneath that of the device. They may also suggest switching to a different device that might have another adhesive, or discontinuing the device altogether. Some devices are purchased without involvement of the diabetes team.

• If a clinician considers reporting a skin reaction as an adverse event, this requires a lot of time to document the event along with other medical information (history of the patient, usage of other drugs, etc) that can be of relevance. The time required to produce the paperwork for each event is not paid for. This additional clinical burden produces no direct benefit nor is feedback provided about any consequences from this report. Without doing so, the question is, will the physician undertake such a procedure more than once? It is well known and discussed in the literature that there is a severe underreporting of adverse events, including those that involve drugs.

• In case patients contact the manufacturer of a given device to report a skin reaction, their complaint most probably is handled by a call center. This center has to document this complaint as a report and give notice to the responsible people working for the manufacturer. Also all reports should be documented in databases of regulatory agencies (MAUDE database in case of the FDA and a different one in Europe). In theory, if such reports show up with an unusually high frequency (whatever this is . . . ), this signal ideally is detected and appropriate countermeasures are initiated by the agencies. In practice, our own attempts to analyze the FDA database (the EU database is not openly accessible) showed that the data stored represent a meaningless mess.¹¹

What is the reason for skin reactions, especially for contact dermatitis? Detailed information about adhesives is not readily available, especially regarding which materials are used in them. Each manufacturer uses different adhesives that are optimized for their device requirements. Device manufacturers get their adhesives from other manufacturers and sometimes regard such data as proprietary and in most countries they are not forced to provide this information to an interested diabetologist or dermatologist. Their concern is that the data might support their competitors. Even if one is able to get such information, the question is, what does this mean from an immunological point of view? Different component materials are somehow “mixed” with each other, and considerable manufacturing technology is involved in producing adhesives. This makes it difficult to tell which of the composite materials in the given adhesive induces an immunological response. Manufacturers have such allergy testing studies, but depending on how different adhesives are made using the same ingredients, the same adhesive component might induce an immunological reaction in one product but not in another product.

Although some adhesive companies are reticent to supply component information, a review of the literature and by means of cooperative from some adhesive manufacturers, it is clear that most of today’s adhesives consist mainly on acrylate polymers. A wide range of different acrylates exist and some are known to induce contact allergies (Table 1). As mentioned above, a few reports already exist about contact dermatitis induced by acrylate-based adhesives from diabetes medical devices.^4,9,10 The glue used in adhesives usually consists of an acrylate polymer which is a mixture of mostly 3 different acrylate monomers. While polymerized acrylates are usually called nonirritant and hypoallergenic, monomers are considered as strong skin sensibilizer,^12,13 acrylates were also named the “Contact Allergen of the Year” by the American Contact Dermatitis Society in 2012.¹⁴ Of course, other substances in adhesives such as benzoyl peroxide may potentially be immune sensitizers.

Table 1.

Patch of the German Contact Dermatitis Association With a Number of Different Substances/Plastics Used in Adhesives.

1	Ethylenglycol-dimethacrylat (EGDMA)	2	%	Vas.
2	2-Hydroxyethylmethacrylat (HEMA)	1	%	Vas.
3	Triethylenglycol-dimethacrylat (TEGDMA)	2	%	Vas.
4	Methylmethacrylat	2	%	Vas.
5	2-Hydroxypropylmethacrylat (HPMA)	2	%	Vas.
6	Benzoylperoxid	1	%	Vas.
7	Hydroxyethylacrylat	0,1	%	Vas.
8	BIS-GMA (Bisphenol A-diglycidylmethacrylat)	2	%	Vas.
9	Diethylentriamin	1	%	Vas.
10	4,4’-Diaminodiphenylmethan	0,5	%	Vas.
11	Isophorondiamin (IPD)	0,5	%	Vas.
12	Butylglycidylether	0,25	%	Vas
13	Cresylglycidylether	0,25	%	Vas
14	Phenylglycidylether	0,25	%	Vas
15	1,4-Butandioldiglycidylether	0,25	%	Vas
16	1,6-Hexandioldiglycidylether	0,25	%	Vas
17	Trimethylhexan-1,6-diamin (Isomerengemisch)	0,5	%	Vas.
18	m-Xylendiamin	0,1	%	Vas.
19	Trimethylolpropan-triglycidylether	0,25	%	Vas.
20	p-tert-Butylcatechin	0,25	%	Vas.
21	Phenol-Formaldehydharz (Novolak)	5	%	Vas.
22	Hydrochinon	1	%	Vas.
23	4,4’-Dihydroxydiphenyl	0,1	%	Vas.

Once an allergic reaction is induced by an acrylate, the immune system can cross-react with other acrylates (Table 2). The frequency with which this shows up depends on the number of times the immune system “sees” these allergic substances and the duration of exposure. It is possible to test if a given patient is sensitive to different acrylates by using a standard patch test block used in dermatology, which contains a number of adhesives, plastic materials, and acrylates (Table 1).^16,17 However, such tests might not be available in all countries and not all different acrylates or adhesives are included in this test. As mentioned, it might be that the given combination of acrylates or the way the adhesives are manufactured that determines their immunogenic potential. Therefore, without knowing the exact composition of a given adhesive is, there is a certain risk that a given test will not provide an accurate outcome. The manufacturer may need to provide the exact materials they use to run an appropriate test. Such a test should not be performed with children or adolescents as their immune system may react more aggressively and induce cross-reactivity. It should be also kept in mind that a skin test is only a test and not a definitive proof, and where the test substances are applied on the human body (usually on the back) may impact the outcome. If more and more patients use adhesives over longer periods of time at the same convenient locations, the risk of a stimulation of the immune system will increase. Careful monitoring for how many case cross-reactions will show up by a potent sensibilization with a given device.

Table 2.

Summary of Studies From a Textbook About Allergology by Dr Roland Irion:¹⁵ Positive Epikutan Test Reactions Obtained With the (Meth-)Acrylat Series Over a Period of 10 Years by the Finish Institute of Occupational Health, Helsinki.

(Meth-)acrylat series (%) (Chemotechnique, Schweden)	Abbreviation	Test conc. (%)	Positive reactions	Allergies	Ranking
Ethylacrylat	EA	0.1 (–0.5)	16/192	8.3	7
Butylacrylat	BA	0.1 (–0.5)	12/242	5.0	12
2-Ethylhexylacrylat	2-EHA	0.1 (–0.5)	0/243	0.0	—
2-Hydroxyethylacrylat	2-HEA	0.1 (–0.5)	16/132	12.1	1
2-Hydroxypropylacrylat	2-HPA	0.1 (–0.5)	14/132	10.6	4
Methylmethacrylat	MMA	2	20/271	7.4	8
Ethylmethacrylat	EMA	2	18/243	7.4	8
n-Butylmethacrylat	BMA	2	6/243	2.5	16
2-Hydroxyethyl-methacrylat	2-HEMA	2	31/273	11.4	3
2-Hydroxypropyl-methacrylat	2-HPMA	2	29/242	12.0	2
Ethylenglycol-dimethacrylat	EGDMA	2	27/272	9.9	5
Triethylenglycol-dimethacrylat	TREGDMA	2	23/275	8.4	6

Sensitization to acrylates in the plastic catheter of the IIS has been reported.¹⁰ Following a skin reaction to an IIS, it is relatively easy to switch to a different IIS as there are a number of these available for each pump that hopefully has a different adhesive. The story is more restrictive with patch pumps (at least in Europe where only 1 such pump is on the market currently) where no alternative adhesive is available if a given patient develops an allergic reaction that blocks the use of this therapeutic option.

When it comes to CGM systems and the FGM system, the number of reports about (severe) skin reactions to the adhesives used to fix the glucose sensor on the skin are quite limited, but it is important to keep the above made comments in mind.^1,4,18 It appears as if in at least some patients a contact allergy developed, and the skin reactions were severe in a number of cases. As the patients are highly interested in being able to continue to use their device, they try many different options to reduce the skin reactions/avoid these. Numerous comments and practical information about the different approaches can be found in the internet. In practice it appears as if these are most often not successful. If such skin reactions show up after several usages of a given medical product as a result of a stimulation of the immune system; it has to be clear, when this is on, than it is on! That means, each time the product is attached again (even after some pause), the skin reaction will show up again, most often within hours and typically becomes more intense/ stronger/ more aggressive. A major concern is that adhesives used for other devices might induce skin reactions as well. In such cases, patients might be blocked to use any device that requires certain adhesives, such as an insulin pump or another CGM system, as has already happened in selected cases in Germany.

We see the need for more safety data about adhesive materials used for medical devices in diabetes therapy. Will skin issues become more prevalent when devices with a longer wearing time reach the market? Can this risk be reduced so it does not become a major issue in patients using medical devices? Before we see more severe skin reactions, we suggest that adhesives should be regarded as a relevant topic for diabetes technology. There is a need for disclosure of the exact composition of medical device adhesives to have the possibility for patch testing. We also encourage development of acrylate-free adhesives, possibly based on silicone, in medical devices in the future. This editorial is aimed to stimulate a constructive dialogue between manufacturer of adhesives, manufacturer of medical devices, physicians, patients, and regulatory agencies.