In Vivo Study of the Inflammatory Tissue Response Surrounding a Novel Extended-Wear Kink-Resistant Insulin Infusion Set Prototype Compared With a Commercial Control Over Two Weeks of Wear Time.

BACKGROUND: Infusion set function remains the limiting factor of insulin pump therapy due to nonmetabolic complications. Here, we tested an investigational extended-wear infusion set prototype with a soft, angled, wire-reinforced cannula with three additional side holes, and compared failure mechanisms and tissue response with a commercial Teflon control. METHODS: A total of 48 Teflon and 48 prototype infusion sets were inserted subcutaneously every other day for 14 days in 12 swine and infused with dilute insulin. After two weeks, tissue around cannulas was excised, and occlusions, leaks, and kinks were determined. Tissue was processed and stained to assess the total area of inflammation (TAI) and the inflammatory layer thickness (ILT) around the cannulas. Data were analyzed using Fisher's exact, analysis of variance-general linear model, Kruskal-Wallis, and post hoc tests. RESULTS: On average, the TAI surrounding the investigational cannula was 52.6% smaller than around the commercial control. The ILT was 66.3% smaller around investigational cannulas. Kinks occurred in 2.1% (investigational) vs 32.4% (commercial) cannulas (P < .001). There was no difference in occlusion alarms and leaks onto skin. CONCLUSIONS: The data suggest that the infusion set prototype elicits less inflammation over an extended wear time and is resistant to kinking, compared with a commercial Teflon device. This is consistent with previously published data on the impact of cannula material/angle on the inflammatory tissue response. We highlight the following important aspects of infusion set design: (1) secure skin adhesion, (2) reliable cannula insertion, (3) automatic removal of the stylet, (4) cannula material/design that resists kinking, and (5) minimization of local tissue inflammation.

Progressive Acceleration of Insulin Exposure Over 7 Days of Infusion Set Wear.

Insulin exposure varies over 3 days of insulin infusion set (IIS) wear making day-to-day insulin dosing challenging for people with diabetes (PWD). Here we report insulin pharmacodynamic (PD) and pharmacokinetic (PK) data extending these observations to 7 days of IIS wear. PWD (A1C ≤8.5%, C-peptide <0.6 nmol/L, ≥6 months pump use) were enrolled in a crossover euglycemic clamp pilot study comparing conventional Teflon angled IISs with an investigational extended-wear IIS. PK/PD data from six participants were obtained for 5 h postbolus. Although PD data were unstable, PK profiles (pooled data from both groups) of insulin lispro (0.15 U/kg bolus) showed statistically significant progressive decreases from days 0 to 7 for tmax (P < 0.001), Cmax (P < 0.05), and mean residence time (P < 0.0001). Area under the insulin concentration curve (AUC0-300) declined by ∼24% from days 0 to 7 (P < 0.05). These results confirm/extend previous observations showing progressive acceleration of insulin exposure over IIS wear time. This may have implications for PWD and designers of closed-loop algorithms, although larger studies are necessary to confirm this. The study was registered in clinicaltrials.gov (NCT04398030).

Feasibility study of a prototype extended-wear insulin infusion set in adults with type 1 diabetes.

AIM: To assess the feasibility of a prototype insulin infusion set (IIS) for extended wear in adults with type 1 diabetes. MATERIALS AND METHODS: The prototype Capillary Biomedical investigational extended-wear IIS (CBX IIS) incorporates a soft, flexible, reinforced kink-resistant angled nylon-derivative cannula with one distal and three proximal ports to optimize insulin delivery. Twenty adult participants with type 1 diabetes established on insulin pump therapy used the CBX IIS for two 7-day test periods while wearing a Dexcom G5 continuous glucose monitor. RESULTS: Participants were able to wear the CBX IIS for an average of 6.6 ± 1.4 days. Eighty-eight percent (36 of 41) of sets were worn for 7 days. No serious adverse events were reported. Five infusion sets failed prematurely because of: unresolvable hyperglycaemia (three); hyperglycaemia with elevated ketones (one); or infection (one). Median time in range (3.9-10.0 mmol/L) was 62% (54-76). Average glucose levels per day of infusion set wear showed a statistically significant increase over time (p < .001). CONCLUSIONS: Our preliminary observations confirm the tolerability of the prototype CBX IIS for extended wear, albeit with a deterioration in glucose control after the third day.

In vivo investigation of the tissue response to commercial Teflon insulin infusion sets in large swine for 14 days: the effect of angle of insertion on tissue histology and insulin spread within the subcutaneous tissue.

Objective: This study investigated the effects of the inflammatory tissue response (ITR) to an insulin infusion set (IIS) on insulin bolus spread over wear time, as well as the effect of cannula insertion angle on the ITR, bolus shape, and pump tubing pressure. Research design and methods: Angled or straight IISs were inserted every other day for 14 days into the subcutaneous tissue of 11 swine and insulin was delivered continuously. Prior to euthanasia, a 70 µL bolus of insulin/X-ray contrast agent was infused while recording a pressure profile (peak tubing pressure, pmax; area under the pressure curve, AUC), followed by the excision of the tissue-catheter specimen. Bolus surface area (SA) and volume (V) were assessed via micro-CT. Tissue was stained to analyze total area of inflammation (TAI) and inflammatory layer thickness (ILT) surrounding the cannula. Results: A bolus delivered through an angled IIS had a larger mean SA than a bolus delivered through a straight cannula (314.0±84.2 mm2 vs 229.0±99.7 mm2, p<0.001) and a larger volume (198.7±66.9 mm3 vs 145.0±65.9 mm3, p=0.001). Both decreased significantly over wear time, independent of angle. There was a significant difference in TAI (angled, 9.1±4.0 mm2 vs straight, 14.3±8.6 mm2, p<0.001) and ILT (angled, 0.7±0.4 vs straight, 1.2±0.7 mm, p<0.001). pmax (p=0.005) and AUC (p=0.014) were lower using angled IIS. As ILT increased, pmax increased, while SA and V decreased. Conclusions: The progression of the ITR directly affected bolus shape and tubing pressure. Although straight insertion is clinically preferred, our data suggest that an angled IIS elicits lower grades of ITR and delivers a bolus with lower tubing pressure and greater SA and V. The subcutaneous environment plays a crucial role in IIS longevity, and the insertion angle needs to be considered in future IIS designs and clinical trials.