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.

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.

Detailed Analysis of Insulin Absorption Variability and the Tissue Response to Continuous Subcutaneous Insulin Infusion Catheter Implantation in Swine.

BACKGROUND: Worldwide, ∼1 million people manage their type 1 diabetes with an insulin pump and a continuous subcutaneous insulin infusion (CSII) catheter. Patients routinely insert a new catheter every 2-3 days due to increasing variability of insulin absorption over time. Catheter insertion and maintenance damage capillaries, lymphatics, cells, and connective tissue leading to an acute inflammatory response. METHODS: We compared an investigational CSII catheter (IC) and a commercial CSII catheter (CC) regarding insulin absorption pharmacokinetics (PK) and tissue inflammation. The two different catheter designs were implanted into the subcutaneous tissue of six swine for 5 days. Insulin boluses were given on days 1, 3, and 5 of wear-time to assess PK. Tissue around catheters was excised and stained to visualize inflammation and morphological changes of adjacent tissue. RESULTS: Insulin absorption was better when infused through a CC with highest Cmax and fastest tmax values on day 5 of catheter wear-time. Both catheter types produced high intra- and intersubject day-to-day insulin absorption variability. The IC caused significantly more tissue disruption and lead to irregular changes in tissue morphology. Both catheter types were surrounded by a layer of inflammatory tissue that varied in composition, thickness, and density over time. A catheter that was manually inserted by pushing a sharp tip through the skin caused more trauma and variability than a 90° Teflon cannula with automated insertion. CONCLUSIONS: Insulin absorption variability could be attributed to the layer of inflammatory tissue, which may function as a mechanical barrier to insulin flow into adjacent vascular tissue. The impact of the acute inflammatory tissue response on insulin absorption has to be considered in future catheter designs. A catheter that was manually inserted by pushing a sharp tip through the skin caused more trauma and variability than a 90° Teflon cannula with automated insertion.