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.

Modeling the permeability of multiaxial electrospun poly(ε-caprolactone)-gelatin hybrid fibers for controlled doxycycline release.

Recent advances in electrospinning allow the formation of multiple layers of micro and nanosize fibers to regulate drug/therapeutic agent release. Although there has been significant progress in fiber formation techniques and drug loading, fundamental models providing insights into controlling individual permeabilities is lacking. In this regard, we first explored forming coaxial hybrid fibers from hydrophobic poly(ε-caprolactone) (PCL) and hydrophilic gelatin (GT) in three different configurations, and the release of hydrophilic doxycycline (Dox) at 37°C over five days. Triaxial fibers were also formed with a GT layer between PCL/GT layers. Fibers were analyzed for fiber thickness, matrix porosity and thickness, surface morphologies, internal structures, stability in hydrated condition, viability and attachment of human adipocyte stem cells (hASC). Formed fibers were 10-30µm in diameter. hASC were viable, and showed attachment. Various release profiles were obtained from these fibers based on the combination of the core and shell polymers over five days. Using fiber characteristics and release profiles from each configuration, we obtained the overall permeability using Fick's first law and then individual layer permeability using resistance in series model. Calculated overall permeability showed dependency on fiber thickness and partition coefficient of the drug in the region where it was loaded. Our modeling approach helps in optimizing the electrospinning process, drug loading, and polymer solution configuration in regulating controlled release of a drug.

Recent advances in multiaxial electrospinning for drug delivery.

Electrospun fibers have seen an insurgence in biomedical applications due to their unique characteristics. Coaxial and triaxial electrospinning techniques have added new impetus via fabrication of multilayered nano and micro-size fibers. These techniques offer the possibility of forming fibers with features such as blending, reinforced core, porous and hollow structure. The unique fabrication process can be used to tailor the mechanical properties, biological properties and release of various factors, which can potentially be useful in various controlled drug delivery applications. Harvesting these advantages, various polymers and their combinations have been explored in a number of drug delivery and tissue regeneration applications. New advances have shown the requirement of drug-polymer compatibility in addition to drug-solvent compatibility. We summarize recent findings using both hydrophilic and hydrophobic (or lipophilic) drugs in hydrophobic or hydrophilic polymers on release behavior. We also describe the fundamental forces involved during the electrospinning process providing insight to the factors to be considered to form fibers. Also, various modeling efforts on the drug release profiles are summarized. In addition new developments in the immune response to the electrospun fibers, and advances in scale-up issues needed for industrial size manufacturing.

Modeling pressure drop using generalized scaffold characteristics in an axial-flow bioreactor for soft tissue regeneration.

The goal of this study was to better understand how analytical permeability models based on scaffold architecture can facilitate a non-invasive technique to real time monitoring of pressure drop in bioreactors. In particular, we evaluated the permeability equations for electrospun and freeze dried scaffolds via pressure drop comparison in an axial-flow bioreactor using computational fluid dynamic (CFD) and experimentation. The polycaprolactone-cellulose acetate fibers obtained by co-axial electrospinning technique and Chitosan-Gelatin scaffolds prepared using freeze-drying techniques were utilized. Initially, the structural properties (fiber size, pore size and porosity) and mechanical properties (elastic modulus and Poisson's ratio) of scaffolds in phosphate buffered saline at 37 °C were evaluated. The CFD simulations were performed by coupling fluid flow, described by Brinkman equation, with structural mechanics using a moving mesh. The experimentally obtained pressure drop values for both 1 mm thick and 2 mm thick scaffolds agreed with simulation results. To evaluate the effect of permeability and elastic modulus on pressure drop, CFD predictions were extended to a broad range of permeabilities spanning synthetic scaffolds and tissues, elastic moduli, and Poisson's ratio. Results indicated an increase in pressure drop with increase in permeability. Scaffolds with higher elastic modulus performed better and the effect of Poisson's ratio was insignificant. Flow induced deformation was negligible in axial-flow bioreactor. In summary, scaffold permeabilities can be calculated using scaffold microarchitecture and can be used in non-invasive monitoring of tissue regeneration.