Maria ThomsenMaria Thomsen

A thesis submitted March 18, 2015 for the degree of Doctor of Philosophy and defended April 25, 2015.

The PhD School of Science
Faculty of Science
Niels Bohr Institute
University of Copenhagen

Robert Feidenhans'l

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Subcutaneous injections: Visualising and optimising device-tissue interactions
This thesis is about visualization and characterization of the tissue-device interaction during subcutaneous injection.

The tissue pressure build-up during subcutaneous injections was measured in humans. The insulin pen FlexTouchr (Novo Nordisk A/S) was used for the measurements and the pressure build-up was evaluated indirectly from the changes in the flow rate between subcutaneous injections and air injections. This method enabled the tissue counter pressure to be evaluated without a formal clinical study approval. The measurements were coupled to a model for the pressure evolution in subcutaneous tissue, based on mass conservation and flow in a porous medium. From the measurements the flow permeability and bulk modulus of the tissue were determined.

In the adipose tissue the drug forms a bolus from where it is absorbed by the blood capillaries. The spatial distribution of the injected fluid in subcutaneous pig tissue was visualized by x-ray computed tomography. The insulin drug was represented by an iodine based contrast agent, and an experimental protocol was implemented and optimized. The tomograms provided quantitative information about the spatial drug distribution and enabled a characterization of how the drug distribution was influenced by the tissue morphology, and the injection parameters.

For ex vivo injections in subcutaneous pig tissue the bolus was characterized for different needle lengths, injected volumes and infusion flow rates. It was shown that the drug distribution at the injection site was influenced by the needle length and the injected volume. Several imaging analysis tools were optimized for the characterization, and these tools were implemented also on subcutaneous injections in rats, visualized by low dose μCT, and used for characterization of the morphology in mouse tibia bone visualized ex vivo by high resolution μCT.

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