Minimally invasive catheter-based technologies

A simple incision procedure in a blood vessel makes the entire vascular system accessible. Through contrast injection and X-ray visualization, the vascular tree can be mapped and navigated through manual manipulation of thin tubes and wires. This utilization of the vasculature as internal pathways is commonly referred to as the endovascular technique. This technique can be used to deliver implants and drugs, retrieve problematic lesions or objects from the vasculature, or take tissue samples. Compared to open surgery, the advantage of this technique lies in the reduced invasiveness, ideally only leaving a small incision scar at the point of entry. Some interventions, however, are still associated with certain risks, requiring medication or complicating further interventions. The development of sequencing technologies presents an opportunity to improve and miniaturize devices, reducing invasiveness. This thesis aims to mitigate these risks and capitalize on the potential of next-generation sequencing through microfabrication technologies, producing devices that are less invasive than current methods or that enable a new procedure.

Initially, the aspect of endovascular heart biopsy is covered. The first work presents the fabrication and in vivo evaluation of a nitinol-based catheter device designed for extracting myocardial tissue. The device is fabricated through picosecond laser machining of nitinol tubes and wires, producing a device that is substantially smaller than what is currently used. The samples are evaluated and compared to samples extracted with conventional devices through RNA-Sequencing, verifying the proof of concept. The second work further emphasizes the device's functionality by evaluating it in a disease model of endomyocardial infarction. Tissue that is affected by the infarct and surrounding healthy tissue is extracted and compared in terms of its genetic expression. This comparison reveals a genetic discrepancy between the sick and healthy tissue, verifying the potential of using the device with RNA-sequencing for diagnostic purposes. The third work evaluates the safety aspects of the novel device in a head-to-head comparison with a conventional device. The study reveals a clear benefit of using the smaller device in terms of the complication rate during the procedure.

The fourth work presents the fabrication and in vivo evaluation of another nitinol-based catheter device designed for endothelial cell sampling. The device is fabricated through two-photon polymerization technologies, producing sub-mm brush structures mounted on a nitinol wire. Currently, there are no devices in clinical use that are capable of exclusively extracting endothelial cells. The novel device presents a solution for selective interaction with the innermost layer of the blood vessel. It represents an important step toward sampling endothelial cells for diagnostic and research purposes.

The fifth and sixth works collectively present two different aspects of a third nitinol-based catheter device designed to sample tissue from soft organs anywhere in the body. The device is fabricated using laser micromachining, grinding, and two-photon polymerization. The work is separated in terms of the in vivo evaluation and the technical solution. The technical aspects of the device are examined in terms of force generation in miniaturized catheter systems and the problems that arise in terms of mechanical scaling. These problems are solved by attaching pistons along the wire surface coupled with applied pressure to increase the force generated. The sampling with this device is realized, similar to the fourth work, with sub-mm brushes mounted on the wire. In vivo evaluation of this device reveals successful sampling of minute tissue quantities from the liver and kidney, in the size range of 10-100 cells per sample.

The seventh work presents the in vivo and in vitro performance of a nanostructure coating on nitinol-based stents. Patients with a stent implant are prescribed an extensive medication regimen to counteract the metal implant's effects on the blood and surrounding tissue. This issue is being continuously targeted by new stent platforms, either with a drug-eluting polymer layer or by being resorbable by the body or through various other means. These implants all have a transient behavior, resulting in different issues over time. Paper VII presents an alternative approach to this problem by instead applying a nanostructure coating that is designed to interact with the blood to a much lesser degree, as demonstrated by CT-angiography and the measurement of multiple biomarkers.

List of scientific papers

I. Myocardial micro-biopsy procedure for molecular characterization with increased precision and reduced trauma. R. Grankvist, A. Chireh, M. Sandell, A. K. Mukarram, N. Jaff, I. Berggren, H. Persson, C. Linde, F. Arnberg, J. Lundberg, M. Ugander, G. La Manno, S. Jonsson, C. O. Daub & S. Holmin. Scientific Reports. 10, 8029, 2020.
https://doi.org/10.1038/s41598-020-64900-w

II. Micro-biopsy for detection of gene expression changes in ischemic swine myocardium: A pilot study. A. Chireh, R. Grankvist, M. Sandell, A. K. Mukarram, F. Arnberg, J. Lundberg, C. O. Daub, and S. Holmin. PLOS ONE. 16(4): e0250582. 2021.
https://doi.org/10.1371/journal.pone.0250582

III. Safety evaluation of high-risk myocardial micro-biopsy in a swine model. A. Chireh, M. Sandell, R. Grankvist, V. Lövljung, J. Al-Saadi, F. Arnberg, J. Lundberg, M. Settergren, and S. Holmin. Heart and Vessels. 37, 697–704, 2022.
https://doi.org/10.1007/s00380-021-01995-9

IV. Endovascular Device for Endothelial Cell Sampling. M. Sandell, A. Chireh, A. Spyrou, R. Grankvist, J. Al-Saadi, S. Jonsson, W. van der Wijngaart, G. Stemme, S. Holmin, and N. Roxhed. Advanced NanoBiomed Research. 2: 2200023, 2022.
https://doi.org/10.1002/anbr.202200023

V. Sampling through a transvascular working channel. M. Sandell, A. Chireh, A. Spyrou, J. Al-Saadi, S. Jonsson, W. van der Wijngaart, G. Stemme, N. Roxhed, and S. Holmin. [Manuscript]

VI. Hydraulic micropistons enable high force operations through miniaturized catheters. M. Sandell, S. Jonsson, W. van der Wijngaart, G. Stemme, S. Holmin and N. Roxhed. [Submitted]

VII. A novel noble metal stent coating reduces in vitro platelet activation and acute in vivo thrombosis formation: a blinded study. M. Sandell, A. Ericsson, J. Al-Saadi, B. Södervall, E. Södergren, S. Grass, J. Sanchez, and S. Holmin. [Submitted]