Development of superselective endovascular tissue access and sampling

Abstract

Endovascular techniques have revolutionized healthcare by allowing effective treatments of vascular diseases not possible through other surgical means. They have also largely supplanted some surgical treatments due to increased safety and equal or sometimes increased efficacy. However, most endovascular techniques concern the treatment of intravascular disease, as the ability to reach the extravascular tissue has been limited. The trans-vessel wall technique is a recent endovascular technique, in the pre-clinical stage, that allows endovascular instruments to exit the blood vessel and gain direct access to the tissue of an organ. The trans-vessel wall technique and other minimally invasive approaches could be used to treat organs directly, and to perform biopsy.

Tissue and cell biopsy are crucial parts of medical diagnosis, and the reference standard for most pathological conditions. In addition, biopsy is an important source of biological material of disease for pre-clinical research. Biopsy is performed using a variety of techniques with different levels of invasiveness, ranging from drilling through the skull to direct needle puncture with or without image guidance. There is a clear trend towards less invasive methods, which may offer a lower risk of complications and lesser need for post-biopsy monitoring, so that tissue crucial for diagnosis can be procured more quickly, safely, and preferably in outpatient settings. This thesis aimed to develop novel methods of accessing hard to reach organs using endovascular navigation, for the purposes of delivery of therapeutic substrates, or for performing biopsy.

In Study I we employed mechanical thrombectomy, an established endovascular treatment method for ischemic stroke, to harvest endothelial cells from vessels affected by thrombosis. We showed that the endothelial cells can be isolated from the devices and thrombus, enriched by cell culture, and analyzed using single cell RNA sequencing.

In Study II we tested an improved version of the trans-vessel wall technique, a method of direct tissue access using endovascular navigation, to access the heart, the kidneys, and pancreas parenchymae without causing significant hemorrhage. We showed that the myocardial wall can be accessed epicardially and endocardially, and that the kidney capsule can be accessed selectively. These access points are suitable targets for cell transplantation. The pancreas and kidney were also highly accessible for potential new biopsy techniques.

In Study III we developed a novel endomyocardial biopsy device that is smaller, less traumatic, and more flexible than currently available methods, which may improve lesion targeting and reduce complications. We showed that the samples gathered by the device could be reliably analyzed using RNA sequencing.

In Study IV we employed the novel endomyocardial biopsy technique in swine affected by myocardial infarction, showing that it is safe to use in a diseased heart and that RNA sequencing analysis of the biopsy samples could detect tissue gene expression changes caused by the myocardial infarction.

In conclusion, this thesis demonstrates a variety of novel approaches to access tissues for administration of cells and therapeutic substances, and to obtain biopsies in safer and less traumatic ways than currently possible, using modern low profile endovascular techniques. It also shows that RNA sequencing can be a valuable tool to gather as much data as possible from the small cell and tissue samples gathered using these techniques.