Arteriovenous fistulas and arteriovenous grafts are the most commonly used vascular access for hemodialysis in patients with end-stage chronic kidney disease. However, both methods face significant challenges due to the hemodynamic disturbances induced by the arteriovenous anastomosis. This causes changes in vascular structure and blood flow velocity near the anastomosis site after the fistula/graft surgery, and introduces abnormal wall shear stress and cyclic stretch. This leads to endothelial cell dysfunction, vascular smooth muscle cell proliferation, and adverse remodeling. The resulting effects include low patency rates due to vascular stenosis caused by intimal hyperplasia and insufficient outward remodeling. Additionally, the high flow conduit has been linked to adverse cardiac remodeling. To address this, various strategies have been explored to correct these localized hemodynamic abnormalities, aiming to improve long-term patency rates. In this review, an overview is provided of the current surgical techniques, anastomosis types, anastomosis angles, external scaffolds, modified fistula designs, and types of grafts. It evaluates the impact of these approaches on local hemodynamics in the access conduit and their potential effects on patient outcomes.

In patients suffering from end-stage kidney disease the kidneys can no longer adequately filter
the body’s blood of excess water and waste products. This life-threatening condition is
diagnosed in thousands of patients each year in The Netherlands alone, with millions affected
globally. Due to a scarcity of suitable donor kidneys, and the difficulties in transplanting them,
most of these patients rely on haemodialysis as kidney replacement therapy. In this
treatment, blood is taken from the body, passed through an external filter, and then returned.
Usually this is performed during 3 sessions of 4 hours per week.
A critical component in haemodialysis is the vascular access (VA), which is necessary to allow
sufficient blood to be taken from the body easily and frequently. This is also known as the
patients’ lifeline. Most often, blood is taken from the arm due to the superficiality of the
vessels. However, the typical flow rates in these vessels of ~50mL/min are far too low to
supply the dialysis machine of the ~350mL/min it requires for efficient filtering. This challenge
is usually overcome by surgically placing an arteriovenous fistula (AVF) in the arm: a vein is
cut open and sutured to a hole in the side of an artery. This essentially creates a short circuit
in the blood circulation which drastically increases blood flow to enables dialysis. In some
cases a synthetic tube is used to create this connection known as an arteriovenous graft
(AVG). Directly after placement, the vein starts to adapt to the altered flow conditions and to
accommodate a sufficiently high flow for dialysis several weeks later, in a process known as
maturation.
Unfortunately the vascular access fails to mature in many patients, and when it does mature,
maintaining patency highly uncertain. Patients thus require frequent interventions to restore
functionality of their vascular access in order to continue their treatment. In contrast,
complications such as aneurysms and high-output heart failure occur when the VA does
remain functional. As such, some patients receive their haemodialysis treatment through
central venous catheters (CVCs) to bypass the need for a high-flow arteriovenous connection.
However, this modality relies on a permanent transcutaneous tube that is placed directly into
a central vein. Although immediately usable, these have their own disadvantages such as
thrombosis and infection risks.
The inherent drawbacks to all vascular access types highlight the critical need for novel
strategies to optimise VA. Due to the mechanical and fluid dynamic nature of vascular access,
innovation through medical devices holds significant promise for improving patient
outcomes. This dissertation aims to develop and evaluate a novel medical device for
improved vascular access for haemodialysis.
Chapter 2 introduces a structured development framework tailored to the European
regulatory environment. The Medical Device Regulation (MDR) imposes stringent
requirements for high-risk devices, particularly around safety and clinical evidence.
A question-based development strategy is proposed to help guide decision-making, identify
knowledge gaps, and improve communication across stakeholders throughout the device life
cycle.
Chapter 3 addresses the off-label use of CVCs for power injection of contrast media during
imaging procedures. An in vitro study demonstrated that pressures during such injections
remained below burst thresholds, suggesting incidental use is unlikely to cause acute device
failure. However, evidence of material fatigue and micro-cracks warrants caution. This study
highlights how expanding the use of existing devices, even beyond their original intent, may
offer clinical benefits if properly evaluated.
A literature review on haemodynamic considerations around arteriovenous VA (Chapter 4)
revealed that there are currently no modalities available that substantially improve patency.
This was further confirmed by a clinical study on a recently introduced external support
device, that locks an AVF in an optimal hemodynamic angle (Chapter 5). This study concluded
that although maturation could be improved, patency did not compared to a historic control
group. The constantly supraphysiological flow causes vessel wall damage which ultimately
leads to VA failure in or frequent secondary complications in many cases. Yet, patients
typically only dialyse during 12 hours per week.
A implantable device was developed that can non-invasively open and close the
arteriovenous connection using magnets (Chapter 6). This allows flow to be raised sufficiently
for dialysis, but the circulation can be normalised otherwise. By removing the
supraphysiological flow for most of the time, patency may be improved and complications
reduced. Benchtop and cadaver studies showed feasibility of this device in non-invasively
controlling the arteriovenous conduit. This device was included in a small number of animal
studies, that focused on the in vivo development and iterative design improvement (Chapter
7). Although some issues remain in the design of the device, these animal studies
demonstrated that the implant holds promise for tackling the core issue in vascular access
for dialysis. However, future studies are necessary to establish long-term functionality and
effects on disease outcomes.
End-stage kidney disease patients will continue to rely on haemodialysis due to limited
treatments and donor kidneys. Their VA will remain their lifeline. Therefore, improving clinical
outcomes of VA is of critical importance. A proposed device to open the high-flow conduit
only during dialysis shows promise but involves significant development risks and long
timelines. Interdisciplinary teams are essential to meet all user requirements. Advancing
vascular access for haemodialysis requires sustained collaboration to develop, validate, and
implement clinically grounded innovations for tangible patient benefits.

Objective: Central venous catheters (CVCs) provide direct access to the central circulatory system, commonly used in hemodialysis and intensive care units for drug administration. Although uncertified for the procedure, CVCs are sometimes used for power injection of contrast medium (CM) during CT scans to avoid peripheral intravenous catheter placement. Previous studies suggest this practice is safe, but incidents are reported. This study aims to measure intraluminal pressure during CM injection through CVCs and assess its impact on the luminal surface to guide responsible clinical use. Materials and methods: An experimental in vitro test setup was developed. Four samples each of three different types of unused CVCs were used. Strain gauges were applied to the exterior walls of either the inflow or outflow lumen of the CVC. These gauges measured material deformation due to intraluminal pressure during CM injections at rates of 4.5 and 8 mL/s, each performed five times. Strain data were calibrated against known pressures in a static system. Three CVCs of each type were then pressurized until bursting, and one was subjected to microscopic analysis of the luminal surfaces. Results: Intraluminal pressures measured (97–545 kPa or 14–79 PSI) were below the burst pressure (779–1248 kPa or 113–181 PSI) in all instances. Strain regression analysis shows a statistically significant (p < 0.01) trend over 10 injections in all CVCs tested except one, indicating material fatigue. Surface microscopy revealed surface micro-cracks from repeated injections, suggesting material damage. Conclusions: The intraluminal pressures from power injections of CM are sufficiently low to prevent CVC bursting. While incidental use for CM injection appears safe, repeated use may cause material damage.

Objective: Hemodialysis patients usually receive an arteriovenous fistula (AVF) in the arm as vascular access conduit to allow dialysis 2-3 times a week. This AVF introduces the high flow necessary for dialysis, but over time the ever-present supraphysiological flow is the leading cause of complications. This study aims to develop an implantable device able to non-invasively remove the high flow outside dialysis sessions. Methods: The developed prototype features a magnetic ring allowing external coupling and torque transmission to non-invasively control an AVF valve. Mock-up devices were implanted into arm and sheep cadavers to test sizes and locations. The transmission torque, output force, and valve closure are measured for different representative skin thicknesses. Results: The prototype was placed successfully into arm and sheep cadavers. In the prototype, a maximum output force of 78.9 ± 4.2 N, 46.7 ± 1.9 N, 25.6 ± 0.7 N, 13.5 ± 0.6 N and 6.3 ± 0.4 N could be achieved non-invasively through skin thicknesses of 1-5 mm respectively. The fistula was fully collapsible in every measurement through skin thickness up to the required 4 mm. Conclusion: The prototype satisfies the design requirements. It is fully implantable and allows closure and control of an AVF through non-invasive torque transmission. In vivo studies are pivotal in assessing functionality and understanding systemic effects. Significance: A method is introduced to transfer large amounts of energy to a medical implant for actuation of a mechanical valve trough a closed surface. This system allows non-invasive control of an AVF to reduce complications related to the permanent high flow in conventional AVFs.

Disturbed flow is one of the pathological initiators of endothelial dysfunction in intimal hyperplasia (IH) which is commonly seen in vascular bypass grafts, and arteriovenous fistulas. Various in vitro disease models have been designed to simulate the hemodynamic conditions found in the vasculature. Nonetheless, prior investigations have encountered challenges in establishing a robust disturbed flow model, primarily attributed to the complex bifurcated geometries and distinctive flow dynamics. In the present study, we aim to address this gap by introducing an in vitro bypass flow model capable of inducing disturbed flow and other hemodynamics patterns through a pulsatile flow in the same model. To assess the model's validity, we employed computational fluid dynamics (CFD) to simulate hemodynamics and compared the morphology and functions of human umbilical venous endothelial cells (HUVECs) under disturbed flow conditions to those in physiological flow or stagnant conditions. CFD analysis revealed the generation of disturbed flow within the model, pinpointing the specific location in the channel where the effects of disturbed flow were observed. High-content screening, a single-cell morphological profile assessment, demonstrated that HUVECs in the disturbed flow area exhibited random orientation, and morphological features were significantly distinct compared to cells in the physiological flow or stagnant condition after a two days of flow exposure. Furthermore, HUVECs exposed to disturbed flow underwent extensive remodeling of the adherens junctions and expressed higher levels of endothelial cell activation markers compared to other hemodynamic conditions. In conclusion, our in vitro bypass flow model provides a robust platform for investigating the associations between disturbed flow pattern and vascular diseases.

Introduction: The recent introduction of the European Medical Device Regulation poses stricter legislation for manufacturers developing medical devices in the EU. Many devices have been placed into a higher risk category, thus requiring more data before market approval, and a much larger focus has been placed on safety. For implantable and Class III devices, the highest risk class, clinical evidence is a necessity. However, the requirements of clinical study design and developmental outcomes are only described in general terms due to the diversity of devices. Methods: A structured approach to determining the requirements for the clinical development of high-risk medical devices is introduced, utilizing the question-based development framework, which is already used for pharmaceutical drug development. An example of a novel implantable device for haemodialysis demonstrates how to set up a relevant target product profile defining the device requirements and criteria. The framework can be used in the medical device design phase to define specific questions to be answered during the ensuing clinical development, based upon five general questions, specified by the question-based framework. Results: The result is a clear and evaluable overview of requirements and methodologies to verify and track these requirements in the clinical development phase. Development organizations will be guided to the optimal route, also to abandon projects destined for failure early on to minimize development risks. Conclusion: The framework could facilitate communication with funding agencies, regulators and clinicians, while highlighting remaining ‘known unknowns’ that require answering in the post-market phase after sufficient benefit is established relative to the risks.