Novel drug delivery systems have been proposed utilizing nano-sized extracellular vesicles that are naturally released by all cell types and carry bio-molecules such as genetic acids. These vesicles play a crucial role in intercellular signaling for short- and long-distances in the body, making them relevant to both physiology and pathology. By engineering these vesicles to target specific cells, new possibilities for minimally- and non-invasive drug delivery systems are opened.
A computational methodology to theoretically quantify and analyze bio-nano communication between cells at the cellular level is essential for the development of a drug delivery system. In this thesis, the heart is used as a case study to investigate the basics of bio-nano communication between cells using extracellular vesicles and external control of cells. This research models the release of extracellular vesicles from cardiac cells such as ventricular and atrial cardiomyocytes mediated by intracellular calcium signaling. Also, this research models the propagation of the released extracellular vesicles in the cardiac extracellular matrix and their uptake and internalization at target cells. The use of computer simulations and mathematical modeling is an important aspect of this research as it enables the detailed analysis and predictions of extracellular vesicles' interactions with cells, which is fundamental for the development of efficient drug delivery systems. The research aims to provide tools for:

• Modeling intercellular bio-nano communication and inter-organ signaling,
• Modulation and control of cardiac cells to release extracellular vesicles,
• Prediction of extracellular vesicles propagation in an extracellular matrix,
• Uptake and internalization of extracellular vesicles to target cells,
• Development of novel externally controllable drug delivery systems for cardiac disorders,
• Providing initial results for optimizing experimental studies on extracellular vesicles and potentially other types of nanoparticles.

This research has the following benefits for medical applications:

• The models given in this research are applicable to other types of nano-sized particles/vesicles.
• The models given in this thesis are applicable to estimate the propagation of nano-sized particles such as extracellular vesicles in other types of extracellular matrix in multiple organs in the body.
• The computer models given in this thesis can be developed for a specific type of disease such as chronic heart failure by importing features from imaging methods in pre-clinical studies.
• The computer models given in this research make the basis of a comprehensive computer model of the human myocardium that can differentiate between different regions of the myocardium such as infarcted and healthy regions of the heart for modeling the treatment of cardiac disorders such as chronic heart failure.
• The models given in this thesis can be developed and expanded for different types of disorders by importing unique features of interest.

SummaryCardiac Resynchronization Therapy (CRT) is used to treat dyssynchronous heart failure, by pacing the right and left ventricles and enhancing the pumping efficiency of the heart. CRT can improve survival, and quality of life, but only 60 % of the patients respond to this therapy, due to suboptimal selection criteria and the lack of acute measurement that can reliably predict the long-term response.
Utilizing sophisticated computational models, we studied the electrical and mechanical characteristics of CRT focusing on defining the optimal pacing site in the left ventricle. We investigated the impact of multisite left ventricular pacing and developed novel measures for the prediction of CRT outcomes.
The outcome of CRT is dependent on the combination of heterogeneities in the individual heart and the specifics of the CRT-stimulation setup. Our findings demonstrate that there is no “one-size-fits-all” solution and that the configuration of CRT must be tailor-made for each patient. A solution that combines imaging, computational modeling, and data science has the potential to improve the decision-making process in patient selection and optimization of therapy.

Summary

This thesis explores ultra-low-power wireless communication methods for biomedical implants. Leadless heart pacemaker (PM) and wireless capsule endoscopy are the two biomedical devices that have been used for prototyping and experimentation purpose.

For patients with heart arrhythmias, PM technology is an important treatment option. Conventional PMs, which are based on multiple leads, are dominant in the current treatment methods. They have one or more sensing and pacing leads connected to a subcutaneous device placed under the skin. The leads are placed in the right atrium (RA) and right ventricle (RV) through the veins or in the coronary sinus. Transvenous PMs have several short-term and long-term problems. Lead placement and lead dislodgement are the most frequent problems. Dual-chamber and multi-chamber leadless PMs are emerging solutions for reducing the limitations of conventional lead-based PMs.

A commonly used method for diagnosing the digestive system is using a leadbased endoscopy video, which can be an unpleasant experience. In addition, the presence of the medical experts during the diagnosing process is essential. Wireless capsule endoscopy (WCE) is an approach to eliminate the mentioned problems. 

In order to migrate from lead-based medical devices to leadless versions, it is necessary to have a power-efficient, reliable wireless communication method. Wireless communication technology is well-developed and established, primarily for free-space applications. However, the communication methods used in free space are not power-efficient for lossy communication mediums like the human body.

In this thesis, three wireless communication methods have been proposed for power constrained medical devices that are deeply implanted in the body. For dualchamber leadless heart pacemakers, two methods are proposed. First, a conductive impulse scheme is proposed to support low data-rate wireless communication between the heart chambers. The conductive nature of the heart muscles and blood is used for electrical signal transmission between two pacemaker capsules that are placed in the right atrium and right ventricle chambers. The communication link utilizes the frequency range from 1 MHz to 10 MHz for conductive signal transmission. 

A one-way backscatter communication based on the conductive coupling is proposed for data transmission from two pacemaker implants to a subcutaneous or on-body device. The implant capsules can communicate with an on-body device without having any active transmitter. Dual-chamber PM communication is enabled by using the subcarrier technique for discriminating the devices in the frequency domain. A low data rate of 11 kb/s is assigned to each PM capsule to communicate their vital information to the reader.

For the WCE system, a modified backscatter technique is used to transmit an analog video signal from the implant capsule to the on-body reader device. The video transmission system is fully passive and removes the battery for the video transmission in the WCE.

The proposed methods are designed and realized using off-the-shelf electronic components. The prototype systems are evaluated in in-vitro and in-vivo experiments. The results indicate that the proposed methods can provide ultra-low-power solutions for biomedical implants communication.