Boris Rubinsky

Irreversible Electroporation: A New Ablation Modality — Clinical Implications

Irreversible electroporation (IRE) is a new tissue ablation technique in which micro to millisecond electrical pulses are delivered to undesirable tissue to produce cell necrosis through irreversible cell membrane permeabilization. IRE affects only the cell membrane and no other structure in the tissue. The goal of the study is to test our IRE tissue ablation methodology in the pig liver, provide first experience results on long term histopathology of IRE ablated tissue, and discuss the clinical implications of the findings. The study consists of: a) designing an IRE ablation protocol through a mathematical analysis of the electrical field during electroporation; b) using ultrasound to position the electroporation electrodes in the predetermined locations and subsequently to monitor the process; c) applying the predetermined electrotroporation pulses; d) performing histolopathology on the treated samples for up to two weeks after the procedure; and e) correlating the mathematical analysis, ultrasound data, and histology. We observed that electroporation affects tissue in a way that can be imaged in real time with ultrasound, which should facilitate real time control of electroporation during clinical applications. We observed cell ablation to the margin of the treated lesion with several cells thickness resolution. There appears to be complete ablation to the margin of blood vessels without compromising the functionality of the blood vessels, which suggests that IRE is a promising method for treatment of tumors near blood vessels (a significant challenge with current ablation methods). Consistent with the mechanism of action of IRE on the cell membrane only, we show that the structure of bile ducts, blood vessels, and connective tissues remains intact with IRE. We report extremely rapid resolution of lesions, within two weeks, which is consistent with retention of vasculature. We also document tentative evidence for an immunological response to the ablated tissue. Last, we show that mathematical predictions with the Laplace equation can be used in treatment planning. The IRE tissue ablation technique, as characterized in this report, may become an important new tool in the surgeon armamentarium.

Irreversible Electroporation Near the Heart: Ventricular Arrhythmias Can Be Prevented With ECG Synchronization

OBJECTIVE Irreversible electroporation is a nonthermal ablative tool that uses direct electrical pulses to create irreversible membrane pores and cell death. The ablation zone is surrounded by a zone of reversibly increased permeability; either zone can cause cardiac arrhythmias. Our purpose was to establish a safety profile for the use of irreversible electroporation close to the heart. MATERIALS AND METHODS The effect of unsynchronized and synchronized (with the R wave on ECG) irreversible electroporation in swine lung and myocardium was studied in 11 pigs. Twelve lead ECG recordings were analyzed by an electrophysiologist for the presence of arrhythmia. Ventricular arrhythmias were categorized as major events. Minor events included all other dysrhythmias or ECG changes. Cardiac and lung tissue was submitted for histopathologic analysis. Electrical field modeling was performed to predict the distance from the applicators over which cells show electroporation-induced increased permeability. RESULTS At less than or equal to 1.7 cm from the heart, fatal (major) events occurred with all unsynchronized irreversible electroporation. No major and three minor events were seen with synchronized irreversible electroporation. At more than 1.7 cm from the heart, two minor events occurred with only unsynchronized irreversible electroporation. Electrical field modeling correlates well with the clinical results, revealing increased cell membrane permeability up to 1.7 cm away from the applicators. Complete lung ablation without intervening live cells was seen. No myocardial injury was seen. CONCLUSION Unsynchronized irreversible electroporation close to the heart can cause fatal ventricular arrhythmias. Synchronizing irreversible electroporation pulse delivery with absolute refractory period avoids significant cardiac arrhythmias.

Micro-electroporation of mesenchymal stem cells with alternating electrical current pulses.

Micro-electroporation is an electroporation technology in which the electrical field that induces cell membrane poration is focused onto a single cell contained in a micro-electromechanical structure. Micro-electroporation has many unique attributes including that it facilitates real time control over the process of electroporation at the single cell level. Flow-through micro-electroporation expands on this principle and was developed to facilitate electroporation of a large numbers of cells with control over the electroporation of every single cell. However, our studies show that when electroporation employs conventional direct current (DC) electrical pulses the micro-electroporation system fails, because of electrolysis induced gas bubble formation. We report in this study that when certain alternating currents (AC) electrical pulses are used for micro-electroporation it becomes possible to avoid electrolytic gas bubble formation in a micro-electroporation flow-through system. The effect of AC micro-electroporation on electrolysis was found to depend on the AC frequency used. This concept was tested with mesenchymal stem cells and preliminary results show successful electroporation using this system.

Magnetic Resonance Imaging Characteristics of Nonthermal Irreversible Electroporation in Vegetable Tissue

We introduce and characterize the use of MRI for studying nonthermal irreversible electroporation (NTIRE) in a vegetative tissue model. NTIRE is a new minimally invasive surgical technique for tissue ablation in which microsecond, high electric-field pulses form nanoscale defects in the cell membrane that lead to cell death. Clinical NTIRE sequences were applied to a potato tuber tissue model. The potato is used for NTIRE studies because cell damage is readily visible with optical means through a natural oxidation process of released intracellular enzymes (polyphenol oxidase) and the formation of brown-black melanins. MRI sequences of the treated area were taken at various times before and after NTIRE and compared with photographic images. A comparison was made between T1W, T2W, FLAIR and STIR MRIs of NTIRE and photographic images. Some MRI sequences show changes in areas treated by irreversible electroporation. T1W and FLAIR produce brighter images of the treated areas. In contrast, the signal was lost from the treated area when a suppression technique, STIR, was used. There was similarity between optical photographic images of the treated tissue and MRIs of the same areas. This is the first study to characterize MRI of NTIRE in vegetative tissue. We find that NTIRE produces changes in vegetative tissue that can be imaged by certain MRI sequences. This could make MRI an effective tool to study the fundamentals of NTIRE in nonanimal tissue.

Enhancing RSSI-based tracking accuracy in wireless sensor networks

In recent years, the demand for high-precision tracking systems has significantly increased in the field of Wireless Sensor Network (WSN). A new tracking system based on exploitation of Received Signal Strength Indicator (RSSI) measurements in WSN is proposed. The proposed system is designed in particular for WSNs that are deployed in close proximity and can transmit data at a high transmission rate. The close proximity and an optimized transmit power level enable accurate conversion of RSSI measurements to range estimates. Having an adequate transmission rate enables spatial-temporal correlation between consecutive RSSI measurements. In addition, advanced statistical and signal processing methods are used to mitigate channel distortion and to compensate for packet loss. The system is evaluated in indoor conditions and achieves tracking resolution of a few centimeters which is compatible with theoretical bounds.

Tissue Characterization With an Electrical Spectroscopy SVM Classifier

This feasibility study introduces the use of a classifier based on electrical spectroscopy measurements for breast cancer tissue characterization. The classifier is of the support vector machine type, and the vector of data is made of electrical voltage measurements at 12 discrete electrical excitation frequencies over the beta dispersion range of the analyzed tissue and at discrete locations selected from information produced by conventional medical imaging. The database was generated through a mathematical simulation model. The performance of the classifier was evaluated through a test of its ability to distinguish between simulations of malignant and benign tissues in the breast. The results demonstrate the feasibility of the concept and illustrate the tissue characterization ability of this classifier.

The Use of Irreversible Electroporation in Food Preservation

The need for food preservation has faced mankind since ancient times. Food preservation technologies have evolved as a result of the progression of human knowledge. The more knowledge we have about the environment we live in, the more sophisticated tools we develop to control it. Any significant breakthrough in physics and engineering has resulted in the improvement of food preservation methods. For example,the invention of electricity in 1600 undoubtedly led to major breakthroughs in fresh food storage. Primarily,various thermal methods were invented; thermal sterilization, refrigeration, and cooled storage are among them. However, as years passed, the additional method of pulsed electric field ( PEF) treatment was developed based on the observation of the effect of certain electric fields on cell membranes when delivered as high amplitude short length pulses. Stimulated by customer demand for high quality products displaying the same properties as untreated food, this method is currently in the latest stages of research progress before being implemented industrially. The exact molecular mechanism by which PEF inactivates cells is not yet known. One proposition is that PEF causes the formation of nanoscale pores in the cell membrane, a phenomenon termed electroporation. In the particular case when the process causes cell death, it is called irreversible electroporation (IRE). In the last four decades, IRE food disinfection has been successfully performed on numerous products and bacteria types. Particular contamination problems concerned with specific products have been evaluated, resulting in the investigation of various process parameters and protocol development. This will allow the implementation of IRE technology in the food industry.

Modulating electrolytic tissue ablation with reversible electroporation pulses

Electrolytic ablation is a minimally invasive tissue ablation technique that operates by delivering low magnitude direct current to the target region over long periods of time, generating electrolytic products that destroy cells. Our study seeks to examine the hypothesis that permeabilizing the cell membrane with reversible electroporation will reduce the electrolytic dose required for tissue ablation, by exposing the interior of the cell to the electrolytic products. The hypothesis is examined by evaluating the extent of tissue damage when electrolytic and reversible electroporation sequences are delivered separately and in combination, it in vivo, to rat liver tissue. The study shows that combining reversible electroporation with electrolysis produces a substantial increase in the extent of tissue ablation compared to that achieved by electrolysis alone.

The detection of brain ischaemia in rats by inductive phase shift spectroscopy.

Ischaemia in the brain is an important clinical problem that is often monitored and studied with expensive devices such as MRI and PET, which are not readily available in low economical resource parts of the world. We have developed a new less expensive tool for non-invasive monitoring of ischaemia in the brain. This is a first feasibility study describing the concept. The system is based on the hypothesis that electromagnetic properties of the tissue change during ischaemia and that measuring the electromagnetic properties of the bulk of the brain with non-contact means can detect these changes. The apparatus we have built and whose design we describe here consists of two electromagnetic coils placed around the head. The system measures the bulk change in time of the phase difference between the electromagnetic signal on the two coils in a range of frequencies. A mathematical model simulating the device and the measurement is also introduced. Ischaemia was induced in the brain of rats by occlusion of the right cerebral and carotid arteries. Experimental subjects were monitored for 24 h. Inductive phase shift measurements were made at five frequencies in the range of 0.1-50 MHz eight times during the observation period. An ex vivo estimation of the percentage of necrosis in the ischemic subjects at t = 24 h was done. The mathematical model was also applied to the experimental tested situation. The results of both experiments and theory show significant phase shifts increase as a function of frequency and ischaemia time. The theoretical and experimental results suggest that the tested technique has the potential to detect the processes and level of ischaemia in the brain by non-invasive, continuous, bulk volumetric monitoring with a simple and inexpensive apparatus.

C-SMART: Efficient seamless cellular phone based patient monitoring system

This work describes the design of a new mobile health (mHealth) platform for a continuous real time remote patient monitoring named C-SMART. The platform is based on a set of sensors for patients physiological condition assessment, a mobile phone, and a centralized healthcare utility. C-SMART is implemented on application layer and thus can be compatible to different existing telemedicine and medical data base standards in particular to IEEE 11073. A major concern in the design of the system is given to exploit existing hardware and software resources and thus reduce the platform overhead with minimal user intervention and minimal cost. Another main concern in the design is to make the platform working in a plug and play manner, but yet to give the user maximum control on the system operation. It is enabled by forming a dedicated remote control and installation center and by using an operation menu at the mobile phone. A feasibility test to the platform demonstrated human activity monitoring through a standard mobile phone and a set of accelerometers, and programming of the sensors through the mobile phone.