An Implanted Closed-loop Chip System On Physiological Regulation: System Design And Effects In Concious Animals

Medication is the most common method in the therapies of hypertension, heart failure, arrhythmia etc. However, these drugs usually result in many side effects. Implantable devices provide a feasible measure to those cases. Instead of taking medicine every day, the patients may prefer receiving an implanted device to relieve the symptoms for a relatively long time. The rapid development of microelectronics technology improves the possibility of the clinical application of implantable devices. The implantable device has become a research focus in biomedical field. However, human body is a complex closed-loop regulation system. In patients with dysfunction control mechanisms, the general open-loop device is not safe and effective to interact with the circulatory system. Therefore, An Implanted Closed-loop Chip System was considered to control the circulatory function. In addition this chip system might be a chronic animal experiment platform for the Closed-loop blood pressure control system which was developed in our lab.The whole system was consisted of the slave machine, the master machine and PC-based user software. The slave machine detected the blood pressure signal from an implantable sensor or the ECG signals from the two precordial electrodes. The signals were amplified with a custom amplifier and fed to an on-chip 10-bit A/D convertor. Simultaneously the PWM stimulation was also generated according to the blood pressure or the R-R intervals which was calculated by the slave machine. The digital data of ECG or blood pressure were sent to the master machine by the Nordic wireless transceiver NRF24L01. On the master side, another wireless transceiver collected the signals and sent back command in the way of half duplex communication. A MSP430 processor was used for buffering the data, formatting the chip and communicating with a PC by a USB bridge circuit. The whole system was configured with the software MD2000WL running on Windows-based PC's. The software of MD2000WL data acquisition system (Nanjing Medical University) was developed by MFC including data plotting, data filtering and data analysis.After the basic tests of the system in vitro was finished, six male SD rats with normal heart rate weighing 400g-500g were used to test the heart rate control system and five male normotensive New Zealand white rabbit weighing 2.5kg-3kg were used to test the blood pressure control system. The procedure was as follow. HR control tests: Each rat was anesthetized with intraperitoneal injection of chloral hydrate (0.4g/kg). The right cervical vagus nerve was isolated, and a pair of silver electrodes was placed around the nerve preparing for the stimulations. Two silver detection electrodes were placed under the skin of the chest to acquire ECG signals with one at the cardiac apex and the other at the cardiac base. The main part of the chip was subcutaneously implanted into the abdomen with wire tunneled under the skin to connect with the stimulation electrodes and the detection electrodes. 1-3 hours after the surgical process, rats were recovered from anesthesia. We spent additional two hours to make rats acting as normal condition. After that each rat was subjected to 30-minute regulation and 30-minute recovery. ECG monitoring lasted for 24 hours after the surgery in order to test if the chip system and its wireless communication were dependable.Blood pressure control pilot test: Each rabbit was anesthetized with injection of sodium pentobarbital (4% 1ml/kg) through veins of rabbits ears. The femoral artery was cannulated for measurement of MAP. A midline incision was performed on the neck to introduce stimulation electrodes. The left aortic depressor nerve (ADN) was isolated and identified preparing for the stimulation. The main part of the chip was subcutaneously implanted into the abdomen with wire tunneled under the skin to connect with the stimulation electrodes. 1-3 hours after the surgical process, rabbits were recovered from anesthesia. Blood pressure was monitored after the surgery in order to test if the chip system and its wireless communication were dependable.The ECG signals were successfully recorded during the experiment. The HR was significantly decreased during the period of regulation compared with control (-79.3±34.5, P<0.01, n=6) and then recovered to normal after regulation. The Blood pressure signals were also recorded well during the initial period of the experiment. However, after 6-8 hours, the blood coagulated severely in the arterial cannula which stopped the blood pressure monitoring.In the animal experiments, the goal of closed-loop control of heart rate has been achieved and the system worked steadily without any unexpected problems. Nevertheless, improvement is required such as the method of continuous blood pressure measurement; the improvement of stimulation electrodes; the biocompatible capsulation of the chip system and the method of power supply,et.al. In summary, a closed-loop chip system to regulate animal circulation system was successfully built and it basically accords with the demand of chronic animal tests. The present study laid a foundation for using the chip system to regulate physiological function and potentially to treat disease.