Gastric electrical stimulation is an electrical way to treat chronic drug refractory gastroparesis which can be an outcome of diabetics, post-surgical etiology or some idiopathic reason. Symptoms of patients are dominated by nausea, heart burn, vomiting, fullness and bloating which are severe enough for a patient to complete their daily activities. Gastric electrical stimulation (GES) is done by an implantable device that stimulate the intrinsic gastric electrical activity by propagating natural rhythm of muscles contractions. Stimulus parameters and stimulation site has important role in reducing the symptoms of gasteroparesis and treatment of obesity. Research shows that stimulation parameters also effects on neural hormones and autonomous nervous system. The paper gives a brief review about commercially used Implantable Gastric stimulator, recent research in this area and their success in treatment of gastric disorder.
The stomach is a vital organ in human body. It is responsible for digestion of foods and releases of various enzymes to absorb the vital nutrients in the body. Gastroparesis is a condition resulted from weakness of stomach muscles, which cause poor grinding of food in small particles, and therefore delayed emptying of food from stomach into small intestine. The disorder is often associated with Diabetese (20% to 50% type1,30% type2). Other reasons include surgical procedures like vagotomy, gastrointestinal motor disorders, celiac disease, gastric ulcer etc. Patients are treated with prokinetic drugs, antinausea and antiemetic drugs, low fiber, low fat diet. Nevertheless, there are cases when drugs cause adverse side effects like nervous and cardiac disturbance. Moreover, patients of chronic gasteroparesis, who are unresponsive to drugs, have to go for surgical procedures like jejunostomy and gastrectomy. In 1963 some researchers conceived an idea from cardiac pacemaker and tried to deliver stimulus on the wall of stomach to cure the patients of gastric ailments.
However, for long time the idea remained difficult to apply because the electrical activity of motor muscles of heart is not as simple as of heart. Several studies were conducted on dogs. In 1995, Jian De et al. studied the effects of long term Gastric pacing using portable gastric pacemaeker. Farmiloni showed that frequency four times higher than intrinsic slow waves increases muscle contraction. The results of studies led to the, EnterraTM therapeutic system by Medtronics which is an implantable device to deliver electrical stimulations inside stomach. In 2000, the Food and Drug American Administration (FDA) approved the EnterraTM therapy system as a human use device for patients with chronic drug-refractory nausea and vomiting associated with gastroparesis. Transcend II Implantable Gastric Stimulation System are used for treating obesity with BMI greater than 35. Both devices are licensed by Health Canada. Various novel methods are proposed for GES; multichannel GES, Sequential neurogastricelectrical stimulators, Wireless GES, flexible gastric stimulator. The most recent research prototype is reonfigurable wireless gastric control stimulators. Our goal in this study is to explore the methods, parameters and devices used for gastric electrical stimulation and their affects. In order to understand working of Gastric electrical stimulator, physiology of stomach is briefly described.
The stomach comprises of various regions responsible for different actions help in digesting food. The major reasons are fundus, corpus, antrum and pylorus. Antrum produces enzyme which stimulates grinding and mixing of food. Pylorus is a valve between stomach and the Duodenum and it helps emptying food into duodenum. The time required for emptying of food depends also on viscosity of food whether it is solid or liquid, low fiber or high fiber.
Corpus is the region where gastric pacemaker is located.
The interstitial cells of cajal (ICC), located in corpus region begins the gastric myoelectrical activity. The signal from ICC triggers smooth muscles contraction and the slow waves travel peripherally towards pylorus. The frequency of slow waves in normal human is 3 cycles/minute. As the slow waves reach threshold spike potentials are generated. These slow waves are superimposed with spike potentials and thus are in phase locked with muscle contractions. The slow waves propagate from one cell to another through special membrane contact which is regulated by neurohormonal system which are part of Enteric nervous system. Enteric nervous system is a complex mesh of neural networks that control entire gastrointestinal tract.
In gasteroparesis, electrical activity increases or decreases from 3cycles/minute for more than 4 minutes. Serosal electrodes are placed in proximal and distal area.
The efficacy of GES depends upon stimulus parameters excitability characteristics of tissues. Stimulus parameters; frequency, amplitude, pulse width have been investigated thoroughly. Experiments were conducted on dogs and human by setting different stimulus parameters. To date, there are two types of stimulation techniques used for GES.
Low frequency(LF-GES) or gastric pacing: main purpose is to help in emptying stomach. Frequency is generally in a range of 5-8 cycles/minute, pulse duration is 300 to 500 millisecond and current in range of 2- 4mA.
High frequency GES(HF-GES) uses frequency above 10 cycles/minute show improvement in symptoms like nausea and vomiting. Research shows that frequency higher than 5-10 Hz may release hormone acetylcholine from intamular tissues which causes muscles to contract. Because it affects afferent neural system so the stimulation in this range is called neurogastric electrical stimulation (NGES).
Single channel GES is used in variety of studies in which one pair of electrode is applied in the area of gastric pacemaker or in the area of antrum.
There are various commercially available GES system but only Enterra system is approved by FDA for gasteroparesis.
Enterra therapy system is commercially available totally implantable gastric electrical stimulator which uses HF. Frequency used is 12-14 cycles/minute with a pulse width of 330 microseconds with pulse of 0.1second ON and 5seconds OFF, current amplitude is 5 mA. The system consists of pulse generator 60mm long, 50mm wide and 12mm thick. The pulse generator is powered by a battery having life time of 5-10 years depending upon strength of stimulations. There are two stimulation unipolar leads by Medtronics model 4351 which have polyurathine insulation and flexible electrode coil made of platinum and iridium. An anchor, small silicon disc and sutures are used to secure electrodes which are connected to stimulator. The external programmer is used [image: image5.emf][image: image6.emf]for adjustment of stimulation and it is placed on skin. The Enterra therapy system can be used permanently or temporary depending upon the symptoms. Physician can turn it off.
The system in fact did not fully cure gasteroparesis but it helps in alleviating the symptoms in majority of cases.
Obesity is considered to be link with sympathetic nervous system. Increase in sympathetic nervous system activity causes weight loss. Splanchnic nerve stimulation is investigated for treatment of obesity which is reported to decrease food intake in dogs for 28 days. Experiment with the TranscendTM GES system is carried out to block the afferent vagal nerve impulses which reduces gastric emptying and food intake. The stimulus of frequency 1 Hz, 170 mV and 170 ms pulse duration was used. TantulusTM device consists of pulse generator and three biolar electrodes. Two pair of electrodes are implanted in antrum and one pair is in fundus. The electrode in fundus sense presence of meal, the pulse generator start sending pulses to antrum electrodes in refractory period which began gastric contractions and signal was sent through vagal nerve that stomach is full. 12 subjects were able to decrease 10 kg over 20 weeks.
Strength of antral contraction raised by 43%.
Investigation in curing gastroparesis with GES led to examine the possibility of multichannel implant. Chen et al. implanted eight pairs of bipolar electrodes on the serosa of healthy dogs. An adjustable four channel stimulator was used to stimulate first, third, fifth and seventh pair while other pairs are used for recording myoelectrical activity. He performed experiment with variable stimulating parameters in fasting state. He observed that slow waves were generated with frequency 1.1 times the intrinsic frequency, pulse width of 40ms with current of 1mA, 0.8mA, 0.6mA and 0.4mA in stimulating channels respectively. The study revealed that the energy required to induce slow wave is almost 1/30 of that needed by single channel implant. Moreover, the multichannel system increases the emptying of liquid food. Jaliliean and colleague proposed a design of multichannel implant for neurostimulation in which they used sequential pattern of electrical stimulation based on results of Minchtev et.al. The stimulator uses 3V battery and a magnetic reed switch is used to make device on and off by an abdominal belt. Fig.6. They use 50 Hz frequency with duration per channel is 6s and phase lag between channels are 3s. In order to ensure net ion flow is zero, biphasic stimulation are induced by providing monopolar waveform of opposite polarity to one set of electrodes.
In order to avoid surgical complications, endoscopy seems to bequite appealing for placing GES as it is less expensive and less invasive. However the design of such implant present certain challenges regarding device size, power supply, proper anchoring in the stomach, device packaging.
Maximum volume of device should not be greater than 5cm3 and diameter would be less than 18mm. The packaging should protect device from acidic environment of stomach.
Laurent et al. explored the way of protecting implant with Silicon rubber. He tested two adhesive silicon rubbers in vitro on conventional implant substrate in the highly acidic environment. Two types of Silicon rubbers are selected DC 3140 and Nusil MED4-4220. The substrates are chosen to be glass alumina and glass reinforced epoxy. They found that MED4-4220 combined with alumina substrate may sustain up to 3.9 years at body temperature with failure rate less than 10%. So the device is appropriate for gastrostimulators.
The breakthrough in GES technology, a prototype developed by Sanchali and colleagues. The device offers some attractive parameters such as size reduction compared to Enterra system and wirelessly rechargeable stimulator. Because of its small size (35mm×10mm×8mm), it can be implanted via endoscopy. The device is designed to operate in chargeable and stimulating mode alternatively.
A rechargeable lithium ion battery (3V, 11-mAh) connected with magnetic reed switch is charged with external transmitter. The electromagnetic power of 3W at a radio frequency of 1.3 MHz is transmitted by the transmitter. The battery is required to be recharged after 19 hours of use and takes 30 minutes however; it is needed to be replaced after 100 cycles. A preprogrammed peripheral interface controller (PIC) is used to generate pulses. When the magnetic switch closes, battery becomes in contact with PIC and it starts delivering pulses Fig.7B. This prototype was implanted in 5-months old pig for demonstration.
The problem with device is that it is hard enough to attach firmly with the curvature of stomach.
The electrodes are unable to remain in their position when stomach functionality is resumed. So, Souvik and Chiao presented a novel solution to the problem by developing a gastric stimulator based on flexible substrate. In order to fit in endoscope, device can be rolled into cylindrical tube shape. After placed in stomach, the stress turns device back into flat form. Patients are required to wear belt during eating. Shunt capacitor is utilized to suppress harmonics whereas a spiral coil served as an antenna. On the receiver end, energy is harvested through a coil. The work explored the wireless power transfer in certain conditions, achieved efficiency of 14% at a distance spacing of 4cm.
Synchronized GES has been explored to acquire wave pattern inside stomach to check the efficacy of GES. The system was large enough to be implantable. A capsule telemetry system offers low resolution of EGG. Arriagada et al. proposed a design of feedback controlled NGES system and implemented on four dogs. Microcontroller is used for selection and coordination of different modules. The multiplexer was used to link the electrodes with stimulator or the impedance measurement. The impedance measuring module got the voltage signal proportional to gastric impedence and was fed back to controller then controller took stimulation decision. The stimulator obtained parameters from controller which was adjusted according to feedback and sent stimulation to tissues.
A novel design proposed by Rui Wang and colleagues was a miniature reconfigurable system which wirelessly obtained gastric slow waves and delivered HFS. The system comprises of two units; front end block consists of recording and stimulating module and back end external system was connected to PC. The analog conditioning circuit in recording module got slow wave signals from three channels and after passing from high pass filter is delivered to instrumentation amplifier (gain 100 adjustable) after eliminating noise signal was transferred to next amplifier with gain 200. The amplified signals were sampled at 90 Hz per channel, digitized into 12 bits. The data were wirelessly transmitted by front end transceiver and packets were taken by back end transceiver, then microcontroller sent data to computer. loaded into packets (8 bytes) to be wirelessly transmitted by the frontend transceiver. The packets were received by the back-end transceiver and the microcontroller unloaded the data and sent them to the computer. Monophasic pulses can be delivered by one channel pulses to the stomach through one channel. The boost converter raised the voltage level from3.3-5V to 10V. This voltage drive the programmable current source capable of delivering current up to 10mA. The back end unit was designed to switch between receiving and transmitting mode. It accepts packets from receiver and sent them to PC. Getting command for transmission, it built packet for stimulation.
The size of front end was 44135. The power consumption was 68.4mW to 216 mW. Lithium polymer battery, 260mAh is able to obtain slow waves and transmit them to back end for about fourteen hours. In stimulation mode frond end can work up to 170 hours having pulse width 500ms after every 20s.
Gastric motility structure incorporates many complex systems like ICC network, smooth muscles, enteric neurons, nerve fibers connected to central nervous system. Electric stimulus may affect all these structure.
Different studies show that almost 70% idiopathic and 70% diabetic patients have reduced symptoms but does not improve dysrhythmia and gastric emptying. Complications like infection, skin erosion and pain were reported 5%-10%. Research is required to make implants more flexible with reconfigurable system. Moreover materials used for device packaging should be such that which protects it from acidic environment of stomach. Physiological research is required to understand the complex gastric structure so that engineers can design device with more precise parameters and functionality.
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