Implantable Medical Electronics

Innovations in electronic engineering have flagged the march towards realization of implantable biomedical microsystems. These microsystems are capable of interfacing with interior body parts. By such interfacing, they can monitor, manipulate, and control the functions of body parts in the anticipated manner. Distinguished precedents of such systems are the cardiac pacemakers, deep brain stimulators, those used for controlling respiratory and bladder functions, cochlear and retinal prosthesis, and many others prescribed for sicknesses that are unmanageable by medication. Headway in implantable electronics received a boost only after the invention of the bipolar transistor in 1948 and its market availability in the early 1950s. The miniaturization and low power obligation of this device rendered possible workable telemetry systems for measurement of biological parameters. Human body is an intricate electrical machine. Its operational flaws can be tweaked by inserting electronic devices. Besides remedying such faults through delivery of electrical impulses, these devices also help in an organized, coordinated release of medication to the body at a predetermined rate. In addition, they assist in defining vital strictures and in sensing abnormal variations to enlighten about the health state of the body.

An archetypal implantable microsystem comprises two separate structural units: an external controlling module and a component placed inside the human body (the implant). The internal unit can be partitioned into several sections. These sections include the analog front end, memory, microprocessor (CPU), communication, and power management sections. The analog front end takes care of sensing and stimulation functions. The sensing function decides the magnitude, time, and extent of therapy to be given. It also monitors the therapy of the patient. The stimulation function looks after the output voltage or current pulse delivered by the device to the relevant part of the body. The memory unit stores the computer program and data. The microprocessor is the brain of the implanted device. Communication is established between the implanted device and the external controller for initially setting the device and for its subsequent control. The subsequent control is done to fine-tune the therapeutic parameters. Apart from data telemetry, communication is used for power delivery in rechargeable battery implants. Power management is essential to make best use of the battery life or to minimize the time duration between two consecutive charging steps, if a rechargeable battery is used.

Very low power consumption and impeccable reliability are the crucial requirements of implantable electronics. Extremely small power utilization necessitates close attention to power management and budgeting. Together with reliability considerations, it impacts circuit design and fabrication processes, besides influencing the testing methodologies. Reliability physics and failure mechanisms must also be reexamined. An obvious outcome is that the standard designs and processes available from wafer foundries no longer hold; they need to be suitably modified from the viewpoint of power saving and reliability enhancement. The demands become more appalling in the wake of increasing system complexity without concomitantly making more power available.

The stimulating electrodes are generally configured in monopolar and bipolar configurations. Common simulation modes are the current mode and voltage mode. The usual stimulation waveforms are either monophasic or biphasic. Charge imbalance occurs by semiconductor failure. Such imbalance may also arise from leakage currents. The main cause is cross talk between adjacent stimulating channels (sites) as well as cable failure. Positive charge balance is provided by a blocking capacitor connected in series with each electrode. This protective mechanism is used for electrical safety against fault conditions. The large capacitance value required for the blocking capacitors (sometimes a few microfarads) is realized through off-chip surface-mount components. In applications, e.g., retinal implants, the large-size blocking capacitors cannot be used. This inability is due to physical size limitations. Then, other methods for active charge balancing are resorted to. A stimulator circuit that is foolproof without off-chip blocking capacitors produces an active stimulation phase by high-frequency current switching. This phase is followed by a succeeding passive discharge phase.

A clock circuit is a redstone circuit (a structure built to activate or control mechanisms). It produces a repetitive pattern of pulses referred to as a clock signal. A clock generator IC can perform various functions. The functions include the generation, conditioning, manipulation, distribution, or control of a timing signal in an electronic system. The output of clock generators is toggling on/off constantly. To build clock generator circuits, a number of oscillator designs exist. These circuits produce sinusoidal or square waves. The frequencies of the waves range from <1 Hz to several MHz. A linear or sinusoidal wave RC oscillator consists of a tuned RC network connected to regenerative feedback amplifier. Sustenance of steady oscillations requires the fulfillment of Barkhausen’s criterion stating that the loop gain at the oscillation frequency must be unity in absolute magnitude and the total phase shift around the loop should be zero or an integral multiple of 180°. RC oscillators for producing waveforms of square, triangular, or sawtooth shapes are often called relaxation oscillators. The term “relaxation” is related to the charging and discharging states of a capacitor. Many types of relaxation oscillators have been built, starting from simple two-transistor multivibrator circuits and advancing to more intricate circuit topologies. All these oscillators work on the same operating principle.

The generated square waves are used to control the timing of operations in digital systems, such as clock generators for microprocessors. These different circuits are known by a variety of names, such as monostable, astable, and bistable multivibrators. The multivibrator functions can be easily implemented with timer integrated circuits. These circuits are therefore extensively used in timing applications.

The electrical stimuli stand out as the most widely applied among the physical and chemical aids used in medicine. This has primarily transpired owing to their similarity to natural biological stimuli. Stimulation is a technique in which low-level electrical currents are applied via electrodes for exciting nerve cells or muscle fibers. For treatment by electrostimulation, simple and complex schemes of stimulation must be evolved. To evolve such schemes, manually operated as well as computer-controlled/microcontroller-based programmable stimulators are necessary. These stimulators must have multichannel outputs. In turn, for building stimulators, high-performance, manual/programmable, and low-cost pulse generators are needed. In this chapter, timer IC-based pulse generator is first described for easy understanding. Then microcontroller-based pulse generators are dealt with. Both types of pulse generators permit adjustability of pulse parameters. But in the microcontroller-based pulse generators, the stimulation parameters can be programmed. Important parameters are the frequency of stimulation, width of the pulse, inter-pulse duration, and amplitude of the pulse. These pulse generators provide more convenient, automated adjustments.

Essential to the success of an implantable electronic device is the choice of its constructional biomaterial. This biomaterial must neither corrode in the body nor elicit any adverse response from it. Due to immune response from the host body, tissue inflammation occurs along with fibrous encapsulation of the implant. Functionality of the implant is thereby inhibited. Surface modification techniques have been devised for improving the biocompatibility of the implant. Besides the age-old “stainless steel,” implants generally use metals like platinum, iridium, titanium, and tantalum. Bioceramic materials like aluminum oxide are also used. Polymeric materials, e.g., polyimide (PI), polyvinylidene difluoride (PVDF), poly(p-xylylene) (parylene), polyetheretherketone (PEEK), polydimethylsiloxane (PDMS), liquid crystal polymer (LCP), etc., have appeared as substitutions for metallic and ceramic biomaterials to serve as the draping covers of medical devices to be lodged inside the human body.

Batteries for implants must possess characteristics such as safety, reliability, high volumetric energy density, low self-discharge, and long duration of service, which represent essential commitments from manufacturers. The state of discharge must be indicated. In the primary batteries, lithium metal anodes are used. The cathode systems include iodine, manganese oxide, carbon monofluoride, silver vanadium oxide, and crossbreed or hybrid cathodes. This choice of batteries caters to the power levels required by implantable devices, which are spread over a broad range of current values from microampere to ampere levels. Limited battery life is a major impediment to the development of advanced medical implant devices, e.g., when a pacemaker battery runs out, it has to be replaced by surgery. With progressive shrinkage of implant size, more emphasis is laid on building smaller, longer-lasting batteries. Applications involving high power usage rates such as neurostimulators working at milliwatt powers employ secondary rechargeable batteries to achieve longer life span with reduced size.

Communication and powering facilities augment the capabilities of the implants by providing remote monitoring of therapy and charging of implant batteries to avoid replacement by surgery. At short distances in the range of a few centimeters, inductive links are used. The transference of data and power pose conflicting requirements. These requirements are sometimes fulfilled by using separate coils. The cost is a larger footprint and increased electromagnetic interference. Load-shift keying (LSK) technique is applied for uplink data transmission. Downlink data transmission is implemented by one of the three techniques: binary amplitude-shift keying (BASK), binary frequency-shift keying (BFSK), or binary phase-shift keying (BPSK), with BASK representing the plainest approach. Long-distance telemetry >2 m is restricted to the agreed 402–405 MHz band for therapeutic implants or the industrial, technical, and medicinal/curative radio bands: 902–928 MHz, 2.4–2.4835 GHz, and 5.725–5.875 GHz frequency bands with transmission range up to 10 m.

Many lifesaving implantable devices are equipped with wireless technology. This technology enables remote device checks and relieves patients from recurrent consultant visits. But this convenience is associated with unforeseen hazards. These hazards are the security and privacy of data. The labor needed to defend patients from exploits of stealing or nastiness gains more significance. This is especially so with increasing use of wireless telecommunication facilities and the services of global computer network or Internet by implanted devices. The susceptibilities of medical devices are of two types, viz., control or privacy susceptibilities. In control susceptibilities, an unauthorized person acquires control of device operation. The unlicensed person reprograms the device without the patients’ knowledge to disable its therapeutic services. In privacy susceptibilities, confidential patient data are disclosed to an unsanctioned party. Both vulnerabilities are detrimental to patient’s health outcome. Both are avoidable by incorporating well-thought-out measures in device design.

The neural signals are low-frequency (mHz–kHz) and low-amplitude signals (μV–mV). Therefore, the amplifiers for these signals must be low-noise circuits. Additionally, the front-end amplifiers must reject interference due to the common-mode signals as well as electrode effects. Amplification techniques based on clocking and continuous-time approaches are described. The clock-based techniques include switched-biasing, chopper and auto-zeroing methods. The traditional continuous-time circuit is the AC-coupled-operational transconductance amplifier based neural amplifier endowed with capacitive feedback. The unavoidable tradeoff between input capacitance and area of the chip against the gain of the amplifier can be relaxed. This is achieved when a clamped T-capacitor network replaces the feedback capacitor.

Sensors are the primary components of a monitoring system. Micro- and nanofabrication technologies have now advanced to the stage at which wireless sensor systems can be included in the implants with minor modification. These systems provide unique, personalized data for each patient to be used for optimizing outcomes. An acceleration sensor mounted on an artery is used for blood pressure measurement. Coupling a pressure transducer to the right ventricle (RV) lead of a pacemaker or defibrillator helps in continuous intracardiac pressure monitoring. Implantable chemical sensors are employed for real-time monitoring of clinically important species, e.g., blood gas measurements (pH, pO₂, and pCO₂). Subcutaneously implanted enzymatic glucose sensors enable continuous glucose monitoring. Single-walled carbon nanotubes (SWCNTs) encased in alginate work as inflammation sensors, which can be implanted for detection of nitric oxide.

Ever since the introduction of the first artificial pacemaker in 1932, pacemaker technology has advanced rapidly. The early pacemakers could not sense the electrogram. They were brainless devices which only paced the ventricles asynchronously. Subsequent advanced devices called demand mode pacemakers contained a sense amplifier. This amplifier measured the cardiac activity of the patient to evade competition of the actual rhythms of the heart with paced rhythms. Furthermore, single-, dual-, and biventricular pacemakers were launched. Single-chamber pacemakers (one lead) were used to set the pace of only chamber of the heart; this single chamber was usually the left ventricle. Dual-chamber pacemakers (two leads) could set the pace of two chambers of the heart. Biventricular pacemakers used three leads. One lead was placed in the right atrium. The other two leads lay inside the ventricles, one lead per ventricle. Another noteworthy feature is that the early devices were an assembly of discrete resistors, transistors, and capacitors wired together on printed circuit boards, whereas the new devices are highly complex and integrated microprocessor-based systems. They are essentially extremely small computers equipped with RAM and ROM facilities. The topical topologies of pacemakers are tremendously complicated. They include two parts: the analog part and the digital part. The analog portion comprises the sense amplifier and an output stage which performs the pacing. The digital portion consists of sections containing the microcontroller with associated circuitry and the storage memory with accessories. The pacemakers are capable of implementing diagnostic scrutiny of the received electrograms. They provide device programmability. Also, they offer adaptive rate pacing, i.e., they are able to change the paced rate in proportion to metabolic workloads using an accelerometer.

Implantable defibrillators represent the most significant innovation to thwart sudden cardiac death caused by ventricular arrhythmias. Devices have also been designed for the treatment of atrial fibrillation. ICDs are generally implanted in subjects who have withstood more than one incident of ventricular tachycardia or fibrillation. They are also applicable in subjects whose clinical synopsis indicates highly probable, up-and-coming persistent ventricular tachycardia or fibrillation. Chosen highly suggestive subjects with atrial fibrillation too can benefit from ICDs. In contrast to pacemakers, ICDs are endowed with capability of dispensing electrical shocks of high energy to the heart. These shocks are imparted to set right serious, life-threatening, rapid, and sustained arrhythmias. Ventricular fibrillation and ventricular tachycardia are such arrhythmias. Atrial fibrillation too has devastating effects. Such abnormalities are unmanageable by pacing with electrical pulses of low energies and are often irredeemable if not bothered about. The battery chemistry of ICDs uses silver vanadium pentoxide. Large and bulky capacitors are necessary to change the 3–6 V battery output into the 750 V shock required to defibrillate a heart.

Deep brain stimulation is used as a substitute for permanent neuroablative procedures (destruction/inactivation of nerve tissue by surgery, injections, lasers, etc.) in the management of disorders associated with movement, notably Parkinson’s disease, essential tremor, and dystonia. The technique involves stereotactic placement of an electrode into the identified area of the brain and delivering electrical pulses to that area. “Stereotactic surgery or stereotaxy” relates to “stereo-axis,” a combination of “stereo” and “taxis,” originating from “stereo” meaning “three-dimensional” + Greek “taxis” meaning “orientation,” to direct the tip of an electrode in the brain. For the treatment of Parkinson’s disease in sophisticated phase, the target area of the brain is subthalamic nucleus (STN). For medically refractory tremor, the focal area is ventral intermediate nucleus (Vim) of the thalamus. For both cervical and generalized dystonias and Parkinson’s disease, the area of interest is the globus pallidus internus (GPi). Therapeutic stimulation parameters generally used are amplitude, pulse duration, and frequency. The high-frequency stimulation (100–200 Hz) given in this method impersonates the effects of surgical ablation. The method combines the advantages of adjustability of stimulus parameters with the reversibility of treatment. These merits have enabled deep brain stimulation to largely supersede the ablation practice.

Spinal cord stimulation was first hosted in 1967 as a technique for treating chronic back pain. In this treatment, the nerves in the spinal column, also called the spine or backbone, are imparted mild electrical impulses or shocks. The impulses are supplied through leads that are implanted into the epidural space. The location of these leads is adjoining the lower facet of the spinal cord between T9 and L1. The implantation is carried out under fluoroscopic control in a relatively minor surgical procedure. The leads are supplied current from the pulse generator positioned between the skin and the fascial layers (connective tissue fibers, largely collagen). The electric impulses interfere with and modify the nerve activity to minimize the sensation of pain propagation to the brain. An additional available feature is programmability of electrode activation. Either constant-voltage or constant-current pulse trains can be chosen. Facility to minimize stimulus energy requirements is provided. The technique is vulnerable to migration of the lead. Shunting of the stimulus currents by the cerebrospinal fluid (CSF) and various other complications diminish its clinical efficacy.

Vagus nerve stimulation (VNS) therapy is used for halting those seizures of medically refractory epilepsy patients in which therapy by antiepileptic drugs (AEDs) has failed to provide any reasonable comfort. Another disease which can be treated by VNS is chronic or recurrent depression in adult patients that is unmanageable by antidepressant drugs. In VNS, the stimulator device is implanted in the upper region of the patient’s chest. The electrodes are fastened to the vagus nerve in the neck. Although not yet confirmatively known, it is believed that constant and recurrent electrical stimulation of the vagus nerve causes the release of brain neurotransmitters that decrease seizure activity, as required for epilepsy control, or regulate the patient’s mood, as needed for the treatment of depression. Actually, the therapy for clinical depression was started on the basis of improvements in cognition and mood that were observed in patients who were treated for epilepsy. Encouraging results have also been reported by VNS for the management of rheumatoid arthritis.

Diaphragmatic/phrenic nerve stimulation is an alternate stand-in to mechanical ventilation for persons suffering from immedicable ventilatory insufficiency or failure. Suitable patients to receive benefit from this stimulation include those whose phrenic nerves and diaphragms are undamaged, and whose pulmonary function is satisfactory. The phrenic nerve begins from the cervical spine. It starts from the C3, C4 and C5 roots. It is the nerve that regulates and governs the movements of the diaphragm. The diaphragm is accountable for the volume of the air movement throughout natural breathing. The phrenic nerve stimulation device consists of an electrode surgically inserted and winding over the phrenic nerve. It is connected to a receiver operating at radio frequencies. This receiver is placed in the wall of the chest. Upon interception of radio-frequency signals from an external transmitter by an antenna that the patient wears over the receiver, regular electrical pulses are applied to the phrenic nerve. These pulses initiate contractions of the diaphragm, and the diaphragm contractions lead to the intake of air, similar to natural breathing. Hence, the implanted stimulator is called the breathing pacemaker. The respiratory rate is determined by the intensity, duration and rate of impulse. It is controlled by the external transmitter.

Urinary and fecal incontinence are the two principal disorders for which sacral nerve stimulation is an effective treatment. This treatment involves the application of electrical stimulation to the sacral nerves via an implantable system. The system consists of an electrode placed extradurally (outside the dura mater), close to the third sacral anterior nerve root (S3). Along with the electrode is stationed an implantable pulse generator (IPG). An extension cord connects the electrode to the generator. The rationale of the therapy is that the functioning of pelvic floor muscles supporting the bladder and bowel can be controlled by stimulating the sacral nerves electrically. It has been reported that moderately low amplitudes of the signal ~0–3.0 V suffice to provide relief. Within the advocated parameter limits (210 μs, 10–16 Hz), uninterrupted stimulation is practicable without evoking any sensation of pain.

Cochlear implantation is a multidisciplinary therapy capable of treating acute-to-overwhelming sensorineural hearing loss in children and adults. The cochlear implant system comprises a two-piece equipment. The equipment consists of an internal part that requires surgical placement, and an external part generally worn behind the ear. The internal part of the implant consists of a receiver–stimulator containing the electronic circuitry, the receiving antenna, a magnet, and an electrode array. Direct electrical stimulation is provided to the auditory nerves by inserting the electrode array inside the cochlea. The external part is battery-powered. It consists of a microphone to pick up sound, a speech processor with manual controls, and a transmitting coil to convey information to the internal part of the implant. The two parts work in tandem. Following this implantation, most adults can converse on the telephone, while children can pursue mainstream classrooms.

Severe visual impairment up to the level of blindness is caused by either age-related macular degeneration or retinitis pigmentosa. These are the two usual diseases that lead to degeneration of the outer part of the retina. But even after cellular degeneration in these diseases, i.e., degradation of light-sensing photoreceptors, the remaining visual system of neural networks in the retina may not be damaged in many patients. For such cases, a subretinal implant containing microphotodiodes is placed beneath the retina. Currents produced in the photodiodes by the incoming light energize microelectrodes which stimulate sensory neurons in the retina. Otherwise, an epiretinal implant placed on the surface of the retina is employed along with a video camera. The camera captures the light signal and translates the data into an electrical signal through a microprocessor. This signal is transduced across the nerve cells, through the optic nerve, and eventually to the brain for the conception of an image.

Implantable drug delivery devices, nondegradable reservoir or biodegradable types, have shown great prospects. These devices have revealed ostensible possibilities of advancement in several applications demanding onerous efforts in controlled and precise, highly localized liberation of decisive doses of drugs with fewer side effects and without direct medical intervention. Actively controlled devices are more propitious than passive release devices. This greater potentiality of active devices is because the drug delivery process can be controlled postimplantation and even by telemetry, involving automatic measurements and telecommunication. Dissenting from passive devices, they do not rely on the chemistry of degradation of specific materials in the premeditated region of implant. Numerous implantable drug delivery devices have been reconnoitered for use in chronic and terminal diseases. Diabetes, osteoporosis, and cancer are a few such examples.