Microstimulators: Minimally Invasive Implantable Neuromodulatory Devices

Background

The International Neuromodulation Society defines therapeutic neuromodulation as “the alteration of nerve activity through the delivery of electrical stimulation or chemical agents to targeted sites of the body” ( ). Neuromodulation is often used to replace surgery with implanted neurostimulators that use electrical current to affect neuromodulation.

Neurostimulators were originally developed by adapting cardiac pacing technology, and it is not surprising that most neurostimulators are similar in appearance to cardiac pacemakers. There is typically a titanium enclosure (or implantable pulse generator—IPG) of approximately 38 cc and a flexible lead interfacing with the IPG via a connector at one end, and with electrodes at the other end to be placed proximate to a neural target ( ). This configuration has the advantage of ample volume for an internal battery, and a flexible lead allowing for IPG placement at an anatomic location convenient for the IPG volume (such as the chest) and at a distance away from the neural target (for example the spinal cord or brain). It has long been appreciated that radical miniaturization of the implantable system to under 1 cc could dramatically reduce surgical invasiveness, thus enhancing patient comfort. In William Heetderks wrote an influential article on the feasibility of designing millimeter- and submillimeter-scale neurostimulators using the coupling of radiofrequency (RF) coils for power transmission. Heetderks presaged the concept of wireless devices by speculating on the ability to “provide power without a tethering power cable” to implantable sensors and stimulators. He analytically showed that such powering is feasible, and concluded that “if relatively high transmitter power consumption can be tolerated, this analysis suggests that receiver-stimulators can be designed which can be implanted through a 14 gauge (1.6 mm i.d.) hypodermic needle.” Building on this work, described the first injectable microstimulator concept (the Bion) including packaging, electrode materials, and electronics design.

Definition of a Microstimulator

The term “microstimulator” is not used uniformly in the scientific, academic, and patent literature. Sometimes “microstimulator” is used synonymously with wireless RF-powered implantable devices—though that definition is not satisfactory, as some RF devices are quite large and do not meet the intent of minimally invasive implantation. For the purpose of this chapter, microstimulators are chronically implanted devices and must be implantable by a minimally invasive means, although not necessarily by injection.

A further distinction is whether a microstimulator is “active” or “passive” ( ). Technological choices for small implantable devices include passive microstimulators which have very simple circuits, such as a rectifier attached to a coil or antenna, and can be thought of as the implanted output stage of a remote stimulator located outside the body. In contrast, active microstimulators are complete stimulators with circuitry enabling them to regulate therapy, measure electrode impedance, and possibly have programmable operating modes. Particularly when considering human factors, it is helpful to distinguish between active and passive devices: active neurostimulators comprise a complete neurostimulator in a minimally invasive package (although perhaps lacking a battery), and passive microstimulators use an external device to produce the pulses delivered by the implanted microstimulator.

Microstimulators may have onboard batteries or other power sources, or may rely completely upon external power. Almost by definition, passive microstimulators are not powered, whereas active microstimulators may either have a power source or rely on RF or other external power sources such as microwave, light, or ultrasound.

Technical Aspects of Microstimulators

The technical development of implantable neurostimulators is driven by biocompatibility, reliability, and functionality. For microstimulators, functionality includes the requirement that the product be implanted by a minimally invasive route, thereby driving the need for miniaturization. With miniaturization comes special technical challenges that can impact reliability and functionality.

Packaging

For active microstimulators (i.e., those with electronics within the implantable device), protecting circuits from moisture is key to achieving long-term reliability ( ). While epoxy, rubber, and other polymers have been used to protect electronics, these materials do not provide a hermetic enclosure, allowing water vapor to filter readily through the polymer. Theoretically water vapor alone will not cause circuit corrosion, but in practice there is always some small amount of ionic contamination in the package that results in the formation of a salty fluid which causes corrosion of the thin metal layers used in microelectronic circuit manufacturing. To maintain high reliability a hermetic seal is required, often achieved by using thin metal enclosures sealed with welding. For an electrical connection to be made outside the enclosure, typically a ceramic feedthrough is used, often taking the form of a small ceramic cylinder with a wire through the central axis. The standard hermeticity measurement technique in the manufacture of active implantable medical devices is helium leak testing ( ). However, microstimulators are so small that helium leak testing is not sensitive enough to confirm long-term reliability. As a consequence, microstimulators generally include a “getter” that absorbs water vapor to ensure that the internal environment stays dry ( ).

In some microstimulators the stimulation electrodes are mounted directly on opposite ends of a small glass package ( Fig. 22.1 ) ( ). This construction can be used for miniaturization, though it can be technically challenging to achieve a reliable glass-to-metal seal. Furthermore, as glass is not as tough as ceramic, mechanical failures may be more likely to occur ( ).

Microstimulator Human Factors

One key driver in microstimulator development is to improve the acceptability of the surgical procedure for both patients and clinicians. Thus microstimulators must be designed such that they can either be placed through a small incision or be injected. However, placing a small microstimulator proximate to a particular neurological target using minimally invasive surgical techniques may be challenging. In open procedures the nerve of interest is directly visualized and a cuff electrode can be directly applied; for injectable microstimulators, anatomical landmarks are generally required to locate a neural target implicitly. However, relying only on anatomical landmarks may cause the microstimulator electrodes to be placed at an excessive distance from their intended location, potentially resulting in stimulation-related side effects, higher stimulation thresholds, or an inability to achieve the desired therapeutic result. It is also critical that microstimulators, once appropriately placed, be anchored to prevent migration away from the target nerve.

A microstimulator with no battery has the advantage (in addition to small size) of never having to be surgically replaced due to battery failure. While random electrical failures occur at a low rate in implantable devices, batteries have an inbuilt wear-out mechanism that eventually means a near 100% explantation rate due to battery failure. Battery-free microstimulators avoid that eventuality, but require the patient to use or wear an external powering device. The largest markets for implantable neurostimulation are deep brain stimulation (DBS) for movement disorders, spinal cord stimulation (SCS) for angina, back, and limb pain, and sacral nerve stimulation for incontinence ( ). In these applications continuous stimulation is often required, and a battery-free microstimulator requiring the continuous use of an added external device is inconvenient for the patient.

Clinical indications that require less frequent stimulation are often better suited for battery-free microstimulators. For example, acute stimulation in the treatment of severe headache ( ) may be applied on demand by patients using an external controller. Cluster headache is a disabling condition caused by dysfunction involving the superior salivatory nucleus in the brainstem and the sphenopalatine ganglion (SPG) in the head. Excessive parasympathetic outflow from the SPG causes a sterile inflammation of the meninges of the brain, resulting in severe acute pain ( ). A typical therapy is for the patient to use a subcutaneous injection of sumatriptan to treat each headache when it occurs. However, it is medically inadvisable to use more than a certain number of injections per week, and many cluster headache patients have more headaches than can be safely treated with injections. Furthermore, some patients dislike these injections or find the side effects of the medications undesirable or intolerable. To provide an additional therapeutic option for cluster headache sufferers, an SPG microstimulator was developed (see Fig. 22.2 ) that is implanted through a transoral minimally invasive procedure ( ). Upon getting a headache, the patient uses a handheld controller to power and activate the implanted microstimulator. This form of episodic microstimulator use has been reported to be a good use of the technology and one that is easy for the patient to employ ( ).