Interfaces with the Peripheral Nervous System
In recent years, many scientific and technological efforts have been devoted to develop hybrid bionic system (HBS) that link, via neural interfaces, the hu-man nervous system to electronic and robotic prostheses, with the main aim of restoring motor and sensory functions in patients with spinal cord injuries, brain injuries, degenerative disease, or limb amputations. A number of such neuropro-stheses include interfacing the peripheral nervous system by means of electrodes that allow neuromuscolar stimulation and neural signal recording.
Several approaches have been developed and tested:
(1) Functional Electrical Stimulation (FES) systems that artificially replace central motor control by stimulating the intact peripheral nerves or muscles of patients with Central Nervous System (CNS) injuries, and attempt to reproduce move-ments that mimic normal actions; (2) artificial prostheses that aim at substituting missing limbs of the body: movements are controlled by the signal recorded from the neural efferent nerve; sensory feedback can be provided to the user through stimulation of afferent nerve fibers in the residual limb; (3) exoskeletons, inten-ded to augment or restore reduced human capabilities; (4) tele-operated robots to carry out tasks in environments where the direct intervention of human beings is not possible ? ?.
There are different methods of coupling these devices to the Peripheral Nervous System (PNS), however the electrical coupling is the most common and best-known. Although this coupling method is associated with some degree of inva-siveness into the biological system, the contemporary research field has devoted considerable attention to the development and testing of interfaces that do not damage the nerve (low invasiveness) and allow access to electrical activity of
specific groups of axons (high selectivity).
In this chapter an overview of different types of electrode that interface with the PNS is presented: main characteristics, suitability, degree of invasiveness into the biological system and biomedical applications are described.
1.1
Organization of the Peripheral Nervous System
The PNS is constituted by neurons that extend from the spinal cord, where their cell bo-dies are located, to the periphery, where they reach different target organs. Peripheral nerves contain several types of nerve fibers. Afferent sensory fibers terminate at the periphery either as free endings or in specialized sensory receptors in the skin, the muscles, and the deep tis-sues. They bring the information from various classes of sensory input, mainly mechanical, thermal, and noxious stimuli to the CNS. Efferent motor fibers originate from motoneurons in the spinal cord and end in neuromuscolar junctions in the skeletal muscles. The majority can be divided into alpha-motor fibers that innervate the skeletal extrafusal muscle fibers and gamma-motor fibers that innervate the spindle muscle fibers. These fibers control the recruitment of different muscle, by the efferent neural signals generated in the CNS. Each spinal motoneuron makes synaptic contacts with a number of muscle fibers, constituting a motor unit. Graded contraction of each muscle is produced by increasing the number of motor units activated, and by increasing the frequency of impulses to each motor unit. The number and type of fibers in each nerve is highly variable, depending on the nerve and the anatomical location. Most of the somatic peripheral nerves are mixed, providing motor, sensory and autonomic innervation to the corresponding target organ.
Nerve fibers, both afferent and efferent, are grouped in fascicles surrounded by connective tissue. The fascicular architecture changes throughout the length of the nerve; the fascicles eventually give origin to branches that innervate distinct target. Fascicular groups destined to the same target remain localized within the nerve for some long distances, thus facilita-ting the selective interface of different fascicles within a given common nerve.
Peripheral nerves are composed of three supportive sheaths: epineurium, perineurium, and en-doneurium. The epineurium is the outermost layer, composed of loose connective tissue and carries the blood vessels supplying the nerve. The perineurium that surrounds each fascicle in the nerve is composed of inner layers of flat perineurial cells and an outer layer of colla-gen fibers. The perineurium is the main contributor to the tensile strength of the nerve, acts as a diffusion barrier, and maintains the endoneurial fluid pressure. The endoneurium is com-posed of fibroblasts, collagen and reticular fibers, and extracellular matrix, occupying the space between nerve fibers within the fascicle. The endoneurial collagen fibrils are packed around each nerve fiber to form the walls of the endoneurial tubules, in which axons are accompanied by Schwann cells, which either myelinate or just surround them.
(a) (b)
Figura 1.1:(a) Transverse section of a pheriferal nerve (fromSclerosing perineurioma: case report
and literature review, Vargas et al.); (b) Structure of the pheriferal nerve (from Hand
Surgery 1st Edition, Lippincott Williams Wilkins).
1.2
Neural interfaces
The term interface includes all the elements of a system between the machine processor and the human tissue, or rather the electrode or sensor with the internal wires, that connect the inner body with the outer processor, the data-acquisition circuitry, and the command unit for controlling the artifact or effector.
From an engineering point of view, the neural interface is a bidirectional transducer that allo-ws an exchange of information between the Nervous System and a technical device. From a biological point of view, such an interface is a foreign body, therefore the biocompatibility of the device must be evaluated. The compatibility between a technical device and a biological system can be discriminated in structural biocompatibility and surface surface biocompatibility. The structural biocompatibility comprises the adaptation of the artificial material structure to the mechanical properties of the surrounding tissue. Device design and material properties should mimic the biological structure of the target tissue. The mismatch of mechanical pro-perties of the technical material and target tissue leads to cellular reactions that attack and encapsulate the implant, resulting in a less effective electrical performance.
The surface biocompatibility deals with the interaction of the chemical, physical, biological, and morphological surface properties of the foreign material and the target tissue. Chronic and electrically active implants have to fulfill high demands with respect of biostability and biofunctionality.
The design and size, as well as the material choice and the interface surface, have to ensure stable transducer properties of the electrode-electrolyte interface throughout the lifetime of the implant. The selection of an adequate electrode size and material, in combination wi-th a ’structural compatible’ design, is always a compromise between electrode impedance, invasiveness, signal-to-noise ratio, and selectivity. In recent years, different type of neural
interfaces have been developed, capable of creating a stable and selective contact with the PNS that permits the electrical recording and stimulation of the neural fascicles, so to restore afferent and efferent fiber activity.
PNS electrode
Selectivity
In
v
asi
vene
ss
Extraneural
Intrafascicular
Intraneural
Regenerative
a
b
c
d
Figura 1.2:The different types of electrodes apllied to interface peripheral nerves classified regarding invasiveness and selectivity ?
The choice of the interface to use for a specific application depends on the degree of selectivity and invasiveness required. The selectivity is defined as the capability of electrical-ly stimulating some fibers of interest instead of other fibers. In a highelectrical-ly selective interface system within a mixed peripheral nerve, two types of selectivity can be defined: topographi-cal selectivity of the targeted population of nerve fibers, that relates to the anatomitopographi-cal region (skin or muscle) supplied by a given fascicle, and functional selectivity of distinct classes of nerve fibers, that relates with the type of function conveyed by the targeted axons.
The invasiveness can be defined as the impact of the device on the body that can modify, punch or cut tissue and structure of the nervous system. This interaction may result in ner-ve damage and affect chronic stability of the interface.
The desired selectivity of stimulation or recording from individual nerve fibers or motor units usually increases in parallel with the invasiveness of the electrode implant. To summa-rize, a successful neural interface should be able to selectively stimulate or record the neural signal from a small group of axons, induce little damage to the nerve after the electrode im-plant and be stable over time (high selectivity - low invasiveness - high stability).
The choice of an electrode depends on the grade of selectivity required. For example surfa-ce and muscular electrodes can record EMG activity and stimulate only the underlying or
implanted muscles. Extraneural electrodes, such as cuff and epineurial electrodes, provide a simultaneous interface with many axons in the nerve, whereas intrafascicular and rege-nerative electrodes inserted in the nerve may interface small groups of axons with a nerve fascicle but they would inevitably induce a greater damage of the nerve. On the other hand, the choice of the interface depends also on the state of the nerve where it should be implan-ted: cuff and intrafascicular electrodes can be applied to intact nerves in acute or chronic studies, whereas, regenerative electrodes are implanted in transected nerves that need to regenerate across the electrode over several months.
Nerve electrodes can be classified into three main classes: extraneural, intraneural, and regenerative.
1.2.1 Extraneural Electrodes
Cuff electrodes are composed of an insulating tubular sheath that completely encircles the nerve and contains electrode contacts on the inner surface that are connected to insu-lated lead wires. They have been fabricated in several configurations, ’split-cylinder’ and ’spinal’ cuffs ?. Cuff electrodes placed around the nerves have several advantages compared to surface electrodes, placed on the skin, and epimysial electrodes, fixed on the surface of the muscle. They allow a correct positioning of electrode that leads to minimize mechanical distortion and failure, and the stimulating current is confined to the inner space of the elec-trode, thus avoiding the stimulation of other neighboring nerves and tissue. In comparison to more invasive devices, such as penetrating and regenerative electrodes, cuff are less pro-ne to damage the pro-nerve and easier to implant.
Despite their advantages of simplicity and handling, and the ability to stimulate and record general activity from the outer part of the nerve, they still have many disadvantages. Fir-st, since they are placed around the nerve, they have a poor selectivity that is limited to subgroups and superficial fibers in the nerve. Secondly, the nerve can be damaged due to micromotion of the electrode array. Multisite cuff electrodes, with several contacts ?, and small cuffs placed around different fascicles or branches ?, as well as advanced processing algorithms have increased the potential selectivity of cuff electrodes.
To achieve better selectivity a new variation of the cuff electrode, that slowly reshapes the nerve into a more electrically favorable geometry, has been designed ?. The Flat-Interface Nerve Electrode (FINE) transforms the nerve from an elliptical shape into a flatter ribbon li-ke shape, giving access to deeper fascicles since the central fibers are moved closer to the electrode contacts in comparison to cylindrical cuff. The surface area of the nerve is also enlarged, increasing the interface surface and allowing more contacts to be placed around the nerve. Since this reshaping requires the slow application of a relatively high force, only moderate flattering of the nerve is possible without inducing nerve damage.
interfa-Figura 1.3:Examples of cuff electrode (from IBMT) ?
scicular design combines the simplicity of the extraneural electrodes with the closer axon contact and stimulation selectivity of intrafascicular electrodes. Here, the epineurium is pe-netrated without compromising the perineurium, thus placing the electrode sites within the nerve trunk but outside the nerve fascicles. The Slowly Penetrating Interfascicular Nerve Elec-trode (SPINE) achieves this aim through blunt elements extending radially into the lumen of a silicone tube that encloses the nerve ?. The elements place stimulation contacts within the nerve for greater access to the central axonal population.
1.2.2 Intraneural Electrodes
Intraneural Electrodes are placed inside a peripheral nerve. They have been developed in order to allow enhanced selectivity with respect to extraneural electrodes and also to increase the signal-to-noise ratio of recordings. Infrafascicular electrodes are placed within the nerve and are in direct contact with the tissue they are intended to activate or record. Sti-mulation through them specifically activates the nerve fascicle in which they are implanted with little cross-talk to adjacent fascicles. Comparatively, smaller stimulus intensities can be used to achieve equivalent levels of recruitment with respect to those used for extraneural electrodes.
One type of intraneural electrode is the Intraneural Multielectrode Array (MEA). Penetrating microelectrodes are most widely used for CNS applications, but can be used also for the PNS. These devices consist of 1D, 2D, 3D arrays of shafts of needles that are inserted transversally into the nervous system. The shaft can be made of different materials with different stiffness, such as silicon or glass. MEAs present the advantage of a high number of electrical contacts, that can considerably increase the number of channels and resolution while minimizing the invasiveness and the number of electrodes to be implanted in a nerve. However, they have some limitations, such as the rigid structure of the electrodes. Unlike the CNS, which is a relatively protected environment encased in the bone, the periphery is surrounded by soft structures implying potential greater micromotion and tethering forces produced through longer lead wires.
Figura 1.4:Flat-interface nerve electrode (FINE) ?
Figura 1.5:Slowly Penetrating Interfascicular Nerve Electrode (SPINE) ?
A different approach is used for the Longitudinal Intrafascicular Electrode (LIFEs), where the electrode is implanted longitudinally within individual nerve fascicles. These devices can be of thin insulated conducting wires where the active zone is a short area of the wire ba-red of insulation, or of thin-film polymer filaments. Flexible polymer filaments (tf-LIFE) are preferred to metal wires since the stiffness of the latter presumably leads to motion of the electrode that elicits fibrous encapsulation and subsequent gradual decrease in the recorded amplitude of axon potential. Among all the materials, polyimide is an excellent candidate for thin film electrodes due to its high flexibility and low stiffness that notably increases the structural biocompatibility of the device.
Regarding the placement of the electrode inside the nerve, a tungsten-guiding needle is pushed inside the endoneurium, parallel to the course of the nerve fibers, and then the elec-trode is pulled through the fascicle until the active zone is in the right position. LIFE permits to gather signals from a small number of axons, allowing a more selective interfacing than extraneural electrodes that wrap the whole nerve.
LIFEs offer good selectivity for stimulation and for multiunit extracellular recording: their geometry, their reduced bulk and their flexibility make them suitable for long-term
implan-tation.
Another electrode developed from the tf-LIFE approach is the Transversal Intrafascicular Mul-tichannel Electrode (TIME) ?. The main difference, compared to LIFE, is the transversal moda-lity of insertion inside the nerve. While the LIFE electrode, due to its longitudinal orientation, is able to selectively stimulate nerve fibers in its proximity within the fascicle where it has been inserted, a TIME electrode can interact with different fascicles across its transversal path through the nerve. Thus, different fibers in more fascicles can be activated with only one device. By placing a number of active sites distributed along the intraneural implant, a single TIME electrode could be able to interface several fascicles, thus reducing the number of implanted electrodes and reaching higher selectivity.
Figura 1.6:MEA, penetrating electrodes developed at the University of Utah (Branner et al., 2001)
(a)
(b)
Figura 1.8:Electrode TIME (a) General aspect; (b) Design of the electrode ?
1.2.3 Regenerative Electrodes
Regenerative electrodes are designed to interface a high number of nerve fibers by using an array of holes, with electrodes built around them. They are implanted between the seve-red stumps of a peripheral nerve. Regenerating axons eventually grow through the holes, allowing the recording of action potentials from and the stimulation of individual axons or small fascicles. Applicability of regenerative electrodes is dependent on the success of axo-nal regeneration through the perforations. Moreover regenerating axons grow at random after complete nerve severance, so that regenerated nerves loose their normal topographical architecture, representing a limitation for the selective interfacing of distinct nerve fascicles. Sieve-like devices are a type of regenerative electrodes made of silicon, ceramic or polymers, such as polyimide. Silicon interfaces cause frequent signs of axonopathy and constitute a physical barrier that limits the elongation of regenerating axons depending on the size of the holes. Ideally one-to-one design would allow the access to each individual regenerated axon grown through one hole; however this has been proved impossible since nerve rege-neration fails with holes of such small size. Polyimide-based electrodes have shown a good
(a)
(b)
Figura 1.9:(a) Schematic concept of a regenerative electrode; (b) SIEVE electrode (IBMT) ?
biocompatibility and stability over months after the implant. They present some modifica-tions in the structure such as increased hole diameter and larger open area within the sieve electrode in order to facilitate regeneration of a larger number of axons.
These electrodes can be ethically applied in already transected nerves; a challenging applica-tion is their implant in severed nerves of an amputee limb for a bidirecapplica-tional interface with prostheses.
1.3
Material for neural interfaces
The choice of the right materials for a neural interface is crucial since, once the device is implanted, it should remain stable and functional within the body of the patient for many years.
Thus, the electrode has to be resistant to corrosion during stimulation and to the attack of biological fluids, enzymes, and macrophages produced during the initial body reaction to a foreign device. The electrode should be composed of inert materials to avoid deterioration of the device that may result in implant failure and release of toxic products, when
subjec-ted to electrical stimulation. Typically used materials are platinum, iridium, tungsten, and stainless steel as conductors and silicone elastomer, polytetrafluoroethylene (PTFE), and po-lymide as insulating carriers.
Other important requirements for electrode materials include minimal energy consumption during stimulation, stable electrochemical characteristics, good phase boundary behavior for polarization and after polarization, adjustable and stable impedance and frequency re-sponse, and stability against artifacts and noises ? .
Silicon and flexible polymers, such as polyimide, are the most widespread substrate mate-rials in micromachining and in precision mechanics. Since the silicon- and polyimide-based interfaces are based on micromachining techniques, they have some advantages over hand-made electrodes, like the easily changeable designs with high precision that can assert an accurate control over active zone size and repeatability. In the case silicon is used, to obtain any degree of flexibility, dimensions must be reduced to such a point that the final product is mechanically fragile. However, one advantage of silicon-based microdevices is the ability of monolithic integration of electronic circuits for recording and signal processing. Polyimide-based neural implants showed good biocompatibility with respect to toxicity as well as bio-stability. Silicone elastomer is still the material of choice for encapsulation of cables and also as additional coating for hermetically sealed electronic circuits.
1.4
Nerve stimulation and recording using neural interfaces
PNS electrodes can be used for stimulation of nerve fibers as well as for recording of neural impulses, thus constituting a bidirectional interface with the nervous system.
Nerve stimulation produces larger movements and more reproducible results than intramu-scular or intraspinal stimulation. In addition, the stimulating current required to activate nerve axons using neural interfaces is much lower than that required for intramuscular sti-mulation. Simple configurations are bipolar and tripolar, which reduce current leaks out of the electrode. Neuromuscular stimulating electrodes should provide stimulation below the charge-carrying capacity and density that induces reversible electrochemical processes and axonal damage. Time variations in the current required to generate a particular level of neu-romuscular activation are attributable to changes in the induced fields resulting from tissue encapsulation or inflammation, changes in the physiological properties of the neuromuscu-lar system, including degeneration and regeneration of stimulated nerve fibers. The number of electrodes to be used depends on the application: low number of electrodes for robust use and limited functionality or high numbers for good spatial resolution and selectivity. Selec-tive electrical interface aims at contacting nerve fibers as selecSelec-tively as possible, requiring devices and fabrication technology in the size of micrometers.
Nerve fibers are recruited by electrical stimulation according to their thickness, therefore large motor fibers innervating the fast-fatigue and strong motor units are activated earlier
then the physiologically first-recruited thinner fibers controlling slow fatigue-resistant mo-tor units. This is called inverse recruitment within electrical stimulation, and causes fast muscle fatigue, by the fact that these muscles are activated earlier. However, this phenomenon is advantageous for stimulation of afferent fibers to provide sensory feedback, since tactile or position sensations can be elicited without concomitantly evoking pain. However, smaller fibers that are near the electrode can be activated before larger fibers further away, thus a mixed order of recruitment is possible by placing the electrode very close to the nerve fiber using intrafascicular electrodes.
Neural interfaces, acting as a bidirectional transducer, have also the possibility of extracting action potentials from electroneurographic (ENG) signal recordings. The processing of neu-ral signals is related to the type of electrodes used. Because of the insulating properties of perineurial and epineurial layers, electrodes placed inside a peripheral nerve allow enhan-ced selectivity with respect to extraneural electrodes and increase the signal-to-noise ratio (SNR) of recordings. Using extraneural electrodes, as cuff, the contribution of single axons cannot be extracted because of the low SNR and the overlapping between the frequency range of signals and the noise.
