**3. Spinal cord injury**

Spinal cord injury (SCI) can occur through a variety of mechanisms. The primary modalities fall into two major categories: trauma (e.g., automobile/motorcycle accident, sports injury such as from diving or horse riding, violence, fall), or disease (e.g., spina bifida or tumor). Spinal cord injuries can affect motor function, sensation, and autonomic functions (e.g., bladder control, breathing). Approximately 50% of SCIs in the United States are classified as complete [19]. This means that the spinal cord has lost the ability to transmit information across a segment within it, cutting off all functional communication from the brain to the nerves below the injury site and resulting in no sensation or voluntary control of motor function below the injury site due to lost input from the brain. This usually results in para- or quadriplegia, depending on the site of injury. Although in most cases the cord is not completely transected or even cut, it is significantly damaged by interruption of blood flow supplying one of its segments or through spinal contusion. Even though the vertebral column protects the cord, when trauma is sufficient to compromise this protective cage, the broken vertebrae can impinge on the cord and crush or destroy the axons within it very quickly, with continued loss of axons over time [20]. Some estimates pin the prevalence of spinal cord injury in the United States at approximately 250,000 [21], with an incidence of approximately 10,000 to 12,000 per year [22], while others state the prevalence is significantly higher, at around 450,000 [19]. Approximately 55% of spinal cord injuries occur in young victims between 16 and 30 years of age, making it a disease to bear usually for the rest of their lifetime, and more than 80% of victims are males [22]. In some cases of incomplete injury, function can be recovered over time [23]. However, in most cases, some level of impairment is permanent.

is hand assembled, a fact that limits the resolution possibilities of the device. Indeed, were it still necessary to interconnect integrated circuits by hand, computers would be far less useful to us as they are today. The need exists, then, to bring microelectronics and microfabrication technology to bear on the problem of retinal prosthetic devices. The race is on to build highdensity multielectrode arrays in such a way and with such materials that the method is scalable to the needs of long term, high-density retinal stimulation. Recently, a sixty electrode version of the epiretinal prosthesis has been tested and has gained the CE Mark in Europe for sale for the treatment of retinitis pigmentosa. The FDA is now reviewing the results of these same studies for potential approval in the United States as a therapy for outer retinal blindness.

4 Advances in Micro/Nano Electromechanical Systems and Fabrication Technologies

**Figure 1.** System overview and relative locations of epiretinal and subretinal implants [18].

Spinal cord injury (SCI) can occur through a variety of mechanisms. The primary modalities fall into two major categories: trauma (e.g., automobile/motorcycle accident, sports injury such as from diving or horse riding, violence, fall), or disease (e.g., spina bifida or tumor). Spinal cord injuries can affect motor function, sensation, and autonomic functions (e.g., bladder

**3. Spinal cord injury**

The complexity of the spinal cord is undeniable. In fact, despite the popular misconception that the spinal cord serves only as a communication conduit between the brain to the muscles and organs and from the skin back to the brain, it is much more accurate to view the spinal cord as an extension of the brain. While the spinal cord below a complete injury does indeed lose input from the motor cortex, and its ability to send sensations of touch to the brain is completely compromised, the spinal cord is not rendered useless. Even an intact cord does a lot of the primary processing and reflex control without any input to or from the brain.

In patients with spinal cord injury, there are several approaches to rehabilitation. The footdrop stimulator, wherein stimulation of the peroneal nerve affects localized contraction of ankle dorsiflexors to counteract the problem of foot drag, has been widely studied [24] with mixed results [25-27]. Other functional movements requiring much more coordinated mus‐ culature responses are far more difficult with implantable peripheral nerve or muscle stimu‐ lators because of the need to control timing as well as pulse amplitudes of likely a large number of electrodes in rapid succession. Skin surface electrodes such as those in the ParaStep system [28, 29] suffer from these problems as well as the problem that many muscle groups are difficult to target from this more remote location. In addition, because in complete SCIs the voluntary input from the motor cortex to initiate such movements is lost, an accessory mechanism for determining the desired motion is warranted. This may require recording electrode arrays in the motor cortex as another component of this system, as well as possible electrical stimulatory feedback (in addition to the visual feedback already present). Any such system, then, is likely to be quite complex and difficult to implement in practice.

We propose a system, which eventually will be completely implantable, that is capable of stimulating the dorsum of the spinal cord in such a manner that modulation of the sensory input to the cord, interneruonal activity within, and even motor output from the cord, is possible. Tonic, subthreshold stimulation, applied at precise times and precise locations along the spinal cord, would likely help sustain or stop locomotor activity with the kind of coordi‐ nation and rhythmicity already discussed. Perhaps in combination with both locomotor and standing training as well as appropriate pharmacological administration (e.g., quipazine), it is possible that such an array would give those with both complete and incomplete spinal injury the ability to stand and walk once again. In order to provide appropriate proprioceptive input in the case of complete SCI, it would likely be possible to provide an accessory device or muscle stimulator to initiate this type of activity. However, this approach leverages the innate activity and processing power present in the spinal cord to its greatest extent and likely obviates the need for a stimulation control system of great complexity in order to bring about coordinated muscle activity, as is necessary for a peripheral muscle or motor neuron control system. Such electrical stimulation may also, as has been hypothesized in the case of subthres‐ hold retinal stimulation systems as well, have the capability of promoting axon regrowth [30, 31] and facilitating plastic changes in the cord. Such an array would likely need to be con‐ formable to the cord, and would need to be implanted in relatively close apposition to it, either epidurally (from which location the electrical field would need to penetrate several meningeal layers) or subdurally, such that it is closer to the surface of the cord. In the ideal case, the array would be flexible enough to move with the cord during motion and bending such that functional targets are the same in any position. In addition, it should be the case that such an array can also record from the cord so as to recognize returning action potentials from the dorsal root and modulate this input accordingly. This approach, then, requires a high-density array with many electrode sites from which to choose during training and daily activity, as well as the ability to both record from and stimulate the cord, something which current arrays, such as those for pain management, simply can not do because they are too bulky, inflexible, and of too low a density (up to 16 electrodes).

### **4. Introduction to parylene**

Parylene is the trade name for a family of semicrystalline thermoplastic polymers known as the poly(para-xylylenes) (PPX). These were discovered in 1947 by Michael Szwarc in Man‐ chester, England [32]. It was originally deposited in an investigation of aliphatic carbonhydrogen bonds where the carbon was attached directly to a benzene ring, by heating toluenes and ortho-, meta- and para-xylenes to very high temperatures and looking for degradation products [33]. The very first parylene film deposited, then, was parylene N (with no substitu‐ tions on the benzene ring), and was temporarily known as a Szwarcite snakeskin. This deposition process, however, had the disadvantage that gaseous by-products were an inherent part of the method. William Gorham, an employee at Union Carbide, soon thereafter devised an alternate method of parylene deposition that involved the pyrolysis of a dimerized form of the material, di-para-xylylene, or [2.2] paracyclophane. It was largely unknown at the time how to make this dimer in large amounts as it had only been isolated as an impurity in Szwarc's method. However, in 1951 Donald Cram reported a method for making this material in bulk. On February 17, 1965, Union Carbide announced the availability of parylene films and the new vacuum deposition method, known as the Gorham process. There were over 20 types of parylene actually developed, but only three were considered commercially viable: these were parylene N (no chlorines on the benzene ring), parylene C (one chlorine on the benzene ring), and parylene D (with two chlorines on the benzene ring) (Figure 2). However, a new fluori‐ nated version of parylene, parylene HT, has recently become commercially available, and can be deposited in a new parylene deposition system.

In the Gorham vapor-deposition process [34] (depicted in Figure 3), which takes place at vacuum (~25-35 mT, to increase mean free path to the substrate), a charge of parylene dimer is placed in a vaporizer furnace. The dimer evaporates at approximately 130 to 150 °C, and then passes through a very high temperature pyrolysis (~650 to 750 °C) furnace, where the molecule is split into monomers. The monomers enter a chamber that is held at room temper‐ ature, and polymerize on all exposed surfaces in the chamber conformally and without pinholes. Residual monomer is collected on a cold trap. Different variants of parylene require varying process conditions, but the method remains essentially the same.

**Figure 2.** The three originally commercialized parylene variants.

the spinal cord, would likely help sustain or stop locomotor activity with the kind of coordi‐ nation and rhythmicity already discussed. Perhaps in combination with both locomotor and standing training as well as appropriate pharmacological administration (e.g., quipazine), it is possible that such an array would give those with both complete and incomplete spinal injury the ability to stand and walk once again. In order to provide appropriate proprioceptive input in the case of complete SCI, it would likely be possible to provide an accessory device or muscle stimulator to initiate this type of activity. However, this approach leverages the innate activity and processing power present in the spinal cord to its greatest extent and likely obviates the need for a stimulation control system of great complexity in order to bring about coordinated muscle activity, as is necessary for a peripheral muscle or motor neuron control system. Such electrical stimulation may also, as has been hypothesized in the case of subthres‐ hold retinal stimulation systems as well, have the capability of promoting axon regrowth [30, 31] and facilitating plastic changes in the cord. Such an array would likely need to be con‐ formable to the cord, and would need to be implanted in relatively close apposition to it, either epidurally (from which location the electrical field would need to penetrate several meningeal layers) or subdurally, such that it is closer to the surface of the cord. In the ideal case, the array would be flexible enough to move with the cord during motion and bending such that functional targets are the same in any position. In addition, it should be the case that such an array can also record from the cord so as to recognize returning action potentials from the dorsal root and modulate this input accordingly. This approach, then, requires a high-density array with many electrode sites from which to choose during training and daily activity, as well as the ability to both record from and stimulate the cord, something which current arrays, such as those for pain management, simply can not do because they are too bulky, inflexible,

6 Advances in Micro/Nano Electromechanical Systems and Fabrication Technologies

Parylene is the trade name for a family of semicrystalline thermoplastic polymers known as the poly(para-xylylenes) (PPX). These were discovered in 1947 by Michael Szwarc in Man‐ chester, England [32]. It was originally deposited in an investigation of aliphatic carbonhydrogen bonds where the carbon was attached directly to a benzene ring, by heating toluenes and ortho-, meta- and para-xylenes to very high temperatures and looking for degradation products [33]. The very first parylene film deposited, then, was parylene N (with no substitu‐ tions on the benzene ring), and was temporarily known as a Szwarcite snakeskin. This deposition process, however, had the disadvantage that gaseous by-products were an inherent part of the method. William Gorham, an employee at Union Carbide, soon thereafter devised an alternate method of parylene deposition that involved the pyrolysis of a dimerized form of the material, di-para-xylylene, or [2.2] paracyclophane. It was largely unknown at the time how to make this dimer in large amounts as it had only been isolated as an impurity in Szwarc's method. However, in 1951 Donald Cram reported a method for making this material in bulk. On February 17, 1965, Union Carbide announced the availability of parylene films and the new vacuum deposition method, known as the Gorham process. There were over 20 types of

and of too low a density (up to 16 electrodes).

**4. Introduction to parylene**

**Figure 3.** center) Gorham process for parylene deposition. (left) Chemical structures at corresponding points. (right) PDS 2010 Labcoater System.

The existing variants of parylene have varying properties as well as uses. Parylene N is primarily used as a dielectric and when lubricity and crevice penetration is important. Parylene C is an ISO 10993, United States Pharmacopeia (USP) Class VI material (the highest biocompatibility rating for plastics in the United States) and has excellent water barrier properties. In addition, it has a very large elongation to break. Parylene D has now been largely replaced by parylene HT [35], but is used when mechanical strength is of primary concern. Parylene HT has extremely low coefficients of static and kinetic fric‐ tion, excellent thermal stability and good water barrier properties, high ultraviolet stability, and is also ISO 10993 biocompatible [35-37]. Finally, very recently, Kishimoto Sangyo Co., Ltd. in Japan has devised additional parylenes in which amino groups have been added to the benzene rings. The amino group may add even more improved biostability, but could also generate bioactivity that may or may not be beneficial to device functionality. We have preliminarily tested these amino parylenes have found them to be compatible with standard parylene processing technology, such as oxygen plasma reactive-ion etching (RIE), in our cleanroom, but they will not be explored further in this text.

The advantages of using parylene, and, more specifically, parylene C, as the structural material for neuroprostheses, when compared with technologies based on the use of other materials such as PDMS, polyimide [38] and silicon [39], include parylene's pinhole-free conformality due to its unique room-temperature chemical vapor deposition process, its low water perme‐ ability, its chronic implantability and its high flexibility and mechanical strength (Young's modulus ~4 GPa). The Young's moduli of two other commonly used materials for neuropros‐ theses, PDMS and polyimide 2611, are graphed alongside that of parylene C in Figure 4. PDMS arrays have been handled by surgeons in our vivarium, and these are often as reported as too floppy and difficult to handle due in part to the low Young's modulus, hence requiring very large thicknesses to handle appropriately. In addition, polyimide 2611 (often chosen because its water permeability is lower than that of other polyimides) has a Young's modulus larger than that of parylene C. It has been suggested that polyimide arrays often are too rigid and can damage the retina. In addition, they tear quite easily. Parylene C handles very well under surgical manipulation, and, as we will show, behaves very well when implanted. In addition, the thickness of parylene films is determined by the mass of dimer placed in the vaporizer. As such, thicknesses can be very thin or very thick, and thicknesses are very repeatable and well controlled, more so than spin-on coatings, especially when deposited over step junctions. Parylene thickness can be controlled so as to match the rigidity to the application of interest, more easily than most other materials. Since parylene is deposited at room temperature (we have verified this using Temp-Plate irreversible temperature recorders traceable to NIST (Wahl Instruments, Inc., Asheville, NC, USA)), the coating process is post-IC compatible. Parylene C is also optically transparent, enabling the anatomy to be seen through the cable and the array during ophthalmic surgery, post-implantation examination, and follow-up. While many groups use parylene C as a coating on their arrays for many of these reasons, we have chosen to use it as the main substrate for our devices [40, 41], a paradigm that leverages these advantages to the greatest extent.

**Figure 4.** Comparison of Young's moduli of various materials. Ordinate is logarithmic.

The existing variants of parylene have varying properties as well as uses. Parylene N is primarily used as a dielectric and when lubricity and crevice penetration is important. Parylene C is an ISO 10993, United States Pharmacopeia (USP) Class VI material (the highest biocompatibility rating for plastics in the United States) and has excellent water barrier properties. In addition, it has a very large elongation to break. Parylene D has now been largely replaced by parylene HT [35], but is used when mechanical strength is of primary concern. Parylene HT has extremely low coefficients of static and kinetic fric‐ tion, excellent thermal stability and good water barrier properties, high ultraviolet stability, and is also ISO 10993 biocompatible [35-37]. Finally, very recently, Kishimoto Sangyo Co., Ltd. in Japan has devised additional parylenes in which amino groups have been added to the benzene rings. The amino group may add even more improved biostability, but could also generate bioactivity that may or may not be beneficial to device functionality. We have preliminarily tested these amino parylenes have found them to be compatible with standard parylene processing technology, such as oxygen plasma reactive-ion etching

8 Advances in Micro/Nano Electromechanical Systems and Fabrication Technologies

(RIE), in our cleanroom, but they will not be explored further in this text.

advantages to the greatest extent.

The advantages of using parylene, and, more specifically, parylene C, as the structural material for neuroprostheses, when compared with technologies based on the use of other materials such as PDMS, polyimide [38] and silicon [39], include parylene's pinhole-free conformality due to its unique room-temperature chemical vapor deposition process, its low water perme‐ ability, its chronic implantability and its high flexibility and mechanical strength (Young's modulus ~4 GPa). The Young's moduli of two other commonly used materials for neuropros‐ theses, PDMS and polyimide 2611, are graphed alongside that of parylene C in Figure 4. PDMS arrays have been handled by surgeons in our vivarium, and these are often as reported as too floppy and difficult to handle due in part to the low Young's modulus, hence requiring very large thicknesses to handle appropriately. In addition, polyimide 2611 (often chosen because its water permeability is lower than that of other polyimides) has a Young's modulus larger than that of parylene C. It has been suggested that polyimide arrays often are too rigid and can damage the retina. In addition, they tear quite easily. Parylene C handles very well under surgical manipulation, and, as we will show, behaves very well when implanted. In addition, the thickness of parylene films is determined by the mass of dimer placed in the vaporizer. As such, thicknesses can be very thin or very thick, and thicknesses are very repeatable and well controlled, more so than spin-on coatings, especially when deposited over step junctions. Parylene thickness can be controlled so as to match the rigidity to the application of interest, more easily than most other materials. Since parylene is deposited at room temperature (we have verified this using Temp-Plate irreversible temperature recorders traceable to NIST (Wahl Instruments, Inc., Asheville, NC, USA)), the coating process is post-IC compatible. Parylene C is also optically transparent, enabling the anatomy to be seen through the cable and the array during ophthalmic surgery, post-implantation examination, and follow-up. While many groups use parylene C as a coating on their arrays for many of these reasons, we have chosen to use it as the main substrate for our devices [40, 41], a paradigm that leverages these

Although parylene is known to be biocompatible in many sites of implantation, in order to initially assess the intraocular biocompatibility of the material in the unique immune envi‐ ronment of the eye, an approximately 2 cm × 0.5 cm piece of unmodified 20 µm thick parylene C was implanted in the vitreous cavity of the right eyes of two rabbits for six months. The retinas of the right eyes of both rabbits were compared post-mortem with those of their left eyes that served as controls. Histological evaluation revealed no discernable difference between right and left eyes, indicating that there was no detectable adverse retinitis, choroi‐ ditis, endophthalmitis, or scleritis seen as a result of parylene implantation in the vitreous cavity [40]. These results supported the tenet that parylene C is a biocompatible bulk material for an intraocular retinal prosthesis and other ocular implants, and paved the way for the design and fabrication of a flexible electrode arrays and a packaging system using parylene C as the primary substrate. Given these biocompatibility results, we have also been investigating parylene in several other ocular implants, with excellent results to date [42-44]. Similar experiments were performed with parylene C implanted on the spinal cord of mice. The arrays were well tolerated, with no obvious immune reaction or gliosis.
