Biomaterial Method for Reducing Incidence of Meningitis in Cochlear Implants Jordan D. Rich Department of Bioengineering / University of Utah

Introduction.

The cochlear implant is the most widely clinically used brain machine interface in medicine, with implantation rates reaching ten thousand implants per year in the United States and a total of over 250,000 implantation procedures performed to date. To analyze and speculate on areas that the device may improve to allow even more reliability and efficacy, this research investigates the biocompatibility of the materials that compose the implant. Ultimately, the goal of this research is to present areas in which a change of material may increase the performance of the device in restoring loss of hearing.

Hearing Loss.

Hearing loss is a debilitating condition that affects every aspect of daily life. It is a condition that isolates the afflicted from society and places strain on relationships with friends and loved ones. Beyond misunderstanding during communication, affected individuals experience heightened stress and unnecessary fatigue. Moreover, children with deafness experience difficulties in acquiring essential language skills. Clearly the provision or restoration of hearing is a very big deal.

Hearing loss may be caused by various pathologies or injuries to the auditory system. Damage or defect to the middle and/or inner ear, cochlea, hair cells, and auditory neurons is characterized by mild to profound loss of auditory perception, and is caused by a multitude of events from ear infection, head injury, or medications to birth defects, extremely loud noises, or aging. Hearing loss may occur in both ears or just on one side or be a compounding of multiple forms of injury, nevertheless, for most cases, the cochlear implant can provide the ability for a person once afflicted with loss of hearing to hear once more.

Cochlear Implant.

The cochlear implant functions by transducing a sound wave that is received by the microphone into a signal that is transmitted to the stimulator by radio frequency. The signal, which is a digital representation of the sound wave separated into its respective frequency components, is transduced to the nervous system by electrical stimulation of the appropriate auditory neurons.

The cochlear implant consists of an internal and external component. The external part is composed of a microphone, battery

Fig. 1. Cochlear implant system consists of an external and internal part. The exterior piece is contains a microphone (1), sound processing unit (2), transmission coil (3), receiver (4), stimulation microprocessor (5), and electrode array (6).

magnet, transmitting antenna, and sound processing unit. The internal part, called the receiver/stimulator, is composed of a microcomputer enclosed in titanium case19, transmitter coil encased in a silicone sheath, an electrode with platinum contacts in a silicone array, and a silicone cable that resides in the middle-ear/mastoid region upon implantation, and a magnet with opposite polarity of the external to hold the external device over the internal (Fig 1).

Before implantation, it must be determined which ear will be implanted, although typically the better hearing ear is chosen because the greater the amount of surviving spiral ganglion cells allows for better interfacing with the electrodes and thus a better stimulation site. During the procedure the patient is placed under anesthesia. Implantation is performed in the following manner: a well is created in the bone of the skull above the ear to recess the receiver14; incision of the round window and cochleostomy is peformed by drilling into the scala tympani of the basal turn of the cochlea (Fig 2); stimulating electrodes are inserted into the cochlea to interface with auditory neurons; and finally, fascial grafting of the round window is performed to seal the cochleostomy by applying either an autograft of muscle or a porous Teflon

mesh.5 To reduce fibrous tissue formation at the electrodes which causes higher impedance and decreases the efficacy of the device, postoperative application of glucocorticoids is applied alongside antibiotics to reduce the risk of infection.

Biocompatibility.

Although much of the components of the internal implant are encased in silicone and does not cause a large inflammatory response, the risk of basilar membrane perforation has been identified due to larger, stiffer, and preformed electrode arrays. To reduce these complications, newer devices utilize smaller and more flexible arrays. The most important issue that has been discovered is the risk of bacterial meningitis occurring up to 24 months postoperatively12. Originally it was thought that the there was minimal risk for development of meningitis, however, in 2002 the FDA took notice of a higher than average prevalence of meningitis in patients implanted with a 2-component electrode array developed by Cochlear ltd.4 The second component of the array aided in positioning the electrodes closer to auditory neurons and thus increasing the efficacy of the device, however the system was withdrawn from the market due to the increased prevalence of meningitis. In a study conducted not long afterwards, it was found that electrode arrays without positioner posed a 4.1% prevalence of bacterial meningitis with 3.0% serious cases requiring surgical intervention8.

Fig 2. Cochleostomy performed at round window to allow insertion of stimulating electrodes.14

Meningitis.

Though many bacteria can cause meningitis, the primary pathogens are Neisseria Meningitidis (gram-negative), Spretococcus pneumoniae (gram-positive), and Hemophilus influenza (gram-negative)2. Bacteria can reach the meninges by primary hematogenic spread, secondary infection from nearby infections, or contact of the cerebrospinal fluid (CSF) with the exterior (primarily caused by injury). It has been speculated that the secondary infection caused by CSF drainage at the round window is the main cause of the high prevalence of meningitis in cochlear implant patients due to an improperly sealed cochleostomy site. Thus bacteria may migrate through a weak or imperfectly sealed cochleostomy, forming a biofilm on the electrode and infiltrating the cochlear turns and finally, following perineural and/or perivascular pathways into the auditory canal and the meninges. So, the round window is where the focus should be to lower the risk of infection because the seal to the cochleostomy is a primary defense against invading pathogens. Failure of the fibrous tissue seal could be due to a number of different conditions such as improper grafting, movement of the electrode, internal pressure on a weak seal, or even degradation of that seal by inflammatory cells (Fig 3).

One method of preventative care is to require all cochlear implant patients to receive meningitis inoculations which have lowered the prevalence of infection, but meningitis still remains a serious problem.18 When a cochlear implant patient develops meningitis, treatment will vary dependant on the seriousness of infection. Initially, infusion of an antibiotic regimen, is performed (e.g. vancomycin, cefotaxime, or ceftriaxone). If persistent, surgical intervention is required. This intervention may be to drain inner ear and remove inflammatory granulations, however if there is a lot of granulations present, it may be best to partially remove the device, inject antibiotics into the fistula, and reinsert. If all else fails though, the device must be removed until infection has ceased.

Recommended Innovation.

To prevent bacterial meningitis, the focus must primarily be on maintaining a well sealed round window and secondarily, if fibrous tissue at the round window is damaged or weakened, preventing biofilm adhesion on the electrode wire which should prevent infection of the meninges. These two objectives may be accomplished by: 1.) utilizing quaternized poly(2-dimethylamino)ethyl methacrylate (pDMAEMA) as a non-fouling surface coating applied to the silicone sheath of the electrode wire to prevent biofilm adhesion; 2.) incorporation of nalidixic

Fig 3. Various conditions of fibrous tissue necrosis at grafting site of round window.2

acid for drug delivery to prevent postoperative infection; and 3.) utilizing a collagen/polyglycolic acid (PGA) scaffold impregnated with transforming growth factor beta (TGF-beta) and platelet derived growth factor (PDGF) as a grafting material to seal the incision site at the round window and encourage fibroblast migration and fibrous tissue formation.

Quaternized pDMAEMA is an appealing non-fouling coating for use in this application because it is easily grafted to silicone which means that there would not be a requirement to change the manufacturing process of currently available implant systems and is directly grafted to silicone using gamma-rays and quaternized using methyl iodide7. Experimentation has shown that pDMAEMA is effective against both gram-positive and gram-negative bacteria by direct binding, diffusion through the cell wall, and disruption of the cell membrane leading to cell death.16 Moreover, an interesting property of pDMAEMA grafted to silicone is that grafting occurs both at the surface and in the bulk, causing swelling behavior which allows the incorporation of drugs for sustained release during the course of several hours and Nalidixic acid is a good candidate for this application because of its effectiveness against gram-positive and gram-negative bacteria.

As for the graft, collagen is an appealing material for the scaffold because it encourages fibrous tissue formation, but because porous collagen structures are not very well reinforced mechanically, impregnation with PGA will provide more structural support.10 Through experimentation, it has been found that using a higher concentration of PGA increases the inflammatory response to its implantation however lowering the concentration decreases the structural support it lends to the collagen sponge. A happy medium appears to be a collagen:PGA weight ratio of 0.8. As experimentation has shown, this weight ratio will allow sufficient cell migration within the scaffold (Fig 4). TGF-beta and PDGF were selected because they are the primary fibroblast signaling molecules and generous fibrous tissue formation at the round window is the goal.

Fig 4. Penetration of cells within scaffold based on collagen:PGA weight ratio.10

Conclusion.

It has been shown that although the cochlear implant has had much success as the worlds most utilized BCI in clinical use, there remain areas in which the device can improve. The existence of prevalence for meningitis infection is a serious issue that should be dealt with as technology allows. Currently, the best method of reducing this risk is by utilizing meningitis inoculations which are not completely accurate in preventing infection. Nevertheless, incorporation of a method or treatment that maintains proper seal of the fistula is key to annihilating the risk of infection.

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