Sight Restoration For Individuals With Profound Blindness
Richard Normann, Ph.D., Professor of Bioengineering, Ophthalmology, and Physiology
The Center for Neural Interfaces, and the John A. Moran Eye Center, University of Utah
With the successful development of a penetrating microelectrode array for implantation in the brain, artificial vision is ready to step beyond the original systems built in the 1960’s. The development of the Utah artificial vision system is being guided by four principles: 1) long-term safety and biocompatibility of the implant, 2) vision capable of navigation without a guide dog, family member or friend, 3) vision capable of reading printed text, and 4) a prosthesis that is as unobtrusive as possible. As a general high-level description, the Utah Artificial Vision system will consist of a micro-video camera hidden in a pair of eyeglasses to transform light in the visual scene into electrical signals, signal processing electronics to convert these signals into patterns of electrical stimulation for the brain as well as a power source carried in a shirt pocket, a totally implanted multichannel stimulator with power and data to be delivered to the implant system via a radio-frequency telemetry link, and an electrode array with 625 microelectrodes.
Work is ongoing at the John Moran Laboratories at the University of Utah to develop the cortically based visual prosthesis system described above. The program conducts research in the following broad areas:
The historical foundations for a cortically based visual prosthesis. The concept of cortically based artificial vision had its origins in studies of the functional architecture of the cerebral cortex that were started in the early twentieth century, and were pursued by Wilder Penfield. Penfield and Rasmussen observed the behavioral consequences of electrically stimulating various regions of cerebral cortex and noted that electrical stimulation of the surface of the visual cortex generally evoked the perception of points of light (called phosphenes) at specific regions in space. He also observed that the location of the phosphenes in front of the observer appeared to be deterministically related to the region of primary visual cortex which was being electrically stimulated (a ‘visuotopic’ organization). These preliminary observations on the visuotopic organization of visual cortex have been extended by many others using electrical stimulation of human visual cortex, by recording of receptive fields in primate visual cortex, and recently validated in humans with fMRI.
The observations of the visuotopic organization of electrically evoked phosphenes have led a number of investigators to propose that electrical stimulation of visual cortex via arrays of electrodes might provide the profoundly blind with a limited form of functional vision. Subsequent experiments in the late sixties and early seventies by Brindley, Dobelle, Pollen, and their co-workers demonstrated that a field of individual phosphenes could be evoked by stimulating visual cortex with an array of electrodes implanted subdurally over its surface. These studies confirmed the visuotopic organization of visual cortex, and demonstrated that subjects could assimilate information that was delivered to the visual cortex by electrical currents passed via groups of electrodes. Dobelle’s subjects were able to read phosphene evoked Braille characters at a faster rate than they could using their tactile sense. However, it was also learned that currents in the milliampere range were required to evoke individual phosphenes, and that currents passed through groups of electrodes that were spaced too close to neighboring electrodes produced highly non-linear interactions between the location and character of the evoked phosphenes. It became clear from these experiments that stimulating visual cortex via an array of surface electrodes would not be an effective means to produce a useful visual sense in individuals with total blindness.
Recent experiments by Schmidt et al. have caused renewed interest in cortically based visual neuroprosthetics. In their most recent experiments, they chronically stimulated visual cortex of a profoundly blind human volunteer with groups of microelectrodes that were designed to penetrate the cortex to the level of its normal thalamic input. The Schmidt et al. study is the most complete to date that explores the psychophysical percepts produced by intracortical microstimulation.
It has long been known that neural stimulation via penetrating electrodes occurs with electrical currents that are much smaller than those used to excite neurons via surface stimulation. Schmidt and his coworkers validated this observation and demonstrated that phosphenes could be evoked with currents that were orders of magnitude lower than those used with surface stimulation (their lowest thresholds were in the 1 to 10 microampere region). More importantly, they showed that simple patterned perceptions could be evoked by current stimulation via small groups of these microelectrodes (simple ‘lines’ were evoked by simultaneously stimulating a set of six electrodes that were close to each other). While their data was anecdotal (in that it came from a single subject), they also demonstrated that electrical stimulation of pairs of electrodes that were separated by 250 microns often evoked two discriminable percepts, while stimulation of electrodes separated by 500 microns almost always evoked two discriminable phosphenes. Unfortunately, the electrode arrays used by Schmidt et al. were too sparse to allow them to answer the key question upon which a cortical approach to artificial vision must be based: does patterned electrical stimulation via a high electrode count electrode array evoke discriminable patterned percepts, or nondiscriminable blobs of light? If this psychophysical experiment can be performed, and the former result maintains, the physiological foundation of cortically based artificial vision could be established.
In order to answer this critical question (and many others associated with phosphene psychophysics), researchers need a new class of tools: arrays of microelectrodes that can be safely implanted into the visual pathways, and that will allow periodic injections of electrical currents at many closely spaced sites. Such arrays could eventually also form the cornerstone of visual neuroprosthetic systems. It therefore is clear that progress in cortically based artificial vision systems is directly linked to progress in the development of high electrode count microelectrode arrays, and over the past decade, such arrays have been developed.
Because of the importance of the neural interface in a visual prosthesis, much of this section will focus on a penetrating cortical electrode array of our own design: the Utah Electrode Array, or UEA. We will discuss considerations that were used in its design, how the array can be implanted in the visual cortex, and its biocompatibility as revealed by histological and electrophysiological experiments. Finally, we will summarize psychophysical experiments we have performed that provide rough estimates about the number of electrodes that may be required to restore some functional vision in an individual with profound blindness.
The historical motivation behind much of what we have developed at the University of Utah has been to create experimental systems that will allow researchers to better understand the vertebrate visual system though electrophysiological and behavioral experiments. These systems have been used for many years, and we now look forward to applying them to study human psychophysical questions that directly relate to the development of a cortically based vision neuroprosthetic system.
A. Electrode Arrays
The cornerstone of a visual neuroprosthesis is the interface between the functioning neurons in the visual pathways and implanted devices that can selectively excite these neurons. The remaining elements in such a neuroprosthesis will require modifying existing technologies, and as such, are simply matters of engineering development. This neural interface must individually stimulate a very large number of neurons that have retained function even though more distal neurons have been irreparably damaged by the etiology of the blindness. This interface will bypass the malfunctioning distal components in the visual pathway and directly excite neural pathways that are proximal to the implant site. Recent work at the University of Utah (Jones, Campbell et al. 1992) , at the University of Michigan by Wise et al. (Hoogerwerf and Wise 1994) , and Stanford University (Kewley, Hills et al. 1997) has focused on the use of silicon as an electrode material from which high electrode count, penetrating electrode arrays can be fabricated. Silicon is highly biocompatible (Stensaas and Stensaas 1978; Yuen, Agnew et al. 1987; Schmidt, Horch et al. 1993) , can be micromachined using standard microfabrication technologies, and can incorporate integrated electronics. The Michigan and Stanford electrode arrays have been built to take advantage of the planar photolithographic manufacturing techniques used in the semiconductor industry, while the Utah arrays were designed ‘from the ground up’ to meet the needs of a neural interface for the cerebral cortex. As such, new manufacturing techniques had to be developed in order to build this device. These techniques have been described elsewhere (Jones, Campbell et al. 1992) .
The Utah Electrode Array (UEA), shown above, provides a multichannel interface to the visual cortex. It has a large number of 1.5mm long electrodes (typically 100 in a 10 x 10 square grid) that project out from a very thin (0.2mm) substrate and that are separated from each other by 0.4mm. The tips of the electrodes are metalized with platinum to facilitate electronic to ionic transduction. As the array’s substrate must rest on the cortical surface, minimizing its thickness (its super-cortical profile) was an important design consideration: if it was too thin, it might break upon insertion, if it was too thick, the dura and the skull would produce a constant downward force on the array, tending to push it into the cortex.
The large number of penetrating electrodes in the UEA presents a very large surface area to the cortex and the implanted array tends to ‘self anchor’ to the cortical tissues. Such an array has the strong advantage that it ‘integrates’ with the cortical tissues and, therefore, ‘floats’ with respect to the cranium. As the cortex moves due to respiration and blood pumping, or to displacements in the skeletal musculature, the array moves with it, thereby producing little or no relative motion between the electrode tips and the neurons near its active tips. This design feature therefore, produces an extremely stable interface with the surrounding neurons.
The penetrating electrodes in an implanted array must compromise as little cortical volume as possible (ideally zero). Thus, each needle must be made as slender as possible yet retain sufficient strength to withstand the implantation procedure. Further, consistent with concept of ‘blunt dissection’ used by neurosurgeons, these penetrating structures should displace the tissues they are inserted into rather than cut their way through them. Thus, the needle should be conical and have a very sharp tip rather than a planar or knife-like geometry. They must also be strong enough so that they are not deflected by the tissues they are inserted into. The needle electrodes in the UEA meet these criteria and are about 80 microns in diameter at their bases. They taper to a sharpened tip that has a radius of curvature of two to three microns. Shown below is an electron micrograph of the tips of these electrodes. Electrodes with these dimensions have been shown to be sufficiently strong to withstand insertion into materials that are considerably less compliant than cortical tissue (cork, balsa wood, even egg shell). These electrodes do not bend during the insertion process, and they only displace about 4% of the cortical volume into which they are inserted.
Each electrode is electrically isolated from its neighboring electrodes with a moat of glass that surrounds each electrode’s base. Each electrode has a bonding pad on the rear surface of the substrate. Conduction of signals along the length of the silicon needles is achieved by the doped silicon used in its fabrication. The entire electrode array (with the exception of the platinum coated tips) is insulated with a 2 micron thick coat of silicon nitride. An electrical connection is made to each electrode by bonding an insulated 25 micron diameter wire to each bond pad, and connecting these wires to a percutaneous connector. The rear of the array (with bonded lead wires) is encapsulated with a silicone elastomer. Electrode impedances (measured with a 100 nanoamp, 1 kHz sine wave current) are typically in the 100 to 500 kW range.
We have used both chronic and acute arrays in our experiments. The acute array has all 100 electrodes brought out to a small printed circuit board containing four, 26-pin IDC connectors. Our original chronic system had only eleven of the 100 potentially functional electrodes brought out to a Microtech connector via eleven, 25 micron diameter, platinum-iridium lead wires (the twelfth was a platinum-iridium reference wire). Our most recent design brings out 38 of the 100 electrodes to a custom made connector. The connector is integrated into a titanium pedestal that is mounted with titanium bone screws to the cranium. The figure below shows a photograph of this ‘tulip’ version of our chronic electrode assembly.
When we have received IRB approaval to perform human experimenation, the UEA will be used in most of our acute and chronic work. However, we will also conduct a series of acute experiments using our ‘Utah Slant Array’, or USA. These experiments will explore the relationship between phosphene thresholds and electrode shank length. The USA is ideally suited for these experiments, as it contains electrodes that vary in shank length from 0.5 mm to 1.5 mm. An electron micrograph of the USA is shown in the figure below. The USA is virtually identical in all aspects to the UEA, except in the varying length of the electrode shanks.
B. Surgical Issues: implanting high count electrode arrays
A cortically based visual prosthesis will be a highly invasive system that, eventually, must contain active integrated electronic circuitry. While relatively large electronic and mechanical systems have been implanted in the body (pacemakers, artificial joints, and the cochlear prosthesis), miniaturized devices of the mechanical and electronic complexity of the UEA have yet to be implanted on a long term basis in any part of the human body, much less the brain. Whether the implant site is intended to be the cortex or the retina (or the optic nerve (Veraart, Raftopoulos et al. 1998) , safe and effective surgical procedures that are cost-effective must be developed and validated in animal models before they are attempted in human volunteers.
The Utah researchers have developed new surgical techniques and tools that enable the UEA to be implanted in cortical tissues. Even though the individual electrodes of the UEA are extremely sharp, early attempts at implanting large numbers of them into the visual cortex only deformed the cortical surface and resulted in incomplete implantation. Further, the compression of the cortical surface produced by slow mechanical insertion can injure blood vessels, causing intracranial hemorrhage and cortical edema.
Because the brain is a viscoelastic material, it will behaves in a much more rigid fashion if the electrodes can be inserted into the cortex at a very high velocity. We have developed a unique surgical instrument based upon this concept that appears to circumvent the above mentioned problems: a system that rapidly inserts the UEA into the cortex (Rousche and Normann 1992) . A drawing of the pneumatically actuated insertion tool we have developed is shown below. Array insertion is achieved by a transfer of momentum between an accelerated piston, and an “insertion mass” that rests against the back-side of the electrode array which is to undergo implantation. When the momentum transfer takes place, the array is rapidly inserted into the cortical tissues in about 200 microseconds. The insertion is so rapid that the viscoelastic properties of the cortical tissues cause the cortex to experience only slight mechanical dimpling and the insertion is generally complete. Occasionally implantation of the UEA through surface vasculature is accompanied by a small amount of subpial bleeding, but this typically resolves itself, and single unit recordings of neural activity can often be made within hours after the surgical procedures are completed. The complete implantation procedure (from anesthesia induction to recovery) takes about four hours from initial incision to final closure.
C. Chronic histology
A neuroprosthetic system must be implanted into the nervous system and remain fully functional for periods that will eventually extend to many decades. This consideration places unique constraints on the architecture, materials, and surgical techniques used in the implementation of the neural interface. Inattention to any of these issues can result in chronic inflammatory responses around the implant site and generate a thick capsule surrounding each electrode. Because the UEA is a unique implantable structure, the consequences of its presence in the body for extended durations must be evaluated. We have studied its biocompatibility using basic histological and electrophysiological techniques.
The materials of which the UEA is built: silicon, silicon nitride, silicon dioxide, platinum, titanium, tungsten, and silicone are known to be well tolerated by the CNS (Stensaas and Stensaas 1978; Edell, Toi et al. 1992) . Our six month histological experiments support this notion (Schmidt, Horch et al. 1993) . The figures below show hematoxylin and eosin stained sections of such tissue. A thin capsule (2-5 microns thick) forms around each electrode track, but neuronal cell bodies are typically seen in close apposition to the electrode tracks (Turner, Shain et al. 1999) . In fact, in sections where the tracks are similar in diameter to blood vessels, it is often difficult to tell a track from a vessel. These figures illustrate that the electrodes of the UEA are not displaced laterally by the cortical tissues during implantation. The histological photographs below are examples of a particularly benign tissue response. However, we also have histological samples showing gliosis, buildup of fibrotic tissue between the array and the meninges, subtle array displacement in the cortex, and the presence of a small number of red blood cells (or hemosiderin) in some tracks. While the histology we have performed to date supports the use of the UEA in acute human experimentation, before we can consider its use in chronic applications, more work will be done to ensure that histological findings like those shown in the histology below can be achieved on every implantation. Specifically, while the hematoxylin and eosin stain has been useful in the gross cytological analyses we have performed to date, it is wholly inappropriate as the sole means of assessing biocompatibility. We must extend these studies and use immunofluorescent techniques for evaluating structures and specific cell types such as capillaries, astrocytes, macrophages, microglia, meningeal cells and endothelia, all of which have been shown to play a role in the brain host response to biomaterial implantation regardless of the material employed. Our preliminary histological observations with hematoxylin and eosin have been elaborated upon in a recent study by Maynard on the long term consequences of UEA implantation (Maynard, Fernandez et al. 2000) .
D. Neuronal recordings
Acute recording capability
An excellent index of the biocompatibility of a cortical implant is its ability to record single- and/or multi-unit activity from the neurons near the electrode tip for prolonged periods of time. If the materials used in the array, or the implantation techniques are not biocompatible, neuronal processes close to the electrode track will degenerate and it will not be possible to record single-unit activity. However field potential activity located far from the electrode tracks might still be recorded from functioning neurons, and such neurons may still be stimulated effectively in a neuroprosthetic application.
We have recorded responses from the UEA in both acute and chronically implanted animals to better understand its short and long term biocompatibility. Specimen responses with high, medium and low signal-to-noise ratios that were evoked by a bar of light moving across the receptive fields of visual cortical units are shown below. To generalize these findings, we have tabulated below the recording quality of our past 17 acute implants. In this table, we classified responses on each electrode using the scale in this figure.
Table legend. Recording statistics from our past 17 acute implants illustrating the mean and standard deviation of the number of electrodes with high, medium and low signal-to-noise ratios for each of the arrays. Minimum and maximum are the lowest and highest number of electrodes with the indicated quality of recording on each of the arrays. Some arrays had a few broken electrodes, so data is presented as percent of potentially functional electrodes.
In our best acute implantations, we have been able to record good single- and multi-unit responses from 68% of the electrodes (because of the curvature of the gyri in the cortex, it is not possible to implant all 100 electrodes in a given gyrus and some electrodes end up in sulci). More typically, however, we are able to record good quality single- and multi-unit responses from 36% of the electrodes in a given array. Global field potentials, non-discriminable multi-unit responses, and an absence of responses are recorded from the remaining electrodes.
Chronic recording capability
We have used chronic implantations of the UEA in visual and auditory cortex and motor cortex to better monitor the stability and long term biocompatibility of the UEA. We have recorded multi- and single-unit evoked activity and identified single-units (based on response kinetics) on many of our electrodes. We have been able to record single- and multi-unit responses for over three years (the longest intervals studied, see examples below). The presence of single- and multi-units on many electrodes, and the stability of these identified units over periods of months provides the most compelling evidence for the biocompatibility of the UEA.
E. Behavioral Experiments
Useful function will be achieved in a visual neuroprostheses by injection of electricalof electrical currents into the visual pathways through large numbers of electrodes. Current injections can produce short term and long term complications depending upon the levels of the currents that are injected (McCreery, Yuen et al. 1994) (or see Agnew, Ch6 for a review (Agnew and McCreery 1990) ). In order to determine the levels of current injections via the UEA that are required to evoke sensory percepts, we have conducted a series of behavioral experiments (Rousche and Normann 1998) . Ideally, these experiments would be performed with implants in visual cortex, but, because of the greater ease of providing auditory stimuli to a behaving animal, we targeted the auditory cortex as our implant site and used auditory stimulation rather than visual stimulation.
Three animals were trained over a one to two month period to lever press as a result of auditory stimulation, and auditory thresholds were measured. Trained animals that performed this task at 90% correct were chronically implanted with the UEA. Following implantation of the UEA, we interspersed current injections via the UEA and conventional auditory stimulation. Current injections that evoked auditory percepts should have resulted in a ‘positive’ lever press in the trained animals. The chronic percutaneous connectors used in these experiments had limited pin counts and permitted access to a total of only 22 of the active electrodes in these animals. Behavioral thresholds, measured on different electrodes as the amount of charge injected per phase of stimulation, ranged from 1.5 nC/phase up to 26 nC/phase. The average threshold, measured in 71 sessions was 8.9 nC/phase. The stability of four of these threshold measurements was recorded in one animal over a three month period. Over the 100 days monitoring interval, thresholds varied by no more than 50%. This provides an additional index of the biocompatibility of the “floating” array design.
F. Human Psychophysical Experiments: visual performance versus number of pixels
Before one can consider conducting experiments on human subjects that relate to a cortically based visual prosthesis, one should have some rough idea about how many electrodes would be required to restore a useful visual sense in a profoundly blind subject. We have performed a number of human psychophysical experiments with a pixelized vision simulator to get rough estimates of this number (Cha, Horch et al. 1992; Cha, Horch et al. 1992; Cha, Horch et al. 1992) . The simulator, shown to the right, is portable, and consists of a battery powered video camera and video monitor. The monitor is masked with one of a number of perforated foil masks that have from 100 to 4000 perforations. Using this simulator, six student volunteers were asked to read text out loud from a computer monitor, and, when trained, to navigate through a complex, programmable maze. After this task had been performed, our subjects were challenged to navigate through normal living environments.
We learned that reading and navigation performance improved as the number of pixels increased, but that it began to plateau at about 625 pixels (simulating a 25 x 25 array of phosphenes) (Cha, Horch et al. 1992; Cha, Horch et al. 1992; Cha, Horch et al. 1992) . The study also suggested that with as few as 100 pixels, trained subjects could navigate our maze without error, and that they could navigate in normal living environments, avoiding objects in their paths. While we fully appreciate the limitations of this simulation, it indicates that significant visual task performance could be achieved with modest amounts of visual input.
This past decade has seen a gradual shift in vision research from basic studies of the cell biology and neuroscience of the visual pathways to application of this knowledge base to restoring sight to the profoundly blind. This shift has taken two broad directions: human engineered or neuroprosthetic solutions, and biologically inspired solutions.
As this informational web-site is focused on the human engineered approach, recent progress in the biological approaches will only be described briefly below. Further, as Utah’s interests are focused on a cortical neuroprosthesis, this review of the retinal and optic nerve approaches will also be intentionally brief.
Retinal based visual neuroprosthetic research. Over the past few years, the research efforts of an increasing number of laboratories around the world have been committed to the development of a retinal based visual neuroprosthesis. The lay media has recently featured this work on television and in the press, and has created a great deal of public interest in the potential of this neuroprosthetic technology. This retinal approach has taken two basic directions: an epiretinal approach where an electrode array will be placed on the vitreal surface in an effort to stimulate ensembles of ganglion cells (or possibly bipolar cells), and a subretinal approach where an electrode array is intended to be implanted between the retina and the pigment epithelium and extrinsic currents are intended to stimulate either remnant photoreceptor inner segments, or bipolar cells.
The epiretinal approach is being aggressively pursued in America by teams at Harvard/MIT and at Johns Hopkins/the Mann Foundation. This approach is also being aggressively pursued in Germany with substantial financial support from the German government. While these teams have yet to publish their efforts to develop a long lasting and efficacious electrode array that could realistically be used as a chronic retinal implant, the American researchers have performed pilot retinal stimulation experiments in human volunteers. The Harvard/MIT and the Hopkins groups have shown that passing transretinal electrical currents can evoke visual percepts in individuals with retinitis pigmentosa, and both have shown that very simple patterned stimulation evokes elementary patterned percepts in these volunteers. The Harvard/MIT and the German epiretinal projects have also focused on developing surgical procedures that will ensure that the implant will be closely apposed to the retina (i.e., removal of all remnant vitreous humor without damaging the delicate retinal tissue). The German counterparts have also directed much of their efforts and research dollars on a ‘retinal encoder’ system that will be used to remap visual input into appropriate patterns of electrical retinal stimulation. Because of various non-visuotopic mapping problems, such a video encoding / neural stimulator system is likely to be needed in any visual neuroprosthesis system (retinal or cortical).
The subretinal approach was originally proposed by Chow in America, and it has been adopted by another German team led by Zrenner. The original idea suggested that a suspension of non-powered microphotodiodes could be inserted into the subretinal space, and that these photodiodes could passively replace the function of lost rods and cones by directly stimulating second order neurons in the retinal pathway. Chow and Zrenner have shown that flat silicon discs can be implanted subretinally, and have developed surgical techniques to achieve this. Recently, both groups seem to have come to understand that silicon photodiodes are many orders of magnitude less sensitive than rods and cones, exclusive of the difficulty of transducing electronic currents into ionic ones and of stimulating the remnant neurons. Both groups seem to be acknowledging that the subretinal implant must be externally powered. All players in the retinal game have begun working with a variety of in vivo and in vitro retinal models in their efforts to develop electrode arrays that can effectively and selectively stimulate retinal pathways.
An optic nerve based visual neuroprosthesis. A recent study has described phosphene generation via optic nerve stimulation. These experiments were conducted in a blind human volunteer who was chronically implanted with an extracellular ‘cuff’ electrode that surrounded the optic nerve, and which contained four surface electrodes. Stimulation with various current levels through different combinations of electrodes evoked a variety of spatially distributed phosphenes. However, the researchers were unable to obtain a rational visuotopically organized relation between stimulation parameters and evoked phosphenes. This approach may show promise if an ultra-high electrode count array of penetrating electrodes were to be implanted in the optic nerve. We have implanted an array of 100 electrodes with varying length shanks in the sciatic nerve (the ‘Utah Slant Array’, or ‘USA’). Because this array architecture distributes the active tips of the electrodes uniformly throughout the entire nerve, we were able to selectively drive individual muscle groups. Although principally engineered as a peripheral nerve interface, such an array might form the basis for an optic nerve based visual prosthesis.
The Pros and Cons of these human engineered approaches: Research in visual neuroprosthetics falls into the four general camps outlined above. Each has advantages and disadvantages that are summarized on the following page. It is clear that all four implant sites have common problems and advantages, and some that are unique. Arguments can be advanced in support of each approach. One common problem is that all approaches are expected to be most beneficial to those with acquired rather than congenital, complete blindness. However, the observation that a cortical approach might provide an effective therapy for most sources of blindness (and the only therapeutic approach for many) is a compelling argument to support this approach to a cortically based visual prosthesis.
Over the past decade, an increasing number of researchers have focused their research activities on biological approaches to sight restoration (or sight prolongation). One of the most encouraging approaches is transplantation of embryonic retina, stem cells, and pigment epithelial cells into the diseased retina. Other researchers are trying to supplement what are believed to be missing nutrients or growth factors to keep the retina from degenerating. As a number of pathological blindnesses such as retinitis pigmentosa (RP) have a genetic origin, a number of molecular biologists are also pursuing genetic approaches. We very briefly summarize progress in these areas below.
Current Status of Retinal Transplantation: Adult photoreceptors and retinal pigment epithelium (RPE) cells have been transplanted in the Royal College of Surgeons (RCS) rat. They have survived 2 months after transplantation and the transplanted photoreceptors appear to form synapses with second order neurons. RPE cell transplantation facilitated photoreceptor cell survival in the RCS rat in early transplants (10-17 days), however, after late transplantation no receptor rescue was observed. Human fetal RPE cells have been reported to rescue photoreceptors in RCS rats and rescued photoreceptors have been shown to have normal metabolism after RPE cell transplantation. Photoreceptors of 1 day old transgenic mice survived for 9 months after transplantation into the subretinal space of rd-mice. RPE has been implanted in human volunteers and some improvement in visual acuity was reported in three out of five patients. RPE transplantation was performed in age related macular degeneration (AMD) patients, however, no improvement in visual performance was observed.
Application of Growth Factors: While control injections of fluid into the subretinal space has been shown to decrease the rate of photoreceptor loss in the RCS rat, intravitreal injection of basic fibroblast growth factor (bFGF) in the RCS rat has been shown to decrease the rate of photoreceptor death. Further, injections of multiple growth factors, cytokines and neurotrophine have also been shown to rescue photoreceptors in light damaged retinas. A variety of other growth factors (bFGF, acidic fibroblast growth factor (aFGF), brain derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), and interleukin 1ß (1ß IL)) have also been shown to provide a short term rescue of photoreceptors.
Gene Therapy: The death of photoreceptors in the rd-mouse has been shown to be delayed by up to 6 weeks after subretinal transfection with ßPDE cDNA (Adenovirus). In another preliminary study, light sensitivity in rd-mouse was shown to improve after ßPDE cDNA transfection with an Adenovirus associated vector. In 1998, the ‘Retinal Gene Therapy Workshop’ was held at Emory University to review progress in this field. The conclusion of this workshop was that while the preliminary results are modest and encouraging, the approach is not yet ready for studies in human beings. The general conclusions of the workshop on the consequences of gene therapy were as follows. Retinal degeneration – retarded; Retinal function – preserved but not improved; Comparison of different gene delivery systems - not available; Long-term studies in animals - not available; and Sufficiency of current assays: limited.
It has long been hoped that these biological approaches will have applications to preservation of sight, but it is not clear if or when these approaches will become accepted therapies to the problem of blindness. We believe that the human engineered approaches are likely to have a shorter time to clinical trials, and could be providing effective therapies while the biological approaches are still in the basic science stage.
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