Tissue engineering applied to the retinal prosthesis: Neurotrophin-eluting polymeric hydrogel coatings

Abstract

Several groups are developing visual prostheses to aid patients with vision loss. While these devices have shown some success in the clinic, they are severely limited by poor resolution, and in many cases have as few as 15 electrodes. Pixel density is poor because high stimulation thresholds require large electrodes to minimize charge density that would otherwise damage the electrode and tissue. A significant contributor to high stimulation threshold requirements is poor biocompatibility. We investigated the application of one system popular in tissue engineering, drug-releasing hydrogels, as a mechanism to improve the tissue-electrode interface. Hydrogels studied (i.e., PEGPLA photocrosslinkable polymers) released neurotrophic factors (i.e., BDNF) known to promote neuron survival and neurite extension in the retina. Hydrogels were examined in co-culture with retinal explants for 7 and 14 days, at which time neurite extension and neurite density was measured. Neurite extension was enhanced in samples exposed to BDNF-releasing hydrogels at 7 days; however, these increases were absent by day 14 suggesting declining drug release. Thus, PEGPLA hydrogels are excellent candidates for short-term (< 14 day) acute release of therapeutic factors in the retina, but will require additional modifications for application with neural prostheses. Additionally, these results suggest that the effects of neurotrophic factors are short-lived in the absence of additional support cues, and tissue engineering systems employing such factors may only produce transient benefits to the patient.

Controlled delivery for neuro-bionic devices

“…All these capabilities are highly desirable for promoting the survival of auditory neurons and neurite outgrowth toward the electrode implant, especially the cochlear implant. Our study [41], as well as others [27], has revealed that the environmental cue via cell adhesion molecules is essential for achieving optimal effect of neurotrophin on neurite extension. Indeed, controlling the presentation of cell adhesion molecules has been seen as an important strategy to improve neural-implant interfaces [80,81,82,83,84].…”

“…This could be achieved by loading each well individually with a different and appropriately formulated bioactive molecule. The importance of complex biological cues in addressing electrode-neural interfacing has been increasingly recognised, and is also supported by recent studies that implied the short-lived effect of neurotrophins eluted from hydrogel coatings of neuroprosthetic devices, and the necessity of presenting other biological mechanisms in order to sustain the effect of eluted neurotrophins [27,28].…”

“…Three approaches are reviewed here. The first involves drug-eluting structures formulated with anti-inflammatory drugs [21,22,23,24,25] and neurotrophin-eluting hydrogels [26,27,28,29,30,31]. The second approach involves integration of microfluidic channels into neural prostheses for in situ delivery of bioactive molecules with high temporal and spatial resolution [32,33,34,35,36,37,38,39].…”

“…For example, biodegradable neurotrophin-eluting hydrogel coatings, based on poly(ethylene glycol)-poly(lactic acid) (PEGPLA), were developed for multi-electrode arrays with sputtered iridium oxide charge-injection sites [26,27]. This was achieved by applying the aqueous solution of PEGPLA precursor and neural growth factor (NGF)/brain-derived neurotrophic factor (BDNF) to the electrode array surface and inducing crosslinking via UV irradiation.…”

Using Polymer Chemistry to Modulate the Delivery of Neurotrophic Factors from Degradable Microspheres: Delivery of BDNF

“…The polymeric delivery via rods, scaffolds and microspheres has been reported to be relatively short (7-14 days) (3,12). Hydrogels have been shown to deliver BDNF for slightly longer (3-4 weeks) (13,14), but longer delivery is desirable for neuroprotection.…”