**2. Retina**

#### **2.1 Anatomy of the retina**

The retina is the innermost multilayered structure of the eye with an approximate thickness of 0.50 mm [40]. Retina first translates light into a biochemical message and then prepared biochemical messages converted into the electrical messages, cause to the visual information with transmitted to the primary visual cortex of the brain via the optic nerve.

The retina is composed of retinal pigment epithelium (RPE) and neuroretina, which is further divided into nine layers. Respectively, the neuroretina layer includes the outer and inner segments of photoreceptors (PL), outer limiting membrane, outer nuclear layer (ONL), outer plexiform layer (OPL), inner nuclear layer [41], inner plexiform layer (IPL), ganglion cell layer (GCL), nerve fiber layer (NFL) and inner limiting membrane (ILM) from nearest layer to choroid up to nearest layer to vitreous [40]. This part is consists of five types of neurons: the visual receptors cells (the rods and cones), the horizontal cells, the bipolar cells, the amacrine cells, and the retinal ganglion cells [42].

RPE with a function to absorb light is a monolayer of pigmented hexagonal cells which are denser in the macular area. Mostly, the interaction between RPE and photoreceptors has a significant effect on the ability of photoreceptors to detect light and convert the light into the electrical signals, which caused vision preparation [43]. RPE is separated from the choroid by the Bruch's membrane. As RPE is located between the outer segments of the photoreceptors and the vascular layer of the choroid, it has a two-directional function. RPE with transports ions, water, and

#### *Application of Nanowires for Retinal Regeneration DOI: http://dx.doi.org/10.5772/intechopen.90149*

with appropriate mechanical properties [19–22]. However, the first definition of tissue regeneration is developing scaffolds with acceptable biocompatibility to implant in the host body to repair damaged tissues or organs. Therefore, the electrospun nanofibers with a high ratio of surface-to-volume, tunable porosity, and similarity to natural EMC show the ability to modify the surface functions with different structures for a wide range of tissue regeneration [23]. Nanofibers have emerged as a potential to simulate the ECM in many tissues such as bone [10], nerves [24], and various techniques have been employed to fabricate the nanofibers

As extracellular electrical simulation involves in neuroscience and neural tissue engineering [26–28], attention is focused on nanowires applications for visual neural system [29–31], brain [32, 33] and cardiac [34]. Nanowires have recognized as widely used nanostructure for the cell microenvironment where the electrodynamic properties [35] have permanently affected cellular functions, such as morphology, adhesion, differentiation, and proliferation [36]. As a consequence, researchers have developed new structures for better electroconductivity, biocompatibility, and

Nanowires have been shown that simulate the nerve signals in the retina and transfer between the layers could improve the vision loss by the damaged retina. To explain the recovery of vision with nanowires, which lost by retinal degeneration, we will begin by describing the retinal anatomy, and how various retinal disorders may cause blindness. Then we will investigate the nanowires which could enhance retinal organization with sensing light and converting it to the electrochemical signals with different materials, structures, and properties. Finally, we will discuss the challenges ahead and prospect in the application of nanowires for recovery of

The retina is the innermost multilayered structure of the eye with an approximate thickness of 0.50 mm [40]. Retina first translates light into a biochemical message and then prepared biochemical messages converted into the electrical messages, cause to the visual information with transmitted to the primary visual

The retina is composed of retinal pigment epithelium (RPE) and neuroretina,

RPE with a function to absorb light is a monolayer of pigmented hexagonal cells

which are denser in the macular area. Mostly, the interaction between RPE and photoreceptors has a significant effect on the ability of photoreceptors to detect light and convert the light into the electrical signals, which caused vision preparation [43]. RPE is separated from the choroid by the Bruch's membrane. As RPE is located between the outer segments of the photoreceptors and the vascular layer of the choroid, it has a two-directional function. RPE with transports ions, water, and

which is further divided into nine layers. Respectively, the neuroretina layer includes the outer and inner segments of photoreceptors (PL), outer limiting membrane, outer nuclear layer (ONL), outer plexiform layer (OPL), inner nuclear layer [41], inner plexiform layer (IPL), ganglion cell layer (GCL), nerve fiber layer (NFL) and inner limiting membrane (ILM) from nearest layer to choroid up to nearest layer to vitreous [40]. This part is consists of five types of neurons: the visual receptors cells (the rods and cones), the horizontal cells, the bipolar cells, the

with excellent properties [25].

*Regenerative Medicine*

cell adhesion [37–39].

**2. Retina**

**120**

vision that lost by retinal destruction.

cortex of the brain via the optic nerve.

amacrine cells, and the retinal ganglion cells [42].

**2.1 Anatomy of the retina**

metabolic products from the subretinal space to the blood and receiving nutrients such as glucose and retinol from the blood to nourish the photoreceptors playing the critical role in the retina layer. However, failure in mentioned functions can lead to retinal degeneration, visual loss, and eventually blindness [43].

PL is the only light-sensitive part of the neuroretina and is composed of outer and inner segments of the rod and cone cells. Cone cells are responsible for color detection and are found in high number in the macula, especially foveal region, whereas rods are more active in the dark and are abundant in the peripheral retina. OLM layer separates PL from the photoreceptor nuclei, and it is not considered as an actual layer. ONL contains the nuclei of photoreceptors, and its thickness varies across the retina with the maximum thickness at the fovea. However, the axons of the photoreceptors cells and their synapses with bipolar and horizontal cells form the OPL. On the other hand, cell bodies of horizontal cells, bipolar cells, amacrine cells, and Muller glial cells are in the INL layer. The INL layer, playing the critical role to transmit inputs signals from IPL to OPL, which is composed of synapses between the bipolar, ganglion, and amacrine cells. The innermost layer of the retina is GCL and located in the place near to the vitreous and contains the cell bodies of ganglion cells and displaced amacrine cells, astrocytes, and Muller cell bodies that their axons converge on the way to the optic disc and form NFL. The latest layer of the retina is ILM, which forms the inner boundary of the retina on the vitreous side. **Figure 1** is showing the retinal layer that divided into nine layers with nine different cell type [40].

The macula is a region inside the retina which contains the highest number of ganglion cells and cause the optimal vision and color perception process [44]. Rods and cones are responsible for the initiation of the scotopic and photopic visual processing, respectively. When the light absorbed by photoreceptors, rod, and cone cells with releasing glutamate as a neurotransmitter cause to transfer the electrical signals from synapse onto the bipolar cells at the OPL layer. Afterward, transferring

#### **Figure 1.**

*The anatomy of retina from outer layer (up) to inner layer (down) is containing of retinal pigment epithelium (RPE), outer segment of photoreceptors (OS), outer nuclear layer (ONL), outer plexiform layer (OPL), inner nuclear layer [41], inner plexiform layer (IPL), ganglion cell layer (GCL), inner segments of photoreceptors (IPL), optic fiber layer (OFL), and inner limiting membrane (ILM) from nearest to choroid to nearest to vitreous, respectively. The retina is consist of nine cell line consisting of rod photoreceptor (R), cone photoreceptors (C), horizontal cells (HC), bipolar cells (BC), amacrine cells (AC), displaced amacrine cells (dAC), retinal ganglion cells (RGC), Muller cells, and astrocyte cells (Astro) [2].*

the electrical signals from bipolar cells synapse by amacrine and ganglion cells at the IPL to the axons of the ganglion cells lead to the output neurons signals formation as the optic nerve and deliver the visual information to the brain [45].

combined with polymers as well as poly (e-caprolactone) cast onto anodized

Gallium phosphide is another example of materials have been employed for the regeneration of retinal. Gallium phosphide as multimodel nanowire employed for different geometries such as rod and cone photoreceptor, ganglion cells, and bipolar cells [56]. Also, the same structure coated with poly-L-ornithine showed that nanowires have significant potential on morphology, adhesion, and metabolism of

The nanostructures designs based on silicone, to simulate the retina photorecep-

tor was improved by nanomaterials coating as well as gold and titanium oxide nanoparticles [59]. Whereas, silicon nanowires have been shown to form spontaneous conjunction with photoreceptor cells. Such nanostructures showed that they could improve the quality of photoreceptor simulation and increase cell adhesion to

Silicon nanowires coated with gold were shown to be more effective at the simulation of photoreceptors; this is mostly attributed to the higher surface to the area for sensing light and charge transfer [61, 62]. Another type of nanostructures is thin films functionalized with the nanoparticle to sense light. Thine film structures were able to simulate cultured photoreceptors when subjected to direct visible

In addition to sense light, nanowires can use for transferring the electrical signals

through the cells such as rode and cone cells [66]. One way for transfer signals between the nanostructures and cells is to simulate solar panels structure in nanosize via materials such as *n-type* and *p-type* silicon, which can sense the light and convert the light signals into the electrical signals. In particular, silicon nanowires are useful to sense light and transfer the signals to the internal layer of

The architecture of nanowires has been clarified as complex core-shell nanowires with complex chemical profiles. These advanced structures have been

**Nanowire Forms Length (μm) Modification Refs** Iridium wire Pillar array electrode 75 Embedded with glass [66]

Gallium phosphide Nanowire 0.5–4 Gold nanoparticles [56] Parylene/silicon Silicon tip Not reported Platinum and gold tine film [59]

*n-type* silicon Nanowire Not reported Gold/palladium nanoparticles [60] Titanium dioxide Nanowire Not reported Gold nanoparticles [67]

*The materials have been used to prepare the nanowires structure for retinal implant applications.*

Nanowire 2.5–27.5 Cast onto anodized aluminum

Short nanowire 2.5 Electrospinning method [55]

Coaxial nanowire Not reported Gold nanoparticles [69]

Not reported Gold/palladium nanoparticles,

oxide template

nanowires coated with poly-L-ornithine

20 Coated by polyimide [62]

[53]

[57]

aluminum oxide template, have been used for retinal regeneration

cells in comparison to the flat surface [57, 58].

*Application of Nanowires for Retinal Regeneration DOI: http://dx.doi.org/10.5772/intechopen.90149*

the retina to recover the eyesight [67, 68].

Gallium phosphide Functionalized

Silicon Nanowire/

nanowire

microelectrode

the nanowires when placed in direct contact with cells [60].

applications [53–55].

light [50, 63–65].

Poly

Poly

(e-caprolactone)

(e-caprolactone)

*n-type*/*p-type* silicon

**Table 1.**

**123**

#### **2.2 Retinal pathology**

It is reported that half of the blindness in the world is related to the various retinal damages. Degenerative damages such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP), optic neuropathy such as glaucoma and vascular retinopathy as well as diabetic retinopathy (DR) are the most common retinal diseases and the leading causes of legal blindness [46].

AMD is an age-related retinal problem occur in two forms of dry and wet. The dry form is mainly diagnosed by drusen and extracellular materials deposition such as lipids and proteins which accumulate in Bruch's membrane, and loss of photoreceptors by geographic atrophy of the macula. However, wet form or neovascular/ exudative AMD is diagnosed by choroidal neovascularization (CNV), blood vessel development and hemorrhage/leakage of blood and fluid accumulation into the neural retina which can lead to the RPE detachment. The hallmark of AMD is the degeneration of neurons in the macula, which may result in central vision loss at the early stage of the disease [47].

RP refers as a hereditary and neurodegenerative disease of the retina may appear in different forms. The outcome in all forms is photoreceptor degeneration and subsequently, cell death. Photoreceptor degeneration starts from the periphery of the retina, which progressively decreases the visual field and consequently makes a tunnel vision for the patient. Vision impairments in RP will start with rod photoreceptors and followed by cone photoreceptors degeneration that latter can lead to alteration and abnormalities in the RPE [48].

Glaucoma is the most common optic nerve disease that can lead to blindness. Glaucoma with increasing the intraocular pressure may cause retinal ganglion cells degeneration. However, disorders in the retinal nerve fiber layer and optic nerve proceed during glaucoma and will lead to irreversible vision loss if the treatment is not appropriate [49].

DR as vascular retinopathy is another cause for blindness in the worldwide which divided into type-one and type-two. There is evidence for possible dysfunction of Muller cell during diabetic neuropathy [50]. DR is classified into the proliferative stage with loss of blood supply and non-proliferative stage with altered retinal vascular permeability, intraretinal microaneurysms, and macular edema [51].

There is no definite cure for retinal diseases, and most of them end up with severe visual impairment or blindness. Current medical treatments may help to decrease the progression of the disease and are unable to cure them. Therefore there is a need for novel approaches to target restoring partial vision by preparing the advanced structure as well as nanowires and nanomedicines.

#### **3. Structure and overview of nanowires**

Nanostructures could be useful to follow the development of advanced structures for retinal applications where functionality depends on materials properties. Moreover, the combination of scaffolds with existing nanomaterials may improve the required functions [52]. In a recent study, nanowires with various structures have been used for regeneration of retina. The synthesis and fabrication of nanowires, with a narrow range of subtracting such as gold and TiO2 nanoparticles *Application of Nanowires for Retinal Regeneration DOI: http://dx.doi.org/10.5772/intechopen.90149*

the electrical signals from bipolar cells synapse by amacrine and ganglion cells at the IPL to the axons of the ganglion cells lead to the output neurons signals formation as

It is reported that half of the blindness in the world is related to the various retinal damages. Degenerative damages such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP), optic neuropathy such as glaucoma and vascular retinopathy as well as diabetic retinopathy (DR) are the most common

AMD is an age-related retinal problem occur in two forms of dry and wet. The dry form is mainly diagnosed by drusen and extracellular materials deposition such as lipids and proteins which accumulate in Bruch's membrane, and loss of photoreceptors by geographic atrophy of the macula. However, wet form or neovascular/ exudative AMD is diagnosed by choroidal neovascularization (CNV), blood vessel development and hemorrhage/leakage of blood and fluid accumulation into the neural retina which can lead to the RPE detachment. The hallmark of AMD is the degeneration of neurons in the macula, which may result in central vision loss at the

RP refers as a hereditary and neurodegenerative disease of the retina may appear

Glaucoma is the most common optic nerve disease that can lead to blindness. Glaucoma with increasing the intraocular pressure may cause retinal ganglion cells degeneration. However, disorders in the retinal nerve fiber layer and optic nerve proceed during glaucoma and will lead to irreversible vision loss if the treatment is

DR as vascular retinopathy is another cause for blindness in the worldwide

There is no definite cure for retinal diseases, and most of them end up with severe visual impairment or blindness. Current medical treatments may help to decrease the progression of the disease and are unable to cure them. Therefore there is a need for novel approaches to target restoring partial vision by preparing the

Nanostructures could be useful to follow the development of advanced structures for retinal applications where functionality depends on materials properties. Moreover, the combination of scaffolds with existing nanomaterials may improve the required functions [52]. In a recent study, nanowires with various structures have been used for regeneration of retina. The synthesis and fabrication of

nanowires, with a narrow range of subtracting such as gold and TiO2 nanoparticles

which divided into type-one and type-two. There is evidence for possible dysfunction of Muller cell during diabetic neuropathy [50]. DR is classified into the proliferative stage with loss of blood supply and non-proliferative stage with altered retinal vascular permeability, intraretinal microaneurysms, and

advanced structure as well as nanowires and nanomedicines.

**3. Structure and overview of nanowires**

in different forms. The outcome in all forms is photoreceptor degeneration and subsequently, cell death. Photoreceptor degeneration starts from the periphery of the retina, which progressively decreases the visual field and consequently makes a tunnel vision for the patient. Vision impairments in RP will start with rod photoreceptors and followed by cone photoreceptors degeneration that latter can lead to

the optic nerve and deliver the visual information to the brain [45].

retinal diseases and the leading causes of legal blindness [46].

**2.2 Retinal pathology**

*Regenerative Medicine*

early stage of the disease [47].

not appropriate [49].

macular edema [51].

**122**

alteration and abnormalities in the RPE [48].

combined with polymers as well as poly (e-caprolactone) cast onto anodized aluminum oxide template, have been used for retinal regeneration applications [53–55].

Gallium phosphide is another example of materials have been employed for the regeneration of retinal. Gallium phosphide as multimodel nanowire employed for different geometries such as rod and cone photoreceptor, ganglion cells, and bipolar cells [56]. Also, the same structure coated with poly-L-ornithine showed that nanowires have significant potential on morphology, adhesion, and metabolism of cells in comparison to the flat surface [57, 58].

The nanostructures designs based on silicone, to simulate the retina photoreceptor was improved by nanomaterials coating as well as gold and titanium oxide nanoparticles [59]. Whereas, silicon nanowires have been shown to form spontaneous conjunction with photoreceptor cells. Such nanostructures showed that they could improve the quality of photoreceptor simulation and increase cell adhesion to the nanowires when placed in direct contact with cells [60].

Silicon nanowires coated with gold were shown to be more effective at the simulation of photoreceptors; this is mostly attributed to the higher surface to the area for sensing light and charge transfer [61, 62]. Another type of nanostructures is thin films functionalized with the nanoparticle to sense light. Thine film structures were able to simulate cultured photoreceptors when subjected to direct visible light [50, 63–65].

In addition to sense light, nanowires can use for transferring the electrical signals through the cells such as rode and cone cells [66]. One way for transfer signals between the nanostructures and cells is to simulate solar panels structure in nanosize via materials such as *n-type* and *p-type* silicon, which can sense the light and convert the light signals into the electrical signals. In particular, silicon nanowires are useful to sense light and transfer the signals to the internal layer of the retina to recover the eyesight [67, 68].

The architecture of nanowires has been clarified as complex core-shell nanowires with complex chemical profiles. These advanced structures have been


#### **Table 1.**

*The materials have been used to prepare the nanowires structure for retinal implant applications.*

made from *n-type* and *p-type* silicon for making connections between the membranes of live bipolar cells and nanowires to sense the light for the recovery of vision [69]. **Table 1** represents the materials have been used as nanowires for vision recovery lost due to retinal disorders.

Recently, Kharaghani and co-workers [76] reported a study emphasizing the importance of morphogenesis in the three-dimension (3D) nanofibers scaffold structure in guiding the seeded cells for ophthalmic tissue engineering mainly for cornea and retinal applications. The necessities for using scaffolds in ophthalmic tissue engineering are cell adhesion besides to tensile strength, effectiveness on cell morphology, and topography of scaffolds [76]. This report stressed the significance of the underlying ECM in endorsing exclusive micro and nanoenvironments that fosters tissue regeneration. However, it is unfortunate that there is no report about the study of ECM simulation by nanowires or surface chemistry of nanowires that shows cell adhesion, where it is used for retinal regeneration. At the moment, all reports have been used the single nanowire for the regeneration of retina.

In attempts to control the cell adhesion on nanowires, researchers repopulated their strategy to change the surface chemistry nanowires prepared based on titanium, silicon, and zinc [77–79]. However, the in vitro and in vivo researches have been don around the regeneration of retina by nanowires, and results show that cells tended to encompass. Also, it should be happening due to electrical stimulation

It is mentioned here earlier that converts light into the neural signals and transfer neural signals to the brain by retina will lead to visual perception. Extracellular electrical involving ion channels has a vital role in nervous systems such as the retina. Photovoltaic polymers such as silk have been shown the great potential to use a connection between the layer of the retina to restore the vision with transfer the electrical signals [80]. The intracellular voltage is one of the unknown metrics that many types of research have been focused on recording signal strength use a nanoscale electrode as well as nanowires. Nanowires have been shown the tremendous potential upon extracellular electrical stimulation of cells to promote cell growth, adhesion, and differentiation. Also, Vodovnik and coworkers showed that the external electrical field had a significant effect on the polarization of cells on the

On the other hand, the positive and negative charge should be optimized for the

Among the various nanostructures, gold nanoparticles due to high electroconductivity, biocompatibility, and chemical inertness have been attracting the attention to develop scaffolds for neural systems such as retinal applications. However, it is unfortunate that the development of high-quality gold nanowires faces challenges in the absence of robust methods for synthesis. Nevertheless, the gold nanoparticle with the electrical resistance of 52 Ω is one of inseparable part of scaffolds have been used for retinal applications as reported in **Table 1**, which gold

In an attempt to design an implantable electronic device for regeneration of retina when photoreceptors are damaged, electrically stimulate of retinal neurons, become an essential challenge. Whereas, several retinal prostheses are going on, but none of them have shown the ability to evoke phosphenes in blindness. Refer to retinal anatomy controlling the signal impedance is the most crucial subject to

clinical implant to achieve successful results. The cationic polymers and nanoparticles with high concentrations of nitrogen may help to compaction of negative charge DNA and RNA and lead to better gens protection and endosomal escape in addition to high transaction efficiency and stability [2]. **Figure 3** is showing how nanowires with simulating the extracellular electric could cause cell adhesion to the nanowires and effect on the recovery of vision after implantation

nanoparticles have embedded with nanowire structures [61].

of place based on the extracellular electrical.

*Application of Nanowires for Retinal Regeneration DOI: http://dx.doi.org/10.5772/intechopen.90149*

cathodal and anodal side of the electrode [81].

in mice eye.

**125**

**4.2 Extracellular electrical simulation**
