gabriel a. silva- nanotechnology approaches for the regeneration and neuroprotection of the central...

8/3/2019 Gabriel A. Silva- Nanotechnology approaches for the regeneration and neuroprotection of the central nervous system

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Nanotechnology approaches for the regeneration and neuroprotection ofthe central nervous system

Gabriel A. Silva, MSc, PhD*

Departments of Bioengineering and Ophthalmology, Whitaker Institute for Biomedical Engineering,

and Neurosciences Program, University of California, San Diego, CA 92037-0946, USA

Received 16 June 2004; accepted 28 June 2004

Abstract Nanotechnology is the science and engineering concerned with the design, synthesis, and

characterization of materials and devices that have a functional organization in at least 1 dimension

on the nanometer (ie, one-billionth of a meter) scale. The ability to manipulate and control

engineered self-assembling (ie, self-organizing) substrates at these scales produces macroscopicphysical and/or chemical properties in the bulk material not possessed by the constituent building

block molecules alone. This in turn results in a degree of functional integration between the

engineered substrates and cellular or physiological systems not previously attainable. Applied

nanotechnology aimed at the regeneration and neuroprotection of the central nervous system (CNS)

will significantly benefit from basic nanotechnology research conducted in parallel with advances in

cell biology, neurophysiology, and neuropathology. Ultimately the goal is to develop novel

technologies that directly or indirectly aid in providing neuroprotection and/or a permissive

environment and active signaling cues for guided axon growth. In some cases, it is expected that the

neurosurgeon will be required to administer these substrates to the patient. As such, in order for

nanotechnology applications directed toward neurological disorders to develop to their fullest

potential, it will be important for neuroscientists, neurosurgeons, and neurologists to participate and

contribute to the scientific process alongside physical science and engineering colleagues. This

review will focus on emerging clinical applications aimed at the regeneration and neuroprotection of

the injured CNS, and discuss other platform technologies that have a significant potential for being

adapted for clinical neuroscience applications.

D 2005 Elsevier Inc. All rights reserved.

Keywords: Nanotechnology; Neuroprotection; Neuroregeneration; CNS; Bioengineering; Stem cells

1. Introduction

Nanotechnology is in a broad sense the science and

engineering concerned with the design, synthesis, character-

ization, and application of materials and devices that have a

functional organization in at least 1 dimension on thenanometer (ie, one-billionth of a meter) scale, ranging from

a few to about 100 nm. A nanometer is 3 orders of

magnitude smaller than a micrometer, 109 vs 106,

respectively, and is roughly the size scale of molecules

(eg, a DNA molecule is about 2.5 nm long, whereas a

sodium atom is about 0.2 nm). In particular, the potential

impact of self-assembling nanotechnology on science,

custom-made molecules that self-assemble or self-organize

into higher-ordered structures in response to a defined

chemical or physical cue, including applications to biologyand medicine, stems from the fact that these nanoengineered

materials and devices exhibit bulk mesoscale (ie, midrange

scale between micro and macro) and macroscale chemical

and physical properties not possessed by the constituent

nanoscale building block molecules on their own. This is an

emergent property because engineering materials and

devices at the nanometer scale imply controlled manipu-

lation of the individual constituent (nanoscale) units and

thus (at least in part) control over their molecular synthesis

0090-3019/$ see front matterD 2005 Elsevier Inc. All rights reserved.

doi:10.1016/j.surneu.2004.06.008

* University of California, San Diego, Jacobs Retina Center 0946,

9415 Campus Point Dr, La Jolla, CA 92037-0946. Tel.: +1 858 822 4591;

fax: +1 858 534 7985.

E-mail address: [email protected].

Surgical Neurology 63 (2005) 301306

www.surgicalneurology-online.com


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and assembly. As such, applications of nanotechnology to

medicine and biology allow the interaction and integration

of cells and tissues with nanoengineered substrates at a

molecular (ie, subcellular) level with a very high degree of

functional specificity and control.

This article represents the second in a series in Surgical

Neurology dedicated to reviewing emerging applications of

nanoscience and nanotechnology to clinical neuroscience.

The first article (Surg Neurol. 2004;61:216-220) provided

an introduction to nanotechnology, an overview of synthesis

approaches, some of the main technical challenges asso-

ciated with developing nanotechnology applications, and a

discussion of applications geared toward different areas of

medicine and biology. This article will describe emerging

applications of nanotechnology aimed at the neuroprotec-

tion and functional regeneration of the CNS after traumatic

or degenerative insults. In addition, other developing

platform technologies are discussed, which may prove to

have broad applications to medicine and physiology,

including some being developed for rescuing or replacinganatomical and/or functional CNS structures.

2. Applications of nanotechnology to the central

nervous system

Clinical nanotechnology applications to the central

nervous system (CNS) are further behind applications to

other areas of medicine and biology, such as, for example,

orthopedic applications, DNA/genomic sensors, and novel

drug and gene delivery approaches (see, eg, Refs.

[1,14,26,27,40,41,45,52,72,73,87]). (The one exception to

this are approaches for drug delivery across the blood-brainbarrier [20,35,36,44], which will be the subject of the next

paper in this series.) This is in part because of some of the

unique challenges imposed by the CNS such as restricted

and difficult anatomical access, an extremely heterogeneous

cellular and molecular environment, and the complexities of

the systems anatomical and functional bwiringQ and

associated information processing. Despite these challenges,

the potential benefits of nanotechnologies for the treatment

of both peripheral and CNS disorders are tremendous and

may eventually offer the patient and clinician novel

therapeutic choices that simply do not exist today. True to

the highly interdisciplinary nature of this area of research, it

is important that technological advancements occur inconjunction with basic and clinical neuroscience advance-

ments. Therefore, three things must occur in parallel for

nanotechnology applications in neurology and neurosurgery

to come to fruition: (1) advancements in chemistry and

materials science that produce ever more sophisticated

synthetic and characterization approaches; (2) advance-

ments in the molecular biology, neurophysiology, and

neuropathology of the nervous system; and (3) the design

and integration of specific nanoengineered applications to

the nervous system which take advantage of the first two

points. As these areas develop in an integrated and parallel

fashion, nanotechnology-based applications for nervous

system disorders should start to reach the clinic.

3. Neuroprotection

Free radical mediated injury is known to play a major role

in the disease process of ischemic, traumatic, and degener-

ative disorders in the CNS [8,19,43,46,49,60,64,82,85].

Chemical species such as superoxide (O2d), hydroxyl(dOH), peroxynitrite (ONOO), and peroxide (H2O2) canproduce a host of oxidative mediated deleterious changes in

cells, including DNA fragmentation, peroxidation of cell

membrane lipids, decreased mitochondrial energy produc-

tion, and transporter protein inactivation [16,46,64,85]. One

approach being developed to deal with this is the develop-

ment of carbon-60 fullerene-based neuroprotective com-

pounds [15-17,28]. Fullerenes are molecules composed of

large 3-dimensional arrays of evenly spaced carbon atoms,

similar to the pattern produced by the rhombuses on a soccer

ball. Fullerenols are hydroxyl (ie, OH) functionalized full-erene derivatives (Fig. 1) and have been shown to possess

antioxidant and free radical scavenger properties that are able

to reduce glutamate-, NMDA-, AMPA-, and kainite-induced

excitotoxic and apoptotic cell death (Table 1) [15-17,28].

The mechanism of fullerenol-mediated neuroprotection is

due at least in part to inhibition of glutamate channels, since

neither GABA(A) or taurine receptors were affected. In

addition, fullerenols appear to lower glutamate-induced

increases of intracellular calcium concentrations, a critical

mechanism of excitotoxicity in neurons [15-17,28].

Other approaches for neuroprotection, including pharma-

cological, gene therapy, and physiological, continue to bevery active areas of research with significant clinical

potential [2,24,25,30,32,33,51,53,57,61,70,79]. Fullerenols

compliment these approaches by representing novel syn-

thesis methods for the development of new neuroprotective

compounds based on the controlled chemical manipulation

and functionalization of these highly ordered synthetic

Fig. 1. Representative structure of a neuroprotective fullerene derivative

functionalized with carboxylic acid groups attached to the cyclopropane

carbons of the C60 molecule. Adapted from Dugan et al. Reprinted with

permission from Parkinsonism Relat Disord. 2001;7:243-246.

G.A. Silva / Surgical Neurology 63 (2005) 301306302


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structures. Given the proposed mechanism of fullerenol-

induced neuroprotection, it will be interesting to see what

clinical applications develop for secondary injury following

traumatic CNS disorders.

4. Neuroregeneration

The authors postdoctoral work in collaboration with

colleagues focused on nanotechnology approaches for CNS

regeneration after spinal cord injury and neural retinal

degeneration [71,76-78]. Peptide amphiphile molecules, that

is, peptide-based molecules with a hydrophobic tail andhydrophilic head group, were designed to self-assemble into

a network of nanofiber scaffolds only when present in

physiological ionic conditions [22,23,54]. The surface of the

nanofibers, made up of the hydrophilic head groups of

aligned peptide amphiphile molecules, consisted of physio-

logically active peptide sequences designed to engage in cell

signaling by acting as ligands for cell surface receptors. In

our case the main peptide sequence we explored was the

neuron-specific extracellular matrix laminin-derived

sequence isoleucine-lysine-valine-alanine-valine (IKVAV)

[76-78], which is known to promote the growth and

development of neurites [11,12,29,39,47,59,81,84,86]. The

peptide amphiphile molecules existed in a solution of water

until they encountered physiological concentrations of

cations such as calcium, which triggered their self-assembly

into nanofibers that bheldQ the water molecules in place,

macroscopically forming a gel-like substrate. Because of

this unique property, we were able to encapsulate neural

progenitor cells or neural retinal cells in these gels by

mixing cell culture suspensions with peptide amphiphile

solutions, trapping the cells in the interior of the gels.

Because the functional peptide sequence formed the outer

surface of the nanofibers, it allowed the functional signalingof encapsulated cells in three dimensions.

The results were quite dramatic (Fig. 2), and in the case of

encapsulated neural progenitor cells included faster and

more robust differentiation into mature neuronal phenotypes

compared with controls. By 1 and 7 days in vitro, 30% and

50%, respectively, of the neural progenitor cells expressed

the mature neuron markerb-tubulin III [76]. We were also

surprised to observe almost a complete exclusion of

astrocyte development in these cultures (less then 1% and

5% at 1 and 7 days in vitro, respectively [76]) despite the

multipotent nature of the progenitor cells. This suggests

Table 1

Protective effects of C60 derivatives in biological model systems

Compound System Injury condition Results References

In vitro Carboxyfullerene

C3, D3

Cortical neuronal

cultures

Excitotoxicity:

NMDA and AMPA

60%-90% A in death [2], Fig. 2A

Fullerenols [3]

C3 Same Apoptosis-induced

serum by deprivation

50% A in death [2]

Fullerenols [3]

C3 Same Ab1-42 toxicity Complete protection [3]

C3 Same Oxygen-glucose

deprivation

80% A in death [3]

C3 Same Apoptosis after

NMDA receptor

blockade

50% A in death Kim-Han J.S.

and Dugan L.L.,

unpublished data

C3 Mesencephalic

dopaminergic

neuronal cultures

MPP+ 40% A in death [7], Fig. 2B

C3 Same 6-Hydroxydopamine Complete protection [7], Fig. 2B

C3 Cerebellar granule

neuronal cultures

Apoptosis induced

by NGF withdrawal

Partial protection [1]

C3 and D3 Hepatoma cells TGFb-induced death Partial protection [5]

C3 Epithelial cells Radiation Partial protection [10]In vivo C3 FALS mice

(with SOD1

G93A mutation)

Progressive motor

deterioration/death

produced by

overexpression of

mutant protein

Improved motor

performance, 9-

to 12-day increased

survival

[2,4]

C3 Rats 6-OHDA intrastriatal

lesioning (systemic C3)

Preserved

dopaminergic terminals

and behavior

[8]

C3 Rats Iron-induced striatal

dopamine depletion

(intrastriatal C3)

Partial preservation

of striatal dopamine

[6]

AMPA indicates a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; FALS, familial amyotrophic lateral sclerosis; MPP, massive periretinal proliferation;

NGF, nerve growth factor; NMDA, N-methyl-D-aspartate; OHDA, Hydroxypamine; SOD1, copper/zinc superoxide dismutase; TGF, transforming growth

factor. Adapted and reprinted with permission from Dugan et al. Parkinsonism Relt Disord 2001;7:243-6.

G.A. Silva / Surgical Neurology 63 (2005) 301306 303


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novel approaches for limiting the effects of reactive gliosis

and glial scarring after traumatic or degenerative events by

transplanting donor cells in vivo with the peptide amphiphile

substrates. Similar results were observed with encapsulated

retinal cells. The ultimate vision is for the peptide amphiphile

solutions to be (minimally invasively) injected stereotax-

ically in combination with donor cells, have the nanofiber

network form in situ and in vivo, and provide functional

cellular signaling to both donor and host cells while at the

same time limiting the effects of reactive gliosis. This

nanofiber system is currently being explored for spinal cord

injury, stroke, and degenerative retinal disorders including

age-related macular degeneration.

5. Platform technologies

In addition to nanotechnologies aimed specifically at

replacing or rescuing CNS cells, which is still quite limited, a

broader group of technologies being developed can be

classified as platform technologies that have the potential for

both basic neurobiology and clinical neurology/neurosur-

gery applications. One area that has received considerable

attention is the growth and selected patterning of neural cell

types on patterned surfaces. Still being explored on surfaces

with microscale physical features or patterns of depositedmacromolecules [9-11,84], this approach has recently been

extended to the nanoscale by photolithography etching on

SiO2-coated Si wafers characterized using atomic force and

scanning electron microscopy [18] (see also Ref. [75]).

These authors determined that the ability of mixed primary

cultures derived from the substantia nigra to grow and

survive on surfaces with nanoscale features were closely

linked to the physical dimensions of surface roughness, with

optimal cell growth falling within a narrow window; features

less than 10 nm or greater than 70 nm were associated with

decreased cell adherence.

Other applications are taking advantage of some of the

unique properties offered by carbon nanotubes to improve

chronic CNS electrical stimulation. Clinically, functional

electrical stimulation implants are being used more and more

to treat intractable pain [34,37,62,69,74] and are also gaining

momentum for the treatment of other disorders such as

urinary incontinence and parkinsonian-related disorders [3-

6,38,58], in most cases involving neurosurgical intervention.

In addition, both stimulating and recording CNS electrodes

are important neurophysiological and neuropathological

experimental tools [4-6,13,21,42,55,56,63,65-69,80]. One

of the most significant problems associated with the develop-

ment of recording or stimulating chronic CNS electrodes is

device failure associated with the fibrotic response mediated

by glial and immune cells [3,6,7,31,50]. To address this,

some groups are focusing on the development of novel

carbon nanofiberbased electrode arrays for CNS neuronal

stimulation either on their own using compressed carbon

nanofiber structures [48] or in combination with other

materials such as using them to reinforce polyurethane

composites [48]. They are also in the earliest stages of being

developed for a retinal prosthesis [83]. In all cases, the idea is

to utilize the unique conductive electrical properties of

carbon nanofibers for highly controlled focal stimulation.

6. Conclusions

Nanotechnology research aimed at the regeneration and

neuroprotection of the CNS will significantly benefit from

continued nanotechnology research in parallel with advan-

ces in cell biology, neurophysiology, and neuropathology.

Ultimately, the goal is to develop technologies that directly

or indirectly aid in providing a permissive environment and

spatial and temporal cues for guided axon growth after

degeneration or secondary injury mechanisms. In some

cases, it is expected that the neurosurgeon will be required

Fig. 2. Immunofluorescence of mouse neural progenitor cells at 7 days in vitro encapsulated in a peptide amphiphile nanofiber network labeling for neurons

(b-tubulin III, green), astrocytes (glial fibrillary acidic protein, orange), or nonspecifically for all cells (Hoechst stain, blue). A: Dissociated neural progenitor

cells. Note the 3-dimensional nature of the peptide amphiphile gel: blurred cells are on a different plane of focus than cells in focus. B: Undissociated

neurosphere (ie, groups of cells derived from the cellular proliferation of cultured neural progenitor cells). Note the extent of neurite development in b-tubulin

positive (green) neurons. In both panels, note the almost negligible degree of astrocyte differentiation and development.



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to provide or administer the nanoengineered substrate to the

patient. As with all therapeutic strategies for CNS disorders,

there is the issue of getting the material, device, or drug to

the site where it is needed in the CNS itself. For example,

the delivery of peptide amphiphile molecules for nanofiber

network formation in vivo in rat models of acute compres-

sion spinal cord injury requires a laminectomy and stereo-

taxic injection. As such, in order for nanotechnology

applications directed toward neurological disorders to

develop to their fullest potential, it will be important for

neurosurgeons, neurologists, and neuroscientists to partic-

ipate and contribute to the scientific process alongside

physical science and engineering colleagues.

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