Kumar 2020

Journal of Drug Delivery Science and Technology 57 (2020) 101617
Contents lists available at ScienceDirect
Journal of Drug Delivery Science and Technology

journal homepage: www.elsevier.com/locate/jddst
Review article
Advances in nanotechnology and nanomaterials based strategies for neural T

tissue engineering
Raj Kumara,∗,1, Keshaw Ram Aadilb,3, Shivendu Ranjanc, Vijay Bhooshan Kumard,2
a
Bar Ilan Institute of Nanotechnology and Advanced Materials (BINA) and Faculty of Engineering, Bar Ilan University, Ramat Gan, 5290002, Israel
b
Department of Biotechnology, National Institute of Technology Raipur, 492001, Chhattisgarh, India
c
Faculty of Engineering and the Built Environment, University of Johannesburg, Johannesburg, South Africa
d
Bar Ilan Institute of Nanotechnology and Advanced Materials (BINA) and Department of Chemistry, Bar Ilan University, Ramat Gan, 5290002, Israel
A R T I C LE I N FO A B S T R A C T
Keywords: Recent development in science and technology and invention of wonderful nanomaterials by nanotechnology
Nanomaterials helps advances in healthcare and treatment. Nerve degeneration, scar tissue formation and loss of commu-
Neural tissue engineering nication between neurons and cells are the major issues of nerve injury. Till date it is remain a major challenge
Neuroengineering the regeneration of nerve tissue at injury site. There are various kinds of nanomaterials-based engineering ap-
Neural cells differentiation
proaches have been developed and under investigation to prevent or treat nerve injuries. Different nanomaterials
Nanoparticles
are classified into two categories such as inorganic and organic nanomaterials. Inorganic nanomaterials such as
metal, alloys, silica, magnetic, upconversion nanoparticles and quantum dots; and organic nanomaterials such as
polymeric nanoparticles, nanofibers, carbon-based nanomaterials namely carbon nanotubes and graphene, li-
posomes, micelles and dendrimers. These are promising nanomaterials with suitable physicochemical properties
and hence employed for neural tissue engineering applications. The nanomaterials showed promising results and
able to support cells adhesion, proliferation and promote neuronal cell differentiation and enhance regeneration
of neuron. Here, in this review we have discussed brief overview of different nanomaterials, their properties,
merits and demerit, promising results and progress towards neural tissue engineering applications.
1. Introduction of peripheral nerve is typical, but not exclusively caused by traumatic

injury. Nerves can also suffer damage due to complications during or-
There are millions of well-organized neurons in the brain per- thopedic surgery. Transection of a nerve by severe injury also results in
forming respective functions and maintaining communication through a loss of nerve function; however, the proximal segments may able to
nervous system to body. Communication loss between neurons and regenerate and reestablish nerve function. The peripheral nervous
cells, nerve degeneration, and scar tissue formation, are the dominant system (PNS) have ability to regenerate after injury. Gaps created by
presentations of nerve injury [1]. Central nervous system (CNS) tissue is injury can be bridged by growth cones of regenerating axons [4].
unfortunately unique with its inability to regenerate. Nervous tissue Though the PNS healing process is slow, large injuries which can't heal,
regeneration is hindered by its complex structure, challenges in the can be treated with neural tissue engineering approaches. There are
restoration of blood brain barrier (BBB) and secondary tissue damage. various approaches of neural tissue engineering techniques were sche-
Damage to the CNS will often result in astrogliosis in which an ex- matically presented in Fig. 1.
cessive number of astrocytes are present. At same time, reactive as- In the United States alone, over 250,000 persons suffering with
trocytes can harm surrounding neural and non-neural cells sometimes spinal cord injury. Around the world, over two million live day to day
resulting is gliosis – glial scar formation. Such scarring prevents re- with an injured spinal cord and with majority of patients younger than
innervation of the site [2,3]. The growth of axons with control direction 30 years of age. Developing treatment for nervous system injuries and
and target, and neural tissue regeneration is then impossible. Damage supporting regenerations is an important focus. Regeneration can be
∗
Corresponding author.
E-mail address: [email protected] (R. Kumar).
1
Department of Pharmaceutical Sciences, University of Michigan, 2800 Plymouth Rd, Ann Arbor 48,109, Michigan, United States of America.
2
Materials Physics and Applications Division, MPS-11, Las Alamos National Laboratory, Los Alamos, New Mexico 87,545, United States of America.
3
Centre for Basic Sciences, Pt. Ravishankar Shukla University, Raipur-492010, Chhattisgarh, India.
https://doi.org/10.1016/j.jddst.2020.101617
Received 13 December 2019; Received in revised form 14 February 2020; Accepted 22 February 2020
Available online 26 February 2020
1773-2247/ © 2020 Elsevier B.V. All rights reserved.
R. Kumar, et al. Journal of Drug Delivery Science and Technology 57 (2020) 101617
Fig. 2. Different type of cells used in neural tissue engineering. Reproduced

with permission from Ref. [20]. Copyright 2017 Elsevier.
Fig. 1. An overview of different neural tissue engineering approaches through

nanotechnology and nanomaterials.
enhanced by implanting cells and growth factors through scaffolds [5].

Despite of decades of research towards reconstructing motor and sen-
sory functions of CNS injury [1,6,7], solutions have remained elusive.
Complete recoveries involving restoring healthy tissue with normal
functions remain unachieved. One major challenge is the development
and implementation of nanomaterials which prevent neural damage
and/or promote nerve regeneration [8]. Fig. 3. Schematic presentation of differentiation of cells into neural network
There are number of conventional techniques used to repair nerve through neural tissue engineering techniques.
injury sites. Cooptation is a process for healing wounds and suturing
lesions in severed nerves [9]. Transplantation or grafting is another
cells into neuron through neural tissue engineering methods. Recent
form of therapy [10,11]. Grafting can occur through allograft (tissue
advances in neuroengineering processes exploiting nanomaterials sug-
donor of same species) and xenograft (donor of a different species)
gest promising results for neural regeneration [28–31]. Fig. 4 represents
[12]. Allografts include a patient's own tissue transplanted from an-
an overview of major topographical elements such as various types of
other part of his or her body. However, these conventional processes
2D and 3D nanomaterials used in neural interfaces used in neural tissue
have their own drawbacks [13]. Breakthroughs in science have fol-
engineering [32]. Following specific nanomaterials properties, merits,
lowed on from advances in technology and methodology. In neu-
demerits and their use in neuroengineering applications with promising
roscience, the development of magnetic resonance imaging (MRI) led
results are explained.
the investigation of activity across the BBB [14]. Confocal microscopy
and two-photon techniques supported understanding through real-time
monitoring of neuronal activity with higher resolution [15–17]. Posi- 2. Nanomaterials for neuroengineering
tron emission tomography (PET) provided neuroimaging with greater
capability to diagnose brain disorders [18,19]. Materials at nanoscale often have novel physicochemical properties
Nanotechnology concerns the manipulation, investigation and un- which are encouraging and promising potential application in neu-
derstanding of the properties of materials at the nanoscale level [21]. A roengineering. Due to their unique properties, nanomaterials are
nanometer (nm) is one billionth part of a meter (m). Over last 20 years, gaining more and more interest for their potential use in a range of
the development of nanoscience and nanotechnology-initiated inter- technological applications as well [33,34]. Nanomaterials are applied
disciplinary fields has contributed to physics, chemistry, material sci- to address the various challenges associated in conventional science.
ence as well as the biomedical sciences [22–25]. Neural tissue en- For example, nanoscale materials can effectively deliver the ther-
gineering is an interdisciplinary field growing faster with researchers apeutics into cells due to smaller size and functional properties. By
arising from medical, engineering and life science backgrounds working tuning the surface functionality, researchers achieved the controlled
together to develop alternative technologies for nerve regeneration. The and targeted delivery of active pharmaceutical ingredient for better
goal is to develop a neural interface which can provide information on healthcare treatment [35–39]. Surface properties of nanomaterials are
the interaction of cells and neural circuits. Optical, chemical and elec- deciding factors on where and how to deliver therapeutic substances in
trical measurements are required to gain a better understanding of the body. The selectively and specificity of each nanomaterial depen-
potential nerve injury treatments [26]. dent on its surface properties such as ligands, antibodies and peptides.
Various nanomaterials such as cues composed of supporting mate- These functional groups also help to prevent such materials from ac-
rials and cells, growth factors and biomaterials used for implantation cumulating in the liver or kidney [40]. Number of nanotechnology-
are collectively called scaffolds. Different type of cells used in neural based products are commercialized and available in market such as
tissue engineering are presented in Fig. 2. Each scaffold can have a Avance® nerve graft and Axoguard® nerve protector [41,42]. Nano-
great impact in tissue engineering but designing the ideal scaffold for technology and devices such as MRI, confocal microscopy and two-
neural tissue engineering remains challenging as materials present in phonon techniques, are increasingly being used to better understand
scaffolds can mimic microenvironment of the extracellular matrix and the anatomy and functions of biological system at nanometer scale
promote attachment, proliferation, growth, migration and differentia- [6,43]. Currently, nanomaterials are a promising candidate for ex-
tion [27]. Fig. 3 representing the schematic view of differentiation of ploitation in the treatment of nerve injury. Manipulating the
2
Fig. 4. Various 2D and 3D topographical elements used for neuron manipulation in vitro and in vivo. Reproduction with permission from Ref. [32]. Copyright 2017
Wiley.
physicochemical properties of nanomaterials can lead to possibilities to

prevent and/or treat neuro degeneration [44].
Here, we schematically classified the nanomaterials and discussed
potential reports on their application in neuroengineering.
Nanomaterials are classified into inorganic and organic nanoparticles
based on their chemical nature. Organic nanoparticles are carbon-based
nanomaterials, and include polymer nanoparticles and nanofibers, mi-
celles, liposomes and dendrimers. In contrast, inorganic nanoparticles
include metallic, bimetallic and alloy nanoparticles, silica nanos-
tructures, magnetic nanoparticles, upconversion nanoparticles and
quantum dots. The synthesis of nanoparticles occurs through either top-
down or bottom-up approaches. In top-down approaches, bulk mate-
rials are the source materials and continuous decreasing of size results
formation of nanoparticles [45]. In contrast, bottom-up approaches, the
nanoparticles formation start from the atomic or molecular level
[46,47,231]. There are large number of reviews on synthesis of nano-
particles through variety of method widely available in literature
[48–50]. Hence, we have not discussed on this aspect here. The primary
focus of our review is to provide a platform with an outline of the
properties, merits and demerits of promising nanomaterials and their
use and recent advances in neural tissue engineering applications.
Fig. 5. Various types of inorganic nanomaterials used for neural tissue en-
gineering applications.
3. Inorganic nanomaterials
3.1. Metallic and alloys nanoparticles
Inorganic nanomaterials are well-studied, and a range of well design
and established protocols are developed for their preparation and are Metals exhibit excellent physicochemical properties at the na-
widely reviewed by various researchers are available in literature. noscale. Due to unique properties they are widely used for various
However, very limited number of inorganic nanomaterials are in- applications including bio imaging, sensing and labelling [51]. Among
vestigated for neuroengineering application. Following is a discussion other gold and silver are the most studied metal nanoparticles. Metallic
on inorganic nanomaterials such as metallic and alloys nanoparticles, (Au and Ag) nanoparticle's optical properties can be tuned by changing
silica nanostructures, magnetic nanomaterials, quantum dots and up- the size and shape of the particles. The surface of metallic nanoparticles
conversion nanoparticles and how they can be useful for neuroengi- is a feasible to conjugate with biomolecules facilitating targeted de-
neering applications. Fig. 5 presenting the various types of inorganic livery of growth factors (nerve growth factor: NGF) and genes (DNA
nanomaterials widely studied for neural tissue engineering applica- and RNA) in neural tissue engineering [52]. Such properties make
tions. metallic nanoparticles useful materials for neuroengineering applica-
tions. Due to unique surface properties of metal nanoparticles, localized
surface plasmon resonance (LSPR) oscillation, can occur. LSPR falls
3
Fig. 6. (I) Schematic overview of preparation of aligned collagen fibers induced by magnetic nanoparticle using external magnetic field and their optical images at
different conditions. (II) HRSEM images of neuroblastoma cells on surface without and with AgNPs coated with different densities and morphological parameters
analysis. Reproduced with permision from Refs. [58,63]. Copyright 2016 Springer Nature and American Chemical Society, respectively.
within the range of visible spectrum for noble metal such as gold and explored and understood. There is also a need to investigate the effect
silver [53]. Noble metals are widely used metallic nanoparticles for of other metallic nanoparticles such as palladium and platinum na-
tissue engineering and biomedical applications. Gold (Au) nano- nostructured for neural tissue engineering.
particles were conjugated with peptide which binds Aβ aggregates,
followed by the application of local heat of Au nanoparticles which
3.2. Silica nanoparticles
dissolved aggregates [54]. Au nanoparticles are also employed in op-
tical biosensor for Alzheimer's disease diagnosis [55]. Gold nano-
Since the invention of silica nanostructures, simple preparation
particles immobilized with silica spheres and showed improved adhe-
methods and feasibility of easy control physico-chemical properties -
sion to neurites was reported by Park et al. [56]. Metal oxide such as
particle size and morphology quickly gained more and more interest.
iron oxide nanoparticles also showed promising results in neural tissue
Silica nanostructures can be bare or porous and easy to prepare through
engineering (Fig. 6(I)) which is discussed in detail in magnetic nano-
simple condensation method. Due to presence of pores, loading of
particle section (section 3.3). Shefi and her colleagues investigated the
target molecules is very high compare to other bare nanostructures. The
effect of coating of gold and silver nanoparticles on culture surfaces for
availability of hydroxy functional group on surface of silica, it is easy to
PC12 cells viability, differentiation and neurite outgrowth. Both na-
functionalize or conjugate with wide variety of compounds and hence
noparticles coated substrate were found highly supported PC12 and SH-
suitable for large number of applications. Recently, various kinds of
SY5Y cells, and enhanced PC12 cells differentiation with improved
silica nanostructures have been developed such as hollow, core-shell,
morphological parameters of neurite network such as neurite length
multifunctional silica nanostructures. Due to good biocompatibility,
and branching number [57,58]. The neuroblastoma cells differentiation
high loading capacity and stability, the Food and Drug Administration
on uncoated and silver nanoparticle coated substrates, number of
(FDA) have approved silica as a Generally Recognized As Safe (GRAS)
neurite emerging from cell soma with function of silver nanoparticle
material [64].
density is presented in Fig. 6(II) [58]. They further extended their
Silica nanostructures have been employed widely in nanomedicine,
studies towards the controlling the direction of neurite regeneration
drug delivery, tissue engineering and catalysis [65]. Mesoporous silica
using surface with patterned silver lines. Interesting results were ob-
nanostructures are studied for their utility in the control and targeted
served and successfully control the growth direction of neuron along
delivery of drugs, proteins and genes through introducing stimuli/
with silver lines on substrate [59]. Due to good contrast efficacy, gold
functional properties through coating the pores with suitable capping
nanostructures are a promising material in MRI imaging and biomedical
agent [66–68]. In a study by Radu et al., in 2004, Second generation
applications were reported widely. Racheal et al. applied gold and
poly (amidoamine) (PAMAM) (2G-PAMAM) was covalently attached
functional gold nanoparticles for detection of neurological diseases and
which worked as a capping agent to the surface of mesoporous silica
cancer using simple cost effective CT scanning technology [60–62]. The
nanostructures (MSN) loaded with plasmid DNA (pEGFPC1). In Radu
results were promising and suggesting new directions and a need for
et al.‘s study, the complex system showed good gene transfection effi-
further use of metallic nanoparticles for the detection and monitoring of
cacy, cellular uptake and biocompatible with neural glia, HeLa and
neural injuries and regeneration using simple CT scan technology. The
Chinese hamster ovarian (CHO) cells [69]. Silica nanostructures are
in-vivo performance of metallic nanoparticles needs to be further
also used as coating materials with mesoporous to enhance drug
4
Fig. 7. (i) Cross section of HRSEM images of porous silicon film as a carrier for NGF controlled release. (ii) DRG neuronal cell culture confocal images, (iii) HRSEM
images of neurtire outgrowth on PSiO2 film, and (iv) morphological parameters analysis of neurite network of PC12 cells. Reproduced with permission from Ref.
[73]. Copyright 2017 Elsevier. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
loading [70]. For example, mesoporous silica coated metallic nanoparticle size with below 100 nm and monodispersed with good stability.
particles are showed promising results in different application compare Magnetic nanoparticles (MNPs) also have broad applications in addi-
to bare metallic nanoparticles. Shah et al. reported the delivery of tion to magnetic based targeted control delivery and in-vivo imaging
siRNA and miRNA into neural stem cell to enhance neuronal differ- techniques such as MRI are promising for biomedical applications
entiation [71]. Due to excellent biocompatibility of silica nanos- [77,78]. Due to their excellent contrast property, magnetic nano-
tructures, they are attracting interest with respect to the brain. In an particles are gaining more interest in MRI applications aiming at high
investigation by Alvarez-Buylla et al. functional silica nanoparticles resolution imaging [79–81]. Magnetic nanoparticles such as Fe2O3 and
loaded with DNA-encoding EGFP, were injected into the mid brain of Fe3O4 have been studied in different tissue engineering applications
rodents and were shown to be non-toxic up to 4 weeks [72]. Shefi et al. including neural tissue engineering [76]. Qiao et al. successfully over-
in their recent study, developed the controlled and prolonged NGF come the issue associated with BBB through coating with polymer on
delivery system using nanostructured porous silicon film. Fig. 7 pre- MNPs [82]. MNPs coated with peptides are used for selective targeting
senting SEM imaging of cross section of porous silica (PSiO2) film to tumor in mice models [83]. In such investigations, MRI can be used
prepared through etching process and formation of neural network after to monitor entire process. In neuroengineering, MNPs were used to
differentiation of PC12 cells, confocal imaging of DRG cells differ- deliver nerve growth factor by conjugation. [84–86], controlling the
entiation. The statistical analysis of morphological parameters of neural direction of neuron generation through collagen fibers using combi-
network showed enhancement in neurite length and number in case of nation of external magnetic field and magnetic nanoparticle containing
NGF loaded PSiO2 film [73]. Porous SiO2 film was showed ability to collagen hydrogels. Hence can be used in formulation of direction-
deliver NGF in a control manner up to 26 days with 90% of loading controlled scaffold or biomaterials for neuroengineering applications
capacity [73,74]. The promising in-vitro results encourages further in- [63,87]. Studies conducted by Scherer et al. reported the successful
vivo studies. The further in-vivo studies will help to understand the delivery of drug or gene using MNPs in vitro and in vivo [88]. Shefi
interaction between cells and neurites with silica nanostructures for et al. investigating MNPs-based composites for directional control
further development in neuroengineering applications such as implant growth of neurite and PC12 cells differentiation [32]. Shefi et al. pre-
porous silicon film. Similarly, in a different study conducted by Lee pared collagen hydrogel, the fiber formed in hydrogel are stretched
et al., 3D hydrogel with combination of MSN and collagen matrix was with mechanical force to make them aligned initially [87]. Then they
able to release loaded nerve growth factor (NGF) in sustain manner up incorporated the magnetic nanoparticles in hydrogel and applied ex-
to 8 days. Compare to NGF alone, the 3D hydrogel exhibited greater ternal magnetic field in opposite direction which results the formation
enhancement of the number and lengths of neurites [75]. 3D hydrogel of well align hydrogel with strings of magnetic nanoparticles. This
can be a potential system to deliver other larger proteins in neural system applied for PC12 neural cells and differentiation was initiated
tissue engineering applications. with treatment of NGF. Interestingly, the neurite were grown in the
direction of fiber and magnetic nanoparticle strings [63]. Fig. 6 (I) re-
presents the schematic overview of process of collagen fiber alignment
3.3. Magnetic nanoparticles induced by magnetic particles and external magnetic field and forma-
tion of magnetic string within collagen gel at different experimental
Magnetic nanoparticles (MNPs) are approved by the Food and Drug conditions [63]. The researchers conjugated NGF with MNPs of dif-
Administration of United States (FDA) and are commercially available ferent sizes and surface functionalities [84]. It was observed that MNPs
in different sizes and functional group [76]. The preparation methods of are enhanced differentiation and outgrowth of neuronal cells. To sti-
magnetic nanoparticles are widely reported and well established. mulate and regenerate neurons, materials should be nontoxic. The
However, most of them suffered with aggregation and difficult to toxicity of MNPs is overcome by coating the particles with biocompa-
control the particle size and stability. Using high temperature con- tible materials such as nanohydroxyapatite. MNPs coated with
densation process or hydrothermal reactions can able to control the
5
nanohydroxyapatite prepared through sonochemistry showed improved spectra, concentration), for advanced neural tissue engineering appli-
viability and enhanced axonal elongation [89]. The promising result are cations. However, further work on UCNPs, development of new up-
encouraging for further studies on effect of different coating materials conversion nanoparticles with control and tunable and extendable op-
and interaction with cells and regenerating axons. Core-shell magnetic tical properties and their effect in neuroengineering needs to be
nanoparticles are gaining interest for various applications. Gold-coated conducted.
MNPs is a example of a promising materials due to its gold surface (thiol
group) which facilitates easy to functionalize with different functional 3.5. Quantum dots
group, enhanced the biocompatibility with stem cells and feasibility of
imaging applications [90]. MNPs coated with gold is used due to easy to Quantum dots (QDs) are a type of fluorescent probes. QDs have size-
introduce positive charge on surface which makes them feasible to bind dependent emissions with broad absorption and narrow emission
negative charge biomolecules [91]. Core-shell ZnFe2O4@Au magnetic spectrums. QDs are of interest in imaging and biosensing due to single
nanoparticles employed for differentiation of neuron stem cells (NSCs) exciting and different emission wavelengths [109]. Most QDs are
to specific lineages to delivery siRNA to stem cells [92]. Core shell composed of heavy metals which leads to cytotoxicity and limits their
magnetic nanoparticles are powerful systems for stem cell applications. applications in tissue engineering. The shortcoming can be overcome by
The promising results are encouraging for further in-vivo investigation. coating with biocompatible materials to control leaching of toxic heavy
The diverse properties of MNPs and promising in-vitro and in-vivo re- metals [110]. The formulation of non-toxic QDs make them interesting
sults will open a new window to explore further clinical studies on materials for neuroengineering applications. Recent investigation of
neural tissue engineering. carbon dots followed by development of various formulation method of
C-dots has also draw academic attention due to the carbon dots unique
3.4. Upconversion nanoparticles properties such as biocompatibility, photoluminescence and solubility
[109,111,232]. Due to fluorescence properties of QDs, they can use to
Upconversion nanomaterials also appear to be a promising material monitor the delivery of drug, gene and nerve growth factors. An in-
for neuroengineering applications [93]. The unique properties of up- vestigation by Jung et al., in 2010, reported siRNA delivery into U87-
conversion nanoparticles (UCNPs) include absorption of low energy glioblastoma brain tumor cells using QDs [112]. NGF functionalized
photos (NIR, > 800 nm) and emission of high energy photons QDs was also used to study the mechanism of transport of retrograde
(300–700 nm) [94,95]. This unique optical properties of UCNPs is due axonal in rat dorsal root ganglion (DRG) [113]. The optical property
to lanthanides which are used as dopant in host matrix. One of the and feasibility of conjugation makes QDs an interesting nanomaterial
widely studied host matrixes is NaYF4. Generally, two lanthanides are for further exploration. Shefi et al. investigated the carbon dot-based
used as dopant in UCNPs such as a sensitizer and activator [96,97]. A nanomaterials such as nanocomposite of carbon dots with magnetic
widely used sensitizer is Yb3+ and activators are Er3+ and Tm3+. nanoparticles (Fe3O4) and gallium doped c-dot on neuroengineering. C-
Fig. 8(i), (ii) and (iii) presents the preparation of upconversion nano- dot with magnetic nanoparticles doped with nitrogen prepared through
particles (PAH-PAA-UCNPs) (UCNPs: NaYF4:Yb3+,Er3+), cell pretreat- sonochemistry showed excellent fluorescence stability promising results
ment and osteogenic induction process and their use in neural differ- in cell differentiation, neurite outgrowth and cellular uptake [86,114]
entiation by UCNPs through NIR light stimulation, respectively Fig. 9(i) represents the formation mechanism of nanocomposite of
[98–100]. The mechanism of upconversion is as, irradiated NIR energy magnetic (iron oxide) nanoparticles with nitrogen doped carbon dots
absorbed by sensitize which transfer to activator through non-radiative and use in neuronal manipulation. The nanocomposites showed lower
process, followed by radiative emission of high energy [101,102]. toxicity and favor the PC12 differentiation process when PC12 cells
Fig. 8(iv and v) represents the mechanism of upconversion in dye treated with NGF and good cellular uptake and fluorescence (Fig. 9(ii
sensitized core/active shell nanocrystal [103]. The UCNP surface is and iii)). Confocal images of cellular uptake in neuroblastoma cell line
suitable for coating with silica which makes them interesting material SH-SY5Y are presented in Fig. 9(iv) [86]. Fig. 10(i) shows preparation
for biomedical, drug or gene delivery and neuroengineering use [104]. of gallium doped carbon dot coated glass substrate through green en-
UCNPs are ideal for in vivo imaging due to intra-configurational tran- ergy source sonochemistry that is sonochemical method. SEM images of
sitions independent of size and shape, good resistant to photoblinking differentiation of PC12 on coated substrate along with control are
and photobleaching, long luminescence lifetime and upconversion of presented in Fig. 10 (ii) [114]. Cytotoxicity studies have suggested that
NIR light which able to penetrate deeper level of tissue [105]. UCNPs sonochemistry based synthesis of carbon dots are less toxic owing to
have gained the attention of researchers in the neuroscience and cancer green energy source and use of non-toxic chemicals. Recent studies of
fields. RGD (tripeptide Arg-Gly-Asp) peptide conjugated UCNPs was direct visualization of endocytosis, redistribution and shuttling of QD
used to targeted human glioblastoma U87MG tumor in mice [106]. bound TrkA receptors have opened a new window for QDs based system
UCNPs are also applied for delivery of neurotoxins namely chlorotoxin. for imaging of biochemical signals and delivery of biomolecules and
UCNPs recently showed differentiation of PC12 cells and enhanced growth factors into the cell [115]. NGF conjugated QDs nanostructures
neurite outgrowth when loaded/conjugated with NGF [107]. Fig. 8 (vi) have shown good bioactivity, TrkA receptor activations and PC12 cells
represents schematic illustration of UCNPs enhanced PC12 cells dif- differentiations [116]. Due to their unique physicochemical and optical
ferentiation through stimulation of NIR light and confocal images after properties, QDs are promising nanomaterials for in vivo cellular ima-
2 days treatment of NGF with different concentration of PEI-UCNPs ging and biomedical applications. However, bare QDs are limited due to
[107]. The conventional optogenetic techniques works based on visible their poor stability and lower permeability through BBB. QDs en-
light which is limited by high scattering and low tissue penetration. Due capsulated poly (ethyleneglycol)-poly (lactic acid) nanoparticles func-
to unique optical properties of UCNPs, they can be applied to study tionalized with wheat germ agglutinin was facilitate safe and targeted
neuronal activity optogenetically using NIR light. Hybrid upconversion delivery into brain with high drug loading, good stability, aqueous
nanomaterials compose of channelrhodopsin-2, a photoresponsive ion solubility and imaging application [117]. Gao et al. prepared quantum
channel was applied for optogenetic control of neuronal activity [108]. dot bearing lectin functionalized nanoparticles and successfully em-
NIR based technology has drawn attention over the last 10 years due to ployed for in vivo brain imaging application [117]. Fig. 10 (iii and iv)
deep penetration efficacy and other unique optical properties. Such presents the preparation and freeze-fracture electron microscopy
hybrid nanomaterials enable NIR-based neuronal stimulation, with images of lectin-functionalized QDs loaded nanoparticles conjugated
comparable efficiency as that of 470 nm blue light. NIR-mediated op- with WGA [117]. Fig. 10(v and vi) shows promising results of dis-
togenetic can be tunable through controlling physicochemical proper- tribution of nanoparticles (WGA-QDs-NP) in the brain at different time
ties of the nanomaterial (e.g. size, morphology, structure, emission intervals after intranasal administration and quantification of
6
Fig. 8. (i) Schematic diagram of upconversion nanoparticle synthesis, (ii and iii) illustration of PC12 cell differentiation by UCNPs with stimulation of NIR light, (iv)
mechanism of multidimention energy cascade upconversion and (v) pathways from NIR dye molecule to lanthanide ions. (vi) Images of PC12 after 2 days of
treatment with different concentration PEI-UCNPs and NGF. Reproduced with permission from Refs. [98,103,107]. Copyright 2016 Elsevier, 2016 and 2014 Wiley,
respectively.
luminescence signal, respectively [117]. The available PEG terminal on lower toxicity up to 0.2 mg/mL concentration against PC12 cells. They
surface facilitates to conjugate various biological molecules and li- also didn't affect the cellular processes of PC12 differentiation and good
gands. Due to fluorescent properties of QDs and physiological and cellular uptake into SH-SY5Y cells. Fig. 11 presents the formulation of
pharmacological properties in cells, QDs can be a molecular tool to metal (Au) doped carbon dots and differentiated PC12 cells presence
develop targeting therapeutics which regulate cell function [118]. carbon dot and metal doped carbon dots [119]. Recently researchers
Imaging agents are vital for diagnosis and treatment of neural injuries. also reported the preparation of elements doped carbon dots such as
However, C-dots use in neural tissue engineering is not yet well un- nitrogen, boron and phosphorous [120].
derstood. Further studies with in-depth analysis need to be explored.
Very recently, Kumar et al. prepared the carbon dots doped with 4. Organic nanomaterials
several metals such as gold, silver, gallium, zinc and tin through
acoustic cavitation method using PEG-400. They showed interestingly Fig. 12 presenting the different organic nanomaterials studied in
7
Fig. 9. (i) Synthesis and mechanism of γ- Fe2O3/NCDs nanocomposites, (ii) cell viability and (iii) differentiation of PC12 cells (light microscope images) after four
days of treated and (iv) fluorescent confocal images of cellular uptake into SH-SY5Y cells. Reproduced with permission from Ref. [86]. Copyright 2018 American
Chemical Society.
neural tissue engineering applications. Liposomes, micelles, den- as organic nanomaterials. In following sections, we are discussed on the
drimers, polymeric nanoparticles and nanofibers, and carbon-based neural tissue engineering application of organic nanomaterials in de-
nanomaterials such as graphene, graphene oxide, reduced graphene tailed.
oxide, single/multiwall carbon nanotubes and fullerenes are classified
Fig. 10. (i) Schematic diagram of glass substrate coated with Ga@C-dots@Ga nanoparticles preparation using acoustic cavitation. (ii) HRSEM images of PC12 cells
differentiated on prepared substrate. (iii) Preparation, and (iv) internal structure of lectin-functionalized quantum dots-loaded nanoparticles (WGA-QDs-NP). (v)
Their distribution and retention in brain after intranasal administration (optical images) at different time interval and (vi) quantification of the luminescence signal.
Reproduction with permission from Refs. [114,117]. Copyright 2017 Royal Chemical Society, and 2008 American Chemical Society, respectively.
8
Fig. 11. Preparation method for carbon dots doped with different metals (Au, Ag, Ga, Zn and Sn) using acoustic cavitation and PC12 cells differentiation presence of
CDs and Au@CDs. Reproduced with permission from Ref. [119]. Copyright 2018 Elsevier.
4.1. Liposomes
Drug or gene delivery to the CNS is a key focus for neuro-surgeons.

Liposomes are vesicles compose of minimum one vesicular bilayer with
spherical shape. The core of the bilayer can be used to load hydro-
phobic compounds. Most used phospholipids are glycerophospholipids
and sphingomyelin or synthesis block copolymers [124,125]. Amphi-
philes are a type of organic molecules with hydrophilic and hydro-
phobic moieties. The amphiphilic molecules are forms ordered nanos-
tructures by interaction between hydrophobic moieties in aqueous
solution. Controlling the assembling of amphiphilic molecules results
different amphiphilic nanocarriers. Fig. 13.I(i) showed schematic
structure of different organic nanomaterials such as liposomes, micelles
and dendrimers [126]. Liposomes and micelles are well-known am-
phiphilic nanocarrier systems [127,128]. Liposomes and micelles have
been in use for several decades. Spherical assembly of amphiphiles in
aqueous solution results the formation of unique bilayer. The bilayer
composes of phospholipids called liposomes. Liposomes using as na-
nocarrier for drug delivery over the long time due to easy preparation
procedure along with limited toxicity and biocompatibility. However,
most of liposomes are limited their use due to short half-lives and
Fig. 12. Graphical representation of different organic nanomaterials studied in modest permeability across BBB [125]. It was reported that through
neural tissue engineering applications. Reproduced with permission from Refs. PEG coating, particle size was reduced to below 100 nm without ag-
[121–123]. Copyright 2013, 2018, 2019 Elsevier. gregation, enhance half-life and permeability through BBB by receptor
mediated transcytosis [129]. Daunomycin, an anticancer agent, has
been used to deliver to rat brain using a liposome which crossed BBB
[130]. Multifunctional liposomes have come into lime light due to their
good stability, efficacy to reach target site of action and excellent in
9
Fig. 13. I: (i) Schematic structure of different nanocarriers and (ii) synthesis of polyamidoamine (PAMAM) dendrimers. (iii) Structure and molar weight of viologen-
phosphorus dendrimers and (iv) images of N2a cells after 24 h exposure to 20 μM viologen-phosphorus dendrimers. (v) Fluorescence distributions of a representative
animal at different time points following an intravenous injection of free quantum dots (0.2%) in an aqueous solution and theragnostic liposomes with quantum dots.
(II): (i) Scheme of polyamine backbone synthesis followed by amidation, (ii) attachment of DexAM, and (iii) its delivery into NSCs to enhance differentiation into
neurons. Reproduced with permission from Refs. [71,126,133,135,136]. Copyright 2013 American Chemical Society, 2009 Nature, 2012 (open access), 1999
Elsevier, 2013 Springer Nature, respectively.
vivo circulation time [131]. Multifunctional liposomes have been used points following an intravenous injection of free quantum dots and
for neurological ailment in vivo, targeting gliomas, treating brain me- functional liposome loaded with QDs [133]. Significant enhanced
tastasis, reducing β-amyloid plaques in Alzheimer's disease [132,133]. fluorescence was observed in mouse brain for QDs loaded liposome
C-J. Wen et al. formulated multifunctional liposomes through in- compare to free QDs. Interestingly uptake of liver and heart reduced
corporation of QDs and apomorphine showed promising results in [133]. Liposomes are also used in gene therapy for age-related diseases
bioimaging and brain endothelial cell uptake. Fig. 13 I(v) shows the such as Parkinson's disease. Transferrin receptor coated PEG im-
fluorescence distributions of a representative animals at different time munoliposome is used to delivery dopamine-depleted rat striatum
10
[126,134]. The promising results of liposomes in the delivery of various dendrimers are highly toxic at concentration of above 1 mM due to
substances supports their use for the delivery of neurotrophins and reactive oxygen species (ROS) generation. Further biomedical applica-
nerve growth factors to brain. tion of CPD dendrimers or can be reduced toxicity through various
approaches to makes facile materials for neural tissue engineering ap-
4.2. Micelles plications [156,157]. Cross linked hyPCL32-BCN-N3-hyPCL32 in-
jectable scaffold was formulated which showed good biocompatibility
Micelles are spherical assemblies with hydrophobic and hydrophilic and support for cell adhesion and proliferation [158]. The promising
inner and outer components. Amphiphilic molecules are also referred to result is encouraging for further studied to develop injectable in situ
as surfactants, compose hydrophobic tail and hydrophilic head. scaffold formation for neural tissue engineering and biomedical appli-
Dispersion of surfactants in water forms micelles, in which core is hy- cations. G4 PAMAM-NH2 dendrimers employed as non-viral carrier for
drophobic and hydrophilic shell. Pluronic block polymers are a material human mesenchymal stem cells transfection in in-vitro [159,160]. Shah
studied in micelles [137]. Peptide TAT functionalized micelles are used et al. developed dendrimer based delivery of siRNA for direct stem cell
to delivery ciprofloxacin for brain infections [138]. Plunoric P105 mi- differentiation. They formulated DexAM carrier which solubilize hy-
celles are exploited to deliver chemotherapeutic drug doxorubicin at drophobic compounds in physiological medium and forms complex
site of action and drug released was achieved by applying ultrasound. with siRNA. Fig. 13. II(i) shows graphical view of the synthesis proce-
The approach can reduce significant side effects of toxic drug on other dure of DexAM and 13.II(ii) shows encapsulation of siRNA in DexAM
tissues and number of doses [139,140]. In drug delivery systems, it is through electrostatic interaction and 13.II(iii) delivery to NSCs to en-
not only limited to deliver the drug at site of action and releasing but it hance differentiation into neurons [71]. This promising nanocarrier
also supports the internalization of drug into cells making it a key step with feasibility to control the core chemical structure may be promising
for therapeutic efficacy of system. The internalization depends on vehicle in neural tissue engineering and drug delivery system with
nature of drug such as hydrophilic or lipophilic. The rate of inter- control and targeted delivery. Further in vivo studies need to be ex-
nalization is high for lipophilic and low for hydrophilic. Controlling the plored [71]. This is one of the major challenges for researcher after
rate of internalization of drug which can be achieved through micelles discovery of stem cells. Lazniewska et al. investigated the viologen-
is a challenge [141]. Micelles can control the internalization rate of phosphorous dendrimers (VPD) on the murine neuroblastoma cell line
highly lipophilic fluorescent probe CM-DiI [142]. (N2a). Different structure and molar weight of viologen-phosphorus
Liposomes and micelles are of great interest to neuro engineers. dendrimers (VPDs) are shown in Fig. 13.I(iii) [136]. Interesting results
Liposomes and micelles are used as carriers to deliver the nerve growth shown very low toxicity and safety profile for N2a cells. Fig. 13.I(iv) the
factors such as NGF and GDNF helping neural regeneration [143]. Li- confocal images of stained cells, clearly showed that good cellular up-
posomes and micelles are also applied in nanobubble therapy using take efficiency after 24 h of treatment of 20 μM concentration [136].
ultrasound for siRNA delivery [144]. Liposomes and micelles are also However, limited ROS formation and mitochondrial function changes
used in the delivery of genes to the brain [145,146]. Due to excellent were reported. Hence, VPD can be promising nanoparticles for biome-
biocompatibility, easy to functionalize and lack of immune response, dical application and neural tissue engineering. Facile preparation
the properties makes amphiphile based nanocarriers an interesting methods, biocompatibility, feasibility of functionalization and further
material for neural tissue engineering applications. modification are makes them promising material for neuroengineering.
Further modification may lead them clinically acceptable.
4.3. Dendrimers
4.4. Polymeric nanostructures
Dendrimers are 3D nanostructures with monodispersity and multi-
valency. The cross linking of repeating monomer subunits forms den- Polymeric nanoparticles are solid nanostructures with size range
drimers. Depending on hydrodynamic size, branching points and sur- from 10 to 1000 nm. Polymers are two classes natural and synthetic.
face functionalities, different dendrimers generations exist. The surface Natural polymers such as alginate, collagen, chitosan and gelatin; and
of dendrimers can be suitable to introduce chemical functional group synthetic polymers such as poly (lactide-co-glycolide) (PLGA), poly
which has great impact in drug or gene delivery [147]. Dendrimers are (butylcyano-acrylate) (PBCA), poly (glycolic acid) (PGA) and poly
promising materials for targeted delivery to the brain also. Drugs can be (lactic acid) (PLA). Mostly polymers are biodegradable. Polymer na-
delivering through dendrimers by encapsulation or attached through noparticles can also form different nanostructures such as nanomatrix
chemical bonding. Dendrimers are used to deliver the drugs such as and nanocapsules [161]. The drug or gene can be delivered by poly-
anticancer, anti-inflammatory and anti-microbial [135]. Dendrimers meric nanoparticle by dissolving, absorbing or dispersing in matrix,
are employed in biomedical applications due to their novel properties attaching covalently or encapsulating into core [162–166]. The
[148]. They can be used as a nanocarrier for delivery of therapeutics, polymer has a protective characteristic which improves therapeutic
contrast agent in MRI and as photosensitizers [149,150]. Due to their substance and in vivo stability [167]. Polymeric nanoparticles studied
feasibility in crossing the BBB, dendrimers are interesting carrier in the sustained delivery of nerve growth factor (NGF loaded PLGA na-
neural tissue engineering [151]. Poly (propyleneimine) (PPI) and poly noparticles) for treatment of neurodegenerative disorders, neural re-
(amidoamine) (PAMAM) is a non-toxic used dendrimers in biological generation, differentiation and outgrowth of neurons [168,169]. The
application including neuroengineering [152]. Fig. 13.I(ii) presents the toxicity level is important and formation of non-toxic byproducts after
synthesis of PAMAM dendrimers [135]. PAMAM dendrimers are dif- degradation is makes it ideal drug delivery system. PLGA is considered
ferent generation depends on size, structure and functionality. Den- as one of the safer polymers in neuroengineering due to the formation
drimers, through systematic administration of PAMAM, showed loca- of water and carbon dioxide after degradation. PLGA nanoparticles
lization and activation of microglia that facilitate the targeted delivery have been investigated for delivery of therapeutics to prevent or treat
of N-acetyl-L-cystein (NAC) to enhance neuroprotection. NAC is an neurological disorders [170]. PLGA microparticles have been employed
antioxidant and anti-inflammatory drug [153]. Dendrimers are safe and in the delivery of NGF and GDNF [171,172]. Retinoic acid loaded PEI
easy to prepare nanostructures for stem cell-based therapies for neural nanoparticles have been used to control neural differentiation after
injuries. Dendrimers are interesting material in neural tissue en- ischemia [173]. Porous nanostructures of polypyrrole (PPy) prepared
gineering as a carrier and contrast agent in imaging [154]. The toxicity using self-assemble polystyrene beads as template which showed en-
of cationic phosphorus dendrimers (CPD) of low generations that is G2 hance cells adhesion and neurite extension when combination of elec-
and G3 were studied on murine embryonic hippocampal cells (mHippE- trical, chemical, and topographical cues are employed together [174].
18) and neuroblastoma cells [136,155]. Results showed that CPD Kang et al. investigated the conducting polypyrrole as a platform for
11
neural tissue engineering. They formulated the well-ordered porous [189]. Fig. 15(II) presents SEM images of different PLLA polymer fibers
polypyrrole surface through electrochemical deposition method doped of different dimensions and patterns, and C17.2 cells seeded on pre-
with NGF. Prepared NGF-doped Ppy surface was coupled with electrical pared fibers [182], presents LSCM micrographs of expression of NF200
stimulation and studied the effect on neural activity of PC12 cells protein by C17.2 neural stem cells [183] and LSCM micrographs
[174]. Fig. 15(III) presents schematic illustration of preparation of showing the expression of NF200 proteins by C17.2 neural stem cells on
porous NGF-doped Ppy surface, cellular interaction with porous surface (A) TCP; (B) PC; (C) PCC1; (D) PCC2; (E) APC; (F) APCC2 [183]. Ra-
presence of electrical stimulation, high-resolution SEM images of dif- makrishna et al. prepared scaffold compose of biodegradable polymers
ferent NGF doped Ppy surfaces and representative fluorescence images such as PLGA and nanocomposites of PCL with gelatin, laminin and
of PC 12 cells cultured for 2 days [174]. Interesting results are observed collagen – natural polymer. The excellent scaffold was greatly involved
in NGF release profile in combination with electrical fields. This sub- in peripheral nerve regeneration [190–192]. Ramakrishna et al. for-
strate also showed enhanced cellular behaviors such as adhesion, me- mulated biomaterial compose of laminin, and polymers chitosan and
tabolic activity and neurite extension over conventional flat supports PCL. Due to good tensile strength, it enhanced cell attachment and
[174]. By tuning the architecture, conducting polymer based nanoma- proliferation of Schwann cells compare to polymer alone [193,194].
terials can be promising material for conventional electrical devices. The study suggests that the formulation of nanocomposites with fea-
Promising material for preparation of electrodes for neural activity sible mechanical properties are more important for neural tissue en-
monitoring. Such materials are of great interest in formulation of gineering applications. Formulation scaffold is not limited to toxicity
scaffold for neural tissue engineering. By tuning the topography of such and interaction with cells but also need to be consider the mechanical
conducting polymer surfaces neural regeneration direction can be properties. Li et al. investigated the use of aligned PLA nanofibers on
control for advanced neural tissue engineering application. However, enhancement of neurite outgrowth. Xia et al. investigated nanofibers
stability and toxicity are the major concern. based scaffold of different orders, structures and surface properties in
Compared to liposomes, polymeric nanoparticles are more stable neural tissue engineering [195]. The researcher also reported em-
but suffer with permeability through BBB. It can be enhanced by surface bryonic stem cells (ESCs) differentiated into neural lineages when
functionalization of polymer nanoparticles with suitable substances/ seeded into nanofibers. The direction of neural lineage along with
molecules which can enhance the BBB permeability. This can enhance neurite outgrowth controlled by aligning the nanofiber directions
pharmacokinetics as well as delivery to targeted site which can facil- [181]. Xie et al. investigated the neural tissue engineering use of na-
itate delivery of drug or gene to brain and CNS [175,176]. It was re- nofibers of PCL in two different condition such as randomly oriented
ported that PBCA nanoparticles are able to cross BBB and deliver da- and aligned nanofibers for embryonic stem cells (ESCs). The PCL na-
largin into brain to induce antinociception [177]. PBCA is also able to nofibers showed enhanced differentiation of mouse ESCs, presence of
deliver doxorubicin, methotrexate, loperamide and temozolomide to aligned fibers, neurite outgrowth in the direction of nanofibers was
the CNS. PBCA nanoparticles are lower in toxicity due to higher rate of reported [181]. Fig. 15(I) presents the SEM images of align and ran-
degradation [178]. It was reported that butane sulfonic acid doped domly oriented PCL nanofibers prepared by electrospinning and Im-
polypyrrole coated surface enhance PC12 cells adhesion, proliferation munohistochemistry performed on RW4 EBs after 14 days of culture on
with improved neuritis number and current intensity 1.7–8.4 mA/cm. aligned PCL nanofibrous and random nanofibers for mature cell mar-
By applying electrical stimulation, neurite outgrowth improved de- kers including (A, B) Tuj1 (for neurons), (C, D) O4 (for oligoden-
pending on current. This was conducted with polypyrrole and showed drocytes), and (E, F) GFAP (for astrocytes) [181]. This can be a pro-
sciatic nerve regeneration in rats [179]. Shefi et al. prepared nano- mising scaffold for neuroengineering application. Mao et al.
composite of PCL nanofibers through electrospinning and incorporated investigated the effect of diameters of fibers on differentiation of neural
gold nanoparticles. This nanocomposite used for PC12 cells differ- stem cells. They found that with increase of fiber diameter decreases
entiation with treatment of NGF to generate 3D network of neuron. migration and spreading. The presence of fibroblast growth factor-2 in
Interestingly promising results are reported with enhanced PC12 dif- serum-free medium and retinoic acid in fetal bovine serum NSCs dif-
ferentiation and formation of 3D neurite network. Fig. 14 presents the ferentiated into oligodendrocytes and neural lineages, respectively
schematic overview of PCL/gelatin nanofiber composite with Au na- [196]. Martin et al. investigated dorsal root ganglia (DRG) neurite and
noparticles preparation process, characteristics (SEM, TEM, confocal axonal growth direction using electrospun nanofibers [197]. Mey et al.
imaging) and use differentiation and formation of 3D network of neu- investigated the cytotoxicity and effect on axonal growth and direction
rons [180]. Polymeric nanoparticles are more interesting material for of collagen-PCL nanocomposite fibers compared with PCL nanofibers.
neural tissue engineering applications. The promising results support PCL-collagen blend nanofibers showed good support for cell prolifera-
continued further studies of polymeric nanoparticles in neuroengi- tion, neurite outgrowth and cell migration for Schwann cell [198]. Si-
neering use. milarly, Meiners et al. studied the neuroactive peptide functionalized
nanofibers to improved adhesion, neurite generation and elongation
4.5. Polymer nanofibers compare to conventional surface [199]. Three different conducting
polymer (PEDOT and PPy) nanotubes and their films and their prop-
Researchers have investigated and explored the use of nanoscale erties such as impedance, charge-capacity density, tendency towards
structures to stimulate and control the differentiation of stem cells in delamination and neurite outgrowth were investigated. The DRG cells
recent years [184]. Electrospun nanofibers are emerging as a new showed more adhesion and long neurite on PEDOT nanotube based
platform that can be exploited for understanding, assessing, and ma- surface [200]. The implication was that conducting polymer nanotubes
nipulating the differentiation of stem cells [185,186]. In principle, the are promising materials in neural tissue engineering. Dexamethasone,
differentiation of stem cells can be manipulated via topographical, an anti-inflammatory drug was loaded (13% (w/w)) in PLGA nano-
biochemical, and electrical cues [32,121]. Stem cell differentiation is particles (400–600 nm) prepared through solvent evaporation process
controlled by a complex pattern of gene regulation, which is governed was embedded in hydrogel matrices. Hydrogel released loaded drug in
by an array of cellular signaling pathways. Physicochemical properties two weeks was around 90%. There was no change in independence
also affect cellular behavior [187]. Ramakrishna et al. reported that when the hydrogel coated on microfabricated neural probes [201]. This
aligned-nanofiber-based scaffold is a promising materials for neural system-based electrode showed promising results in neural tissue en-
stem cells differentiation compare to randomly distributed nanofibers gineering. It was reported that dual component nerve graft compose of
based scaffold [188]. Kumar et al. formulated polycaprolactone (PCL) PLGA and PPD (poly (p-dioxone)) micro/nanofibers promoted re-
nanofibers through plasma treatment with improved hydrophilicity and generation of peripheral nerve in in-vivo [202]. Leong et al. found that
demonstrated good support for adhesion, proliferation of Schwann cells aligned nanofibers of NGCs enhanced peripheral nerve regeneration at
12
Fig. 14. (i) Schematic overview of preparation of nanofibers of PCL/gelatin and AuNPs nanocomposite scaffolds prepared using electrospinning and evaporation of
AuNPs. (ii) E-SEM, (iii and iv) TEM images of scaffold nanocomposite. Confocal microscopy images of single neurons cultivated and neural network formed on
prepared scaffolds nanocomposite (v and vi) and prestine AuNPs (vii and viii), and E-SEM images (ix and x) of neurite growth on prestein AuNps and Nanocomposites
scaffold. Reproduced with permision from Ref. [180]. Copyright 2016 American Chemical Society.
10 mm nerve injury when compared to non-aligned nanofibers [203]. biomedical application and promising materials for neuroengineering
Bellamkonda et al. investigated the 10–12 layers aligned NGCs fibers to [207]. Fig. 16(I) presents the schematic view of carbon based nano-
repair 17 mm nerve injury. They found the 10–12 layers promoted axon materials and their applications [208]. The materials are being used as
regeneration at injury site [204]. These promising results are en- a surface coating materials, supporting material for neural regenera-
couraging further in vivo nerve tissue regeneration can be enhanced tion, differentiation and neurite outgrowth [209]. Various types of
through aligned fiber or fiber based scaffold. nanocomposites and scaffold are produced using carbon-based nano-
materials for tissue engineering and regenerative medicine including
neural tissue engineering. However, there are number of materials
4.6. Carbon-based nanomaterials available with lower toxicity compare to carbon-based nanomaterials.
However, limited their application due to their physicochemical prop-
Carbon nanotubes (CNTs), graphene (G) and fullerenes are called erties [31,210]. Carbon-based nanomaterials are promising materials
carbon-based nanomaterials (CNMs). Carbon nanomaterials contains for tissue engineering. However, cytotoxicity is the major issue asso-
sp2-bonded carbon. Carbon based nanomaterials are classified into ciated with their applications. Finding the suitable low toxic carbon-
three type according to dimensionality such as zero (fullerene-1985), based nanomaterials is a challenging. However, the cytotoxicity of
one (CNTs-1991) and two dimensional (graphene-2004). The corre- carbon based nanomaterials depends on size, thickness, concentration
sponding carbon nanomaterial's year of discovered mention in par- and preparation process [31,211]. It is more important to understand
enthesis. Fig. 16(II) represents the classification of different carbon fundamental of carbon-based nanomaterials before to apply in neu-
based nanomaterials based on dimensionality [205]. Carbon based roengineering. There are number of reports on cytotoxicity of carbon-
nanomaterials are attractive for various applications due to their novel based nanomaterials and effect of different experimental parameters in
physicochemical, optical, thermal, mechanical and electrical properties last few years.
[205,206]. Carbon based nanomaterials are already studied in
13
Fig. 15. (I) Aligned and randomly oriented PCL nanofibers prepared using electrospinning method – SEM images (i) and Immunohistochemistry performed on RW4
EBs after 14 days of culture for mature cell markers Tuj 1 for neurons (A, B), O4 for oligodendrycytes (C, D), and GFAP for astrocytes (E, F) on aligned (ii) and
randomly (iii) oriented PCL nanofibers. (II): SEM of PLLA electro spun fibers of different dimensions and patterns without cells (i), and with C17.2 cells seeded (ii),
and laser scanning confocal micrographs of immunostained C17.2 cells after 48 h culture on prepared PLLA fibers (iii). (iv) LSCM micrographs showing the
expression of NF200 proteins by C17.2 neural stem cells on (A) TCP; (B) PC; (C) PCC1; (D) PCC2; (E) APC; (F) APCC2. (III): (i) Schematic illustration of preparation of
porous polypyrrole surface doped with NGF and (ii) simple of electrical stimulation assisted differentiation of cells on surface and (iii) HR-SEM images of cells
interaction with surfaces presence of electrical stimulation. (iv) Representative fluorescence images of PC 12 cells cultured for 2 days on different surfaces -
stimulated flat NGF-doped Ppy surface and electrically stimulated NGF-doped porous Ppy surface with pore size 200 nm and 1 μm and their SEM images (v).
Reproduced with permission from Refs. [174,181–183]. Copyright 2011 American Chemical Society, 2009, 2010 Elsevier, and 2013 Willey, respectively.
14
Fig. 16. (I) An overview of applications of carbon nanomaterials, (II) classification of carbon allotropes and (III) preparation and directed growth of MSCs on carbon
nanotube patterns. (IV): (i) SEM images of 3D-GFs, (ii) NSC cultured on 3D-GFs surface. (iii) Cell viability of 3F-GFs against NSC and fluorescence images of NSCs
proliferated on 3D-GFs for 5 days, and (v) Western Blot analysis of Ki67 expression on 2D graphene films and 3D-GFs. (V): (i) Mouse embryonic 14-day cortical
neurospheres differentiated as dissociated single cells and small clusters on and (PEI/SWNT)6-, PLO-, and (PEI/SWNT)6(PLO)-coated coverslips. (ii) Light microscopy
and SEM images of differentiated NSCs, and (iii) WST-8 reduction activity of differentiated NSCs. Reproduced with permission from Refs. [205,208,215,216,224].
Copyright 2015 Elsvier, 2015 American Chemical Society, 2007 Willey, 2013 (Open Access) and 2007 American Chemical Society.
Carbon nanotubes (CNTs), due to its unique physical and chemical coupling between somatic and dendritic neuronal compartments by
properties, are widely used range of biomedical application. The in- CNTs [212,213]. Surface modified multi walled carbon nanotubes
teraction of CNTs with the brain is attracting interest for engineering of (MWCNTs) showed enhancement of neurite outgrowth, improved bio-
CNT-based devices. Due to unique electrical property, CNTs are a fea- compatibility, neuron growth and neurite/axonal elongation [214].
sible material for stimulating and recording neuronal activity. On CNT CNTs can form nanocomposites with varying materials and they can be
substrate, neurons exhibit enhanced electrical activity of neuron. The incorporated easily in various bio/nanomaterials. The nanocomposites
enhancement of neuronal electrical activity is due to shortcut electrical compose of CNTs showed different properties compare to CNTs. A wide
15
microscopy images, SEM images and WST-8 reduction activity of dif-

ferentiated NSCs [215]. The prepared thin film showed good chemical
stability, morphological flexibility, physical properties, biocompat-
ibility, neurite outgrowth and expression of neural markers. Results are
matching well with widely used PLO substrate [215]. However, further
detail mechanism needs to be investigated. Chao et al. investigated the
effect of surface charge and functionality of CNTs surface on ESC cells
neural differentiation. Results showed that CNTs topography affects cell
behavior compare to charge of the surface [222]. Human ESCs were
cultured on aligned film of gelatin, collagen and collagen-SWCNTs
nanocomposite by Sridharan et al. Improved cell differentiation was
observed on collagen-SWCNTs surface compare to others [223]. The
implication was that the CNTs with different polymers can be an in-
teresting material for neural tissue engineering use.
Due to its 2D structure graphene can be employed as a coat on
different cell culture surface to understand the interaction of cells with
graphene and its effect on neural regeneration, differentiation and
neurite outgrowth [225]. Graphene is more interesting than CNTs for
tissue engineering applications. The substance shows unique properties
such as high planer surface area, superior mechanical strength, un-
paralleled thermal conductivity, electronic and optical properties.
Graphene oxide, an oxidation product of graphene, is a favorable ma-
Fig. 17. Simple overview of important components for ideal neural tissue en- terials for biomedical applications such as to enhance aqueous solubi-
gineering. lity and feasible to functionalize biomolecules [226]. Graphene coated
surface showed enhanced neurite sprouting and outgrowth of mouse
hippocampal neurons. Neural formation, axonal alignment and neu-
range of CNT based nanocomposites with biomaterial, enhanced dif-
ronal patterning was achieved through coating of graphene on cell
ferentiation of different stem cells has been formulated for different
culture surface [227]. Nanocomposite of graphene and polyethylene
uses. Mouse neural stem cell (NSCs) differentiation into neural cells was
terephthalate (PET) employed in non-toxic, non-contact electrical sti-
achieved on single walled carbon nanotubes (SWCNTs) polyelectrolyte
mulation to enhance cell-to-cell coupling in human neuroblastoma cell
multilayer thin films [215]. Fig. 16(III) presents the schematic overview
line [228]. NSC based therapy provides a promising approach for
of preparation of pattern nanotube substrate by coating on gold surface
neural regeneration [229]. The combination of neural stem cells and 3D
following the direction controlled neurite growth by differentiation of
scaffolds compose of carbon nanomaterials are great interest in neural
mesenchymal stem cells (MSCs) on large scale carbon nanotube pattern
regeneration. Ning Li et al. studied the porous 3D graphene foam (3D-
substrate [216]. Rat and monkey brain electrical stimulation was re-
GFs) for neural engineering which showed support for neural stem cell
corded using tungsten and stainless steel wire electrode coated with
growth, proliferation and Ki67 expression upregulation compare to
CNTs [217]. Pristine CNTs also showed support for the growth of dif-
graphene 2D film. 3D-GFs differentiation NSC into neurons [224,230].
ferent cell types. Garcia et al. reported growth of Schwann and DRG
Fig. 16 (IV) presents the SEM images of 3D-GFs and adhesion and
cells on top of pristine CNTs [218]. Zhou et al. prepared pristine carbon
proliferation of NSC on 3D-GFs. cell viability and fluorescence images
film on silica wafer which showed good support for neuroblastoma,
of NSCs cells proliferated on 3D-GFs after 5 days and Western Blot
carcinoma (P-19), and rat pheochromocytoma (PC-12) cells [219].
analysis of Ki67 expression on 2D graphene films and 3D-GFs [224].
MWCNTs with different surface charge was prepared by Hu et al. em-
The mentioned results give hope of a ideal scaffold (Fig. 17 in near
ployed for hippocampal neuron cells. Neutral and positive charge
future to improved neural tissue engineering applications for treatment
MWCNTs showed significant improvement in neurite growth cone
of nerve injury. However, porous 3D nanomaterials are more inter-
number and branching compare to negative charged surface MWCNTs
esting for further research and development to understand how neurons
[220]. The result supported that positive and neutral charge surfaces
transfer the information and helps in communication need to be in-
are promising materials for neural tissue engineering. Tay et al. in-
vestigate.
vestigated the effect of differentiation medium on mesenchymal stem
cells (MSC) behavior presence of carboxylated SWCNTs [221]. Em-
5. Conclusions
bryonic stem cells (ESC) offer the potential to create uniform popula-
tions of any cell type in the body, including the cells of the brain and
In this review, several nanomaterials were discussed with their
nervous system. It has been demonstrated that ESCs can be induced to
advantages and disadvantages and recent progress of their applications
differentiate toward the neural lineage, and there have been early
in neuroengineering. The importance of these nanomaterials in neu-
studies investigating CNTs materials in this regard [222]. Through li-
roengineering applications was thoroughly reviewed with the aim of
thography technique, SWCNT patterns were fabricated by Park et al.
developing the neuroengineering approach to prevent or treat neuro-
which showed MSC preferred to attached, spread and elongation
logical disorders in mind along with promising results in vitro and in
through patterns [216]. The technique can be suitable for control the
vivo. Compare to other nanomaterials biodegradable natural polymers,
direction of neuron. Kotov et al. thoroughly investigated the various
superparamagnetic iron oxide nanoparticles, carbon based nanomater-
nanotube based nanocomposites for differentiation of mouse neural
ials, silica nanostructures have been shown excellent properties and
stem cells. They found interesting results for layer-by-layer assembled
superior performance in neural cell differentiation and outgrowth.
SWCNT nanocomposite. Jan and Kotov studied the differentiation of
polymeric nanofibers, CNTs and graphene were showed excellent in
mouse embryonic neural stem cells to neuron from the cortex on layer-
vitro and in vivo performance. 10 mm injured peripheral nerve was
by-layer SWCNTs-polyelectrolyte multi layer thin films [215].
successfully regeneration using aligned NGCs nanofibers. Using 10–12
Fig. 16(V) presents mouse embryonic 14-day cortical neurospheres
layers of NGCs aligned fibers 17 mm nerve injury was repaired suc-
differentiated as dissociated single cells and small clusters on and (PEI/
cessfully. Neutral and positive charge MWCNTs showed significant
SWNT)6-, PLO-, and (PEI/SWNT)6(PLO)-coated coverslips, Light
improvement in neurite growth cone number and branching compare to
16
negative charged surface MWCNTs. Rat and monkey brain electrical [10] G.-Y. Wang, K.-I. Hirai, H. Shimada, The role of laminin, a component of Schwann
stimulation was recorded using tungsten and stainless steel wire elec- cell basal lamina, in rat sciatic nerve regeneration within antiserum-treated nerve
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Journal of Drug Delivery Science and Technology 57 (2020) 101617

Contents lists available at ScienceDirect

Journal of Drug Delivery Science and Technology

Advances in nanotechnology and nanomaterials based strategies for neural T

1. Introduction of peripheral nerve is typical, but not exclusively caused by traumatic

Fig. 2. Diﬀerent type of cells used in neural tissue engineering. Reproduced

Fig. 1. An overview of diﬀerent neural tissue engineering approaches through

enhanced by implanting cells and growth factors through scaﬀolds [5].

physicochemical properties of nanomaterials can lead to possibilities to

Drug or gene delivery to the CNS is a key focus for neuro-surgeons.

microscopy images, SEM images and WST-8 reduction activity of dif-

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