Journal Pre-proofs

Biological and synthetic template-directed syntheses of mineralized hybrid

and inorganic materials

Chen-yu Wang, Kai Jiao, Jian-fei Yan, Mei-chen Wan, Qian-qian Wan,
Lorenzo Breschi, Ji-hua Chen, Franklin.R Tay, Li-na Niu

PII: S0079-6425(20)30076-1
DOI: https://doi.org/10.1016/j.pmatsci.2020.100712
Reference: JPMS 100712

To appear in: Progress in Materials Science

Received Date: 28 July 2018

Revised Date: 24 January 2020
Accepted Date: 30 June 2020

Please cite this article as: Wang, C-y., Jiao, K., Yan, J-f., Wan, M-c., Wan, Q-q., Breschi, L., Chen, J-h., Tay,
Franklin.R, Niu, L-n., Biological and synthetic template-directed syntheses of mineralized hybrid and inorganic
materials, Progress in Materials Science (2020), doi: https://doi.org/10.1016/j.pmatsci.2020.100712

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Biological and synthetic template-directed syntheses of mineralized hybrid and inorganic
materials

Chen-yu Wang1, Kai Jiao1, Jian-fei Yan1, Mei-chen Wan1, Qian-qian Wan1, Lorenzo Breschi2,
Ji-hua Chen1*, Franklin. R Tay3*, Li-na Niu1*

1 The Fourth Military Medical University, Xi’an, Shaanxi 710032, P. R. China

2Department of Biomedical and Neuromotor Sciences, DIBINEM, University of Bologna -

Alma Mater Studiorum, Bologna, Italy

3The Dental College of Georgia, Augusta University, Augusta, Georgia, USA

*Corresponding authors: Prof. Li-na Niu, The Fourth Military Medical University, Xi’an,
Shaanxi, China. Email: niulina831013@126.com; Prof. Franklin R. Tay College of Graduate
Studies, Augusta University, Augusta, GA, 30912, USA. Email: ftay@augusta.edu; Prof. Ji-
hua Chen, the Fourth Military Medical University, Xi’an, Shaanxi, China. E-mail:
jhchen@fmmu.edu.cn

1
Abstract
Throughout the course of evolution, organisms have produced biominerals with hierarchical
structures derived from organic templates. Over the last couple of decades, scientists have
adopted sophisticated structures as templates for preparing pure or hybrid inorganic materials
that bear the same morphologies as their biological counterparts. The present review provides
a broad overview on the state-of-the-art research in the field of mineralized inorganic and
hybrid materials, using functional biological or synthetic templates that have been adopted for
biomedical, physical, chemical and environment applications. The synthesis, properties, and
progress of these bio-inspired materials are reviewed to provide a backdrop for future research
in various arenas.

Keywords: biotemplates; hybrid materials; inorganic materials; synthetic templates

2
 Table of contents
1. Introduction
2. Biomineralization – lessons from nature
2.1 Structures of biominerals: insights of engineering
2.2 Mechanisms of biomineralization: insight of biomolecules
3. Synthesis of hierarchical structures
3.1 Bottom-up technologies
3.2 Top-down technologies
3.3 Outlook in engineering of materials
4. Biological templates for materials manufacturing
4.1 Nanoscale templates
4.1.1 DNA-templated materials
4.1.2 Protein-templated materials
4.1.3 Chitin-templated materials
4.1.4 Lipid-templated materials
4.1.5 Virus-templated materials
4.2 Microscale templates
4.2.1 Hierarchically- or periodically-porous structures
4.22 Hollow structures
4.3 Macroscale templates
4.2.1 Protein-templated gradient materials
4.2.2 Hierarchically- or periodically-porous structures
4.2.3 Hollow structures
5. Synthetic templates for materials manufacturing
5.1 Phage display strategy
5.2 Synthetic organic templates
6. Applications of template-directed inorganic and hybrid materials
6.1 Biomedical science
6.2 Chemical industry
6.3 Environmental protection
7. Conclusions and outlook
 Abbreviations

6HB 6-helix bundle

ACC amorphous calcium carbonate
ACP amorphous calcium phosphate
aAPC artificial antigen-presenting cell
AM additive manufacturing
AMP adenosine monophosphate
APTES 3-aminopropyl-triethoxysilane
ATP adenosine riphosphate
CaP calcium phosphate
COM calcium oxalate monohydrate
CNC cellulose nanocrystals
CNT carbon nanotube
CSDA co-structure directing agent
D dimensional (as in 1D: one-dimensional)
DNA deoxyribose nucleic acid
ECM extracellular matrix
Fmoc-Val fluorenylmethoxycarbonyl-valine
g-CN graphitic carbon nitride
GMP guanosine monophosphate
GO graphene oxide
GPTMS 3-glycidoxypropyltrimethoxysilane
HAp hydroxyapatite
HHC human hair-derived carbon
HSA human serum albumin
IDP intrinsically-disordered proteins
MOF metal–organic framework
MSC mesenchymal stem cell
NP nanoparticle
PAMAM poly(aminoamine)
PHMS pollen-structured, hierarchically meso/macroporous silica sphere
RNA ribonucleic acid
SiRNA small interfering RNA
SF silk fibroin
SLN solid lipid nanoparticles
SWCNT single-wall carbon nanotube
TASA template-assisted self-assembly
TEOS tetraethylorthosilicate
TMOS tetramethoxylsilane
TMV tobacco mosaic virus

4
1. Introduction
Biological systems have, through the process of biomineralization, created complex
hierarchical mineralized structures in which the crystalline phases and multi-scale architectures
are precisely orchestrated by a template consisting of biomolecules. The organic template not
only endows mineralized tissues with better resilience compared with the pure minerals, but
also regulates the mineralization process, including nucleation, growth, phase transformation,
orientation and assembly. Biomineralization is an exquisite example of self-assembly in nature,
which cannot be duplicated by synthetic methods without templates. Over the last couple of
decades, scientists have adopted sophisticated natural structures as templates for preparing
inorganic and hybrid organic-inorganic materials, the structures of which are directed by the
self-assembly of biomolecules. These biomaterials possess morphologies that resemble their
biological counterparts. Inspired by nature, synthetic templates mimicking natural templates
have also been used for material assembly, with the manufacturing processes accomplished
under more stringently-controlled conditions.

Reviews on the use of biological templates for creating nanostructured inorganic materials
dated back to 2006 [1]. While most of these reviews are focused on template-directed synthesis
of inorganic materials such ceramic oxides, semiconductors and metals [2], the present review
will include both inorganic and hybrid organic-inorganic materials that are synthesized using
biological or synthetic templates, as well as their potential applications. Current challenges
associated with template-directed synthesis, such as template removal, industrial-scale
production and the toxicity involved in their synthesis will also be covered.

2. Biomineralization – lessons from nature

Since the holding of first symposium on biomineralization in 1970, research on the
structure of biominerals and their substitutes has been nothing short of phenomenal. There are
at least 60 different biominerals in nature, of which calcium phosphate, calcium carbonate or
silica is the most abundant inorganic component [3]. These mineralized structures are
characterized by the presence of an organic matrix produced by the cells of that organism.
These organic matrices are responsible for establishing structural hierarchy and play strategic

5
roles in the mineralization processes and outcomes. They contain a combination of proteins,
polysaccharides and lipids that act as nucleation sites, promotors or inhibitors during
biomineralization [4]. The hierarchical architecture of these templated materials spans from the
nanoscale to the macroscale [3]. Scientists and engineers continue to be fascinated by natural
mineralized structures, which are lightweight and offer a combination of mechanical properties
such as stiffness, strength and toughness that often surpass those of their components by orders
of magnitude [5]. With the advent of contemporary characterization techniques and modeling
tools, scientists are beginning to decipher the intricate interplay between inorganic and organic
components, generally integrated over multiple length-scales, that endow natural structures
with their unique properties [4,6].

2.1 Structures of biominerals: insight of engineering

The adage “structure determines performance” is exquisitely demonstrated in natural
biomaterials [7]. Investigations on biomaterials using computational, experimental and
analytical tools identified that almost all natural biominerals are repetitions of some form,
comprising a relatively small number of polymeric (proteins or polysaccharides, for example)
and ceramic (calcium salts or silica, for example) components or building blocks, which are
often composites themselves [8]. These repetitions are coined “structural-design elements” [9].
It is the ordered arrangement of these elements at the nanoscale level that results in the high
strength and stiffness of biomaterials at the macroscale [10]. Examples of the structure–
function relationships in biomaterials are present in organisms derived from varying taxonomic
ranks (Figure 1).

Using bone as an example, bone displays at the macroscopical level non-uniform

variations in mineral-to-collagen and phosphate-to-carbonate ratios along its length [11]. There
is also a gradient of increasing density in the radial direction from the interior spongy bone to
the exterior compact bone. At the micrometer level, the mineralized collagen fibrils spiral with
varying degrees, periodically around the central axis with local mineral content changes within
the lamellae of osteons [12]. At the nanometer level, the collagen fibrils consist of twisted type-
I collagen molecules with plate-shaped apatite (HAp) nanocrystals [13]. Marked
heterogeneities exist at the nano-scale of individual collagen fibrils because of the underlying
6
local structural and compositional variations [14].

It is apparent from Figure 1 that different organisms have developed diverse material
design strategies to address the natural challenges associated with convergent evolution [15-
19]. For example, fibrous structures provide high tensile strength but effectively no
compressive resistance. This structural-design element is employed in natural materials such
as bone, bamboo and dentin. Helical structures may either be in the form of a twisted ply that
provides in-plane isotropy and increased toughness, or reinforcements that provide torsional
rigidity. As a result, helical structures are found in various structural and protective materials
such as fish scales, crab shells and insect exoskeletons. The contributions of other design
elements are summarized in a recent paper [9]. A design strategy that has been overlooked by
that paper is chiral biomineralized structure. The helical arrangement of biominerals mentioned
above is an embodiment of the chiral structures which are common in nature [20], ranging from
the nanoscale to the macroscale (Figure 2). In the nanoscale, the chiral morphology of calcium
oxalate monohydrate (COM) crystals can be identified in the leaves of Solanacea plants
(Figure 2a and 2b). Related research identified that the crystal-associated macromolecules are
chiral and rich in the amino acid residues Gly, Glx and Ser. These amino acids promote
preferential development of the {120} faces of COM and induce crystal chirality. Most
organisms utilize at least two of these “structural-design elements” to provide a complex array
of multifunctional biological properties. Regardless of the number of “structural-design
elements” applied, the basic tenet for building biological minerals is that organic molecules
provide nucleation sites for the inorganic molecules. The complexity of organic molecular
morphology, in turn, determines the diversity of inorganic minerals.

Among the structural-design elements, gradient draws the most attention from engineers
because of two reasons: a) the scale for gradients is broad in biological materials (e.g.
tendon/ligament-to-bone connections and dentin-enamel junction in the human body, shells
and sponge spicules); b) gradient makes the combination of dissimilar components in
biomaterials possible and enhances the properties and functionalities, including mitigating
stress concentrations, avoiding marked mismatches in properties and preventing crack
propagation at the interfaces [7]. The idea of functionally-graded materials was first proposed
7
in the 1980s [21]. In the context of materials design and evolution, gradients are fundamentally
associated with changes in two sorts of ingredients, chemical compositions/constituents and
structural characteristics. The latter encompasses the arrangement, distribution, dimensions
and orientations of structural building units. Biological materials utilize gradients to enhance a
series of properties and functionalities, including load-bearing and support capabilities, contact
damage resistance for predation and protection, interfacial strengthening and toughening, as
well as other non-mechanical functions [22]. It is important to mention that the interfaces
between dissimilar components play a critical role in maintaining structural integrity and
supporting the specific functions of biological materials [18]. Achieving a sophisticated
structural interface in synthetic materials poses a formidable challenge in contemporary
materials engineering technology.

Exploring the structure of natural biominerals offers a journey toward understanding what
is required for the synthesis of bioinspired materials that possess similar performance, in terms
of (i) hierarchical transport network, (ii) force balancing and (iii) dynamic self-organization as
their natural counterparts. Figure 3 contains examples of templated materials that mimic natural
performance. Nature-inspired engineering is not based on mimicking nature out of context, or
succumbing to superficial analogies, but rather, on taking a scientific approach to uncover the
fundamental mechanisms that are responsible for the desired traits [23]. These mechanisms are
subsequently applied to designing and synthesizing artificial systems that mimic the traits of
the natural model. Thus, nature-inspired designs may not even superficially or morphologically
resemble their natural counterparts, but rather function or behave as such [24]. Nature-inspired
designs have widespread applications in the medical, chemical and physical arenas [25,26].

2.2 Mechanisms of biomineralization: insight of biomolecules

Mineral deposition is a physicochemical process that, in living organisms, is regulated by
cells and by the intracellular and extracellular matrices they produce [4]. In the past few years,
several papers that explore the potential mechanisms of biomineral formation appear to have
shed light on the process of biomineral self-assembly [27-31]. Consensus favors the initial
assembly of an organic womb or cocoon prior to the onset of crystallogenesis. Another
unanimous opinion is that in purely chemical terms, a mineral will not precipitate unless its
8
solubility product is exceeded, either by increase in the concentration of its component ions, a
change in temperature or pressure, or the addition of a surface that lowers the activation energy
for initial mineral formation (Figure 4a). There is, however, less consensus on the contribution
of the classical or non-classical crystallization theory to the mechanics of interfaces in
biological materials. Both of these uncertainties may be interpreted by biomolecules to some
extent.

Investigations of biological macromolecules provide the clues that led to the development
of the non-classical crystallization theory. Previously, the roles of these macromolecules during
biomineralization were unclear because of the difficulty in extracting them from biominerals
[3]. For example, scientist had been able to extract the organic matrix from the nacre of abalone
shell as early as the 1960s. Subsequent analyses indicated that control of the phase of calcium
carbonate formation (calcite, vaterite or aragonite) was achieved by the organic matrix.
However, researchers were unable to isolate the peptides critical for this process from crude
organic matrices because of limitations in peptide analysis during that era [32]. Recent
advances in biotechnology have isolated several principal peptides from the abalone nacre.
Using reverse-phase high-pressure liquid chromatography and sodium dodecyl sulfate-
polyacrylamide gel electrophoresis, the chemical structures of these peptides have been
identified [33]. These peptides interact with Ca2+, provide nucleation sites and exert different
effects on the crystallization of Ca2+ [34-36]. A recent review of intrinsically-disordered
proteins (IDPs) that participate in vertebrate and invertebrate biomineralization reported that
post-translational modification regulates the interactions of those proteins with mineral phases
and modulates the mineralization process [4]. Post-translational modifications in the form of
cleavage and phosphorylation enable IDPs to fold in specific regions of the molecule to
stabilize amorphous mineral clusters, while leaving other unfolded regions to interact with
growth factors, nascent crystal or other noncollagenous proteins (Figure 4b). Although
amorphous mineral clusters themselves are thermodynamic unstable, their interaction with
IDPs results in kinetic stability.

As mentioned above, interfaces play a critical role in maintaining structural integrity and
supporting the specific functions of biological materials. Although the strength and toughness
9
of the interfaces are 2-3 orders of magnitude lower than the strength and toughness of the
materials themselves, large deformations of biomolecules at the interface are critical for energy
absorption and for producing large deformations at the macroscale, as well as generating
powerful toughening mechanisms [6]. The interfaces of nacre, bone and wood utilize three
strategies to achieve this behavior (Figure 5): a) organic materials show large deformations
generated by molecular sacrificial bonds (as seen in nacre and in nanoscale bone); b) frictional
forces provide resistance to interfacial sliding over unlimited sliding distances, as seen in nacre
[37], and along the interfibrillar interfaces and the cement line in bone [38]; c) hydrogen bonds,
which are inherently weak, can still provide appreciable cohesion in large coordinated numbers
[39]. Hydrogen bonds can break and re-form dynamically, providing cohesion over long sliding
distances (as seen in wood). Biomolecules in the nanoscale are responsible for the ductility of
bone and wood and contribute to crack deflection and crack bridging mechanisms that occur
at the microscale. In materials engineering, frictional interaction at the interfaces is used in
composites, most notably in fiber-reinforced composites, but are also adopted for the
development of more recent bioinspired materials [40,41].

3. Synthesis of hierarchical structures

Hierarchical biomaterials, which comprise relatively scanty constituents, are natural
composites that exhibit superior mechanical properties [42]. A salient question to ask is
whether humans can emulate such designs and meet the challenge of creating synthetic
materials with similar forms and functions. Synthesis of templated materials may be divided
into two aspects: the synthesis of organic templates and the deposition of inorganic minerals.
There are two strategies for preparing organic templates. The “top-down” strategy refers to the
extraction of nanostructure from natural macroscopic materials via physical or chemical
methods, whereas the “bottom up” strategy involves assembly of macromolecules into nano-
and macrostructures [43]. The present section will focus on the biotemplating process.
Mineralization of biotemplates derived from living organisms or natural raw materials will be
addressed in subsequent sections.

3.1 Bottom-up technologies

10
 Bottom-up approaches share common features in the manner how living organisms
sequentially deposit matter to build biological materials in nature. Bottom-up strategies are also
known as soft-template methods, implying the use of surfactants to facilitate the generation of
biomolecules from micelles (direct or inverse) [44]. Unlike conventional methods of directly
extracting organic components from natural materials (such as collagen from rat tails [45] and
the chitin from shell nacre [46]), different approaches have been utilized. These approaches
range from self-assembly of biopolymers (peptide, deoxyribosenucleic acid (DNA) and protein)
[43,47,48], to the application of phage display technologies to screen peptides that optimally
promote mineral nucleation [49]. They have been utilized for the design of synthetic organic
or hybrid matrices [50,51]. Self-assembly of biopolymers as organic templates enable control
over the size or shape of particles [52]. An organic framework with ion-binding sites that
promotes heterogeneous nucleation and the formation of hierarchical structures at the
nano/micro scale is necessary to achieve macroscale architecture. Different biomolecules such
as proteins, peptides, DNA and viruses have been used for self-assembly into various
nanostructures including 0D nanoclusters/nanoparticles (NPs), 1D nanofibers/nanotubes, 2D
nanosheets/films/membranes and 3D hydrogels [53-55]. Based on these reviews, it may be
concluded that internal interactions such as hydrogen bonds, electrostatic interaction,
hydrophobic interaction, π–π interaction, DNA/ribonucleic acid (RNA) base-pairing and
ligand–receptor interaction are involved in mediating the self-assembly of biomolecules and
promoting the formation of biological macro, micro and nano-structures. Generally, self-
assembly of biomolecules is related to single or multiple intra- and inter-molecular interactions.
In addition, self-assembly of biomolecules is highly-sensitive to external stimulations.
Accordingly, many strategies, including adjusting the solution conditions (pH, ionic strength
and temperature), using organic stimulators (ethanol, surfactants and others), and adding
nanoparticles or enzyme stimulators, have been found to effectively promote the self-assembly
of biomolecules [56].

Figure 6 summarizes the formation mechanisms and strategies of various biomolecule-

templated nano-materials based on bimolecular self-assembly. Four typical strategies have
been utilized for the generation of bioinspired hybrid materials: (i) molecule–molecule inter-
11
action, (ii) molecule–material recognition, (iii) molecule- mediated nucleation and growth, and
(iv) molecule-mediated reduction/oxidation. For the first two strategies, the binding force
depends on electronic binding forces. For the third strategy, biomolecules or self-assembled
nanomaterials can direct the nucleation and formation of nanoclusters, NPs and others in the
absence of additional reducing reagents. For the fourth strategy, molecule-mediated
reduction/oxidation is based on chemical reactions between the reducing/oxidizing agents and
the organic templates. Bimolecular superstructures serve as building blocks for the binding and
assembly of various inorganic NPs for hybrid nanomaterials.

The rapid development of 3D printing technology brings new insights to material

engineering. The step-by-step element addition in 3D printing is similar in form and principle
to additive manufacturing (AM) [57]. The potential of AM technologies in replicating the
structural features of biological materials lies in their ability to spatially control the local
microstructure and chemical composition from the bottom-up in a layer-by-layer fashion.

3.2 Top-down technologies

Many living organisms develop highly complex structures with unique morphologies. In
the past decade, many of these creatures have been introduced as templates to synthesize nano-
and micro-materials, including diatoms, plants, viruses and bacteria (particularly flagella) [. In
contrast to AM approaches, the top-down strategy involves reducing materials, via reducing
raw materials or physical treatment of raw materials, to render them smaller in size or capacity
but without altering their morphology or chemical composition. This strategy is also known as
the hard-template method, which means that the template is prepared well in advance.
Biopolymers derived from living organisms are strongly bonded and entangled through
hydrogen bonding, van der Waals force and other interactions. These bonds may be destroyed
by mechanical treatment. Apart from grinding [57], other mechanical techniques such as high
pressure homogenization [59], high-speed blending [60], aqueous counter collision [61] and
pulsed ultrasonication [62] have also been used successfully to fabricate organic matrix.

3.3 Outlook in engineering of materials

The capacity for bone to remodel and heal exists in stark contrast to the concept of static

12
biomineralization. This is strikingly different from other biomaterials such as eggshells,
coccoliths and mollusk shells which are initially deposited through biomineralization, and upon
completion, are no longer under direct control of the organism or the cells involved in
mineralization. The teeth of polyphyodonts and diphyodonts are classified as quasi-static
biominerals in which remodeling and self-healing are impossible [63]. Bone simultaneously
grows and functionally operates while its growth and function dynamically adapt to the needs
of the host organism. Dynamic mineralization is a cell-governed process which paves the way
for the development of self-adaptive materials. This phenomenon forms the basis of the
revolutionary 4D organization concept. In this concept, the 3D structure of materials is
integrated with the time dimension contributed by the dynamic roles played by cells involved
in mineralization and demineralization [64].

Successful adaption of such a dynamic concept would be of huge impact in biomaterials

engineering. For example, a hydrogel scaffold that is capable of programing the temporal (4D)
attributes of cellular decision-making in supporting 3D micro-cultures has been reported
recently [65]. Spatial light interference microscopy identifies that the underlying material
chemistry and geometry of the hydrogel nanocomposites are capable of directing cellular
attachment and temporal development within the 3D micro-cultures. This represents a useful
material system for 4D patterning of hydrogel scaffolds. Researchers predict that a self-
remodeling concrete or self-paving street is just the tip of an iceberg with respect to the
potential applications of 4D patterning. Future research lies in the achievement of quasi-static
processes, in which mineralization is continuously tuned and precisely controlled during the
formation of structures. By switching from a static view of ceramics to bio-inspired and quasi-
dynamic concepts, such an approach is pivotal in changing the field of solid-state material
processing [64].

4. Biological templates for materials manufacturing

Biological systems create complex structures and optimized properties to adapt to
environmental changes through billions of years of evolution and natural selection [66].
Although previous studies have analyzed the structures of highly-ordered natural biological

13
materials from the nano to the macro scale, replication of these sophisticated natural
architectures is still beyond the realms of contemporary large-scale manufacturing for
following reasons [4,14,31,67]. Firstly, organic templates found in nature are complex in
structure and chemical composition (mostly proteins), with profound property variations in
different domains. Secondly, most of the biomineralization process proceeds in a biological
fluid environment which supplies a variety of small molecules that participate in the regulation
of such a process. In bioinspired biomineralization, the organic templates are coined hard
templates, which supply nucleation sites and control the external environment of the crystallites.
The small molecules are known as soft templates, which control the size and morphology of
the crystallites, and function as stabilizers to generate kinetically-stable microemulsions,
micelles and other aggregates formed in solution. As such, hydrolyzing the minerals from gross
biological structures and leaving only organic components solves the problem of designing
complex hard templates [68]. Some self-assembling biomolecules (DNA [69] and collagen)
can also control the size or shape of particles. Electrostatic forces play a critical role in this
self-assembly process, and positively-charged biomolecules may interact directly with
negatively-charged minerals to form nanohybrids. Thus, the use of biological templates
directly solves the first problem described above. The second problem is related to the creation
of an artificial environment in vitro to mimic the biological environment in vivo. Two
predominant strategies may be employed: the first by adding small molecule regulators, and
the second by controlling reaction conditions such as temperature, pH, external magnetic field
and electric field [48] to assist in the reaction. In this section, recent achievements in biological
templated manufacturing over the past five years will be summarized, with a classification that
is based on the size and type of the templates.

4.1 Nanoscale templates

Nanostructured materials such as pure nanostructured calcium phosphates (CaP) [70], and
hybrids with metal NPs such as carbon nitrides and metal NPs [71], are recognized as
promising nanocarriers for drug/gene/protein delivery and photocatalysis. This is attributed to
the high specific surface area, pH-responsiveness, degradability, high cargo-loading capacity
and sustained release capability of the nanostructured materials. To control the structure and
14
surface properties, various nanoscale biological templates with excellent biocompatibility,
such as nucleic acids, proteins, peptides, liposomes and polysaccharide have been used for
synthesizing nanostructured materials. These nanoscale templates (1) act as a biocompatible
organic phase to form biomolecule/mineral hybrid nanostructured materials; (2) serve as a
biological template for biomimetic mineralization of nanostructured materials; (3) act as a
biocompatible modifier to coat the surface of nanostructured materials, prevent their
aggregation and increase their colloidal stability. Under heating conditions, biomolecules can
(1) control the crystallization process of nanostructured materials by forming
biomolecule/nanostructured material containing nanocomposites before heating; (2) prevent
the rapid and disordered growth of nanostructured materials by chelating with metal ions to
form precursors. This section focuses on the important roles of nanoscale biomolecules in
guiding the design and controlled synthesis of nanostructured materials [72-74]. Four common
biomolecules that often appear as polymers are DNA, protein, lipid and polysaccharide. When
they are used as biological templates for nucleation, they often combine with one another to
form hybrid compounds. The following subsections are intended to highlight their unique roles
as mineralization templates. Nano-nucleation systems that exist in nature (such as bacteria and
viruses that may be used as mineralized templates) and combinations of the aforementioned
biological macromolecules will be elaborated subsequently.

4.1.1 DNA-templated materials

The most notable feature of DNA is its chiral helix. Establishment of stable double strands
in DNA via hybridization of complementary strands is central to the double helix structures.
Such a process is driven by the formation of stacked Watson–Crick base pairs with the uniform
diameter of 2 nm, pitch length of 3.4 nm and persistence length of about 50 nm. The
arrangement of nucleotides into a double helix makes DNA a perfect candidate for use as a
mineralization template. The double helical structure preserves the chemical integrity of the
nucleotides by placing them inside the hydrophobic core of the helix. The phosphate backbone
accounts for solubility in a biological environment and the sugar moieties support
conformational pre-organization for base pairing [75].

DNA-templated nanostructures may be classified into four types, namely, 0D

15
nanoparticles, 1D wires/nanotubes, 2D films/arrays and 3D structures, examples of which are
shown in Figure 7. DNA-templated 0D Ag nanoclusters of a few tens of atoms have attracted
much attention over the last several years because of their very strong absorption and efficient
emission properties. These DNA-templated Ag nanoclusters show strong, sometimes chiral
absorption bands in the visible to near-infrared range [76]. Such a property is drastically
different from the surface plasmon resonance typically observed around 400 nm for the larger
Ag nanoparticles [77]. The chiral arrangement and ultra-small diameter of the DNA-templated
Ag nanoclusters render them spectrally tunable, photo-stable, strongly absorbing and efficient
emitters with large Stokes shifts. These nanoclusters are highly attractive for sensor, bio-
labeling and drug delivery applications [78]. Figure 7a demonstrates the ability of helical DNA-
grafted supramolecular polymers in loading a model cargo of Au nanoparticles [79]. DNA-
templated MoS nanoclusters [80] and DNA-templated Cu/Ag nanoclusters [81] are emerging
as a new class of functional nanomaterials with promising application in biology, chemistry,
materials and energy science. Compared with other ligand-protected metal nanoclusters, DNA-
templated metal nanoclusters manifest intriguing physical and chemical properties that are
determined by the design of DNA templates. For example, DNA-templated Ag nanoclusters
can be made highly-fluorescent, with tunable emission colors and enhanced stability, by tuning
the sequence of the encapsulating DNA template [81].

Formation of 1D fibers and self-assembled multi-helical DNA-inorganic material fibers

[82] is possible via DNA-templated mineralization. The long, flexible DNA molecules are
capable of coiling and twisting with one another to form multi-helical DNA bundles in
relatively low concentrations. Water-soluble, bio-inspired DNA produced via self-assembly of
phosphodiester-linked pyrene oligomers functions as 1D templates for the synthesis of
silicified hybrid materials [83]. A 3-level helical structure can be identified within the silica
fibers: the DNA double-helix, secondary left-handed DNA packing and tertiary right-handed
twisting (Figure 7b) [84]. Formation of the higher-level helix is the result of competition
between the tendency to release the bending tension produced by the left-handed DNA stacking
and the increasing rigidity of the silica framework during silica condensation. The DNA strands
twisted with adjacent strands to form bundles of right-handed helical fibers. Similarly,
16
polyanionic DNA has been utilized as a template for binding Au nanoparticles, with the latter
functioning as niduses for the nucleation and growth of submicron to nanoscale Au wires [85].
DNA-templated Au wires have been used experimentally for improving the photovoltaic (i.e.
conversion of light into electricity) properties of solar cells.

Biomimetic synthesis of silica materials [75,84] or metals with highly-ordered 2D and 3D

hierarchical structures and complex architectures is made possible by using assembled DNA
as templates. Under ambient conditions of neutral pH and room temperature, 2D hexagonal
DNA-silica platelets with 2D-hexagonal p6mm and 2D-square p4mm mesostructures have
been synthesized by altering the DNA concentration. These DNA-silica platelets are 50-100
nm thick, corresponding to the length of DNA templates. The alignment, and arrangement of
2D mesoporous DNA-silica platelets may be thermodynamically and kinetically controlled on
quaternary ammonium-modified silicon substrate surfaces through template-assisted self-
assembly (TASA). As shown in Figure 7c, 2D p4mm mesostructured DNA-silica platelets are
vertically-aligned on the surface of an unpatterned silicon substrate by changing the pH of the
reaction solution. The aligned arrangement of DNA-silica platelets is attributed to electrostatic
interaction between the negatively-charged DNA and the positively-charged quaternary
ammonium-modified substrate surface [86].

Recently, DNA origami has been encapsulated in a protective silica shell using sol-gel
chemistry, with the addition of a positively-charged co-structure directing agent (CSDA) to
overcome electrostatic repulsion [87]. Introduction of critical bridging CSDA between DNA
and inorganic species results in different structures (e.g. multi-strand, 2D or 3D hexagonal, 2D
square) and different morphologies (e.g. spiral fibers, flakes, impellers, films) (Figure 7d).
Chiral DNA-silica 2D films may also be assembled over mica films via the use of a CSDA, as
well as Mg2+ as the chiral-inducing agent and the bridging ion that connects the crystalline
mica and the DNA molecules [88].

Self-assembly of metal nanoparticles into predefined 3D lattices has been an arduous

challenge until the emergence of 3D DNA origami [89]. DNA origami was first reported by
Dr. Paul Rothemund in 2006 in the form of 2D planar structures; the DNA-templating
technique was subsequently utilized in 2009 for construction of 3D DNA origami structures
17
[90]. Recently, 3D AuNP superlattices have been synthesized using a tetrahedron-shaped DNA
origami frame unit, with AuNP attachment sites at the vertices and inside the tetrahedron
(Figure 7e) [91]. Other 3D AuNP superlattices have been constructed using different
polyhedron DNA origami frames with AuNP connecting sites at their vertices (Figure 7f) [92].
A face-centered cubic lattice is obtained when an octahedral DNA origami frame and single-
stranded DNA-coated AuNPs (core diameter 10 nm) are employed. Likewise, a simple cubic
lattice is obtained from a cubic DNA origami frame; a body-centered-tetragonal lattice is
obtained from an elongated square bipyramidic DNA origami frame and a simple hexagonal
lattice from a prism-shaped DNA origami frame. In a different study, a crystalline 3D
rhombohedral lattice has been assembled from DNA origami-based “tensegrity triangles” (a
rigid DNA motif with three-fold rotational symmetry, consisting of three helices that are
directed along linearly-independent vectors). Using this framework, 20 nm AuNPs may be
positioned precisely on the “tensegrity triangles” prior to lattice growth (Figure 7g) [93]. Other
researchers reported the construction of ordered 3D lattices of AuNPs without rigid DNA
origami frameworks [94]. In that study, short 6-helix bundle (6HB) DNA structures with
single-stranded DNA attachment sites at both ends are used to assemble single-stranded DNA-
coated AuNPs into different configurations, depending on the size of the AuNPs.

Previous studies on the biomimetic synthesis of biominerals templated by DNA were

largely unsuccessful because of electrostatic repulsion between the template molecules and
inorganic source, both of which are negatively-charged under the neutral pH and ambient
temperature. Hence, the major challenge is to overcome electrostatic repulsion to enhance the
interaction between the negatively-charged DNA and silicate. Polyanionic DNA in solution
must be: 1) transformed from “anionic” to “cationic” species; or 2) bridged by structure-
directing agents that can interact with both DNA and minerals. As a result, the structures and
morphologies of DNA-mineral materials strongly correspond to the concentration of DNA
solution, pH values, the types of the structure-directing agents or counterions and the length of
DNA molecules [75].

4.1.2 Protein-templated minerals

Proteins comprise the most basic and important biomolecules in biomineralization. In
18
living organisms, the specific kind of protein utilized as mineralized template is in one-to-one
correspondence with the produced mineral (e.g. collagen to HAp in bones, silaffin to silica in
diatoms, silicatein to silica in sponge spicules and apoferritin to magnetite in bacterial
magnetosomes). In some organisms, the proteins used as templates are so many that scientists
identify them as a group of proteins, instead of coining them with specific titles (e.g. aspartic
acid-rich proteins for mineralization of calcium carbonate in mollusk shells). The use of natural
proteins for in vitro synthesis of inorganic or hybrid materials is attractive for two reasons. The
first is that production of biomimetic materials is conducted under reaction conditions that are
much milder than those used in traditional material-processing techniques. This renders bio-
enabled synthesis inherently a “green” procedure. Green processing improves the scalability
of the production of biological substitutes of natural hard tissues such as bone [95]. The second
reason is that the use of natural proteins enables an unprecedented combination of inorganic
and organic components to produce novel materials with applications ranging from electronics
and energy to medicine [2]. With nanomaterial engineering rapidly emerging in recent years,
the use of natural proteins harnesses the wisdom of natural biomineralization in the design of
novel hybrid materials, rather than simply imitating natural hard tissues. The recent progress
in protein-templated inorganic or hybrid materials will be summarized from two aspects: in
vitro reproduction of natural materials and the development of innovative materials through
adoption of biomineralization principles. The first aspect will be addressed in section 4.3
because most of the templated architectures are in the macroscopic scale. In the present section,
the use of self-assembled protein molecules as templates will be discussed. Materials
developed from these protein templates play strategic roles in biological systems including
gene delivery, tissue regeneration and molecular recognition.

Various 0D-3D self-assembled protein supramolecular structures have been used as

templates over the past 5 years [43,96]. Zero-dimensional protein biomaterials, including NPs,
nanospheres and rings, are examples of hybrid structures produced via protein self-assembly.
Nanocomposites comprising engineered proteins that can template the deposition of inorganic
metal ions have promising applications as biosensors, contrast agents, delivery vehicles and
therapeutics [97]. The macromolecular conformation and overall physicochemical properties
19
of protein-metal NP assembles may be manipulated by altering the protein secondary structure.
For example, pentameric coiled-coil proteins have been designed based on the five-stranded,
coiled-coil, histidine tag-containing structure of cartilage oligomeric matrix protein [98]. The
use of these engineered protein species with intact N-terminal hexa-histidine tags for
templating AuNPs results in the precipitation of large protein-AuNP aggregates. When the
histidine tags are cleaved from the engineered proteins to disrupt their coiled-coil structure, the
unstructured proteins produce protein-AuNP nanocomposites that remain stable and do not
aggregate. These hybrid protein-AuNP assemblies may be deposited on electrodes as tunable
bionanocomposite kinetic barriers. Using similar genetically-engineered proteins with N-
terminal hexahistidine tags for templating the deposition of AuNPs, protein polymer-AuNP
nanocomposites are produced that exhibit enhanced binding and improved delivery of
curcumin, a small hydrophobic drug molecule, to a breast cancer cell line [99]. When compared
to pristine protein polymers, the protein-templated AuNP hybrid material demonstrates a >7-
fold increase in curcumin binding, ~50% slower release profile and >2-fold increase in cellular
uptake of curcumin.

A novel chimeric molecular template has been prepared using 2 proteins, silk fibroin and
albumin, which serve as promoter and inhibitor for HAp formation, respectively [100]. Zero-
dimensional HAp nanospheres are produced by the chimeric albumin-silk fibroin template,
whereas 1D HAp nanorods are generated using the silk fibroin template only. As shown in
Figure 8a, nanoparticle shape has an important impact on the cellular uptake by rat
mesenchymal stem cells (MSCs); HAp nanospheres are internalized faster by the MSCs than
nanorods. Although both HAp nanospheres and nanorods have no significant influence on cell
proliferation and migration, the nanospheres significantly promote osteoblastic differentiation
of the MSCs when compared to the nanorods.

Zero-dimensional Au nanoclusters have been prepared via one-pot reduction strategy

using fibrinogen as the protein template [101]. The Au nanoclusters are experimentally used
as nanoprobes for fluorometric detection of cysteine and Hg(II). The modified fibrinogen-Au
nanocluster exhibits red fluorescence, which is quenched by different concentrations of
cysteine and Hg(II), as determined by fluorometry (Figure 8b). Likewise, self-assembled
20
bovine serum albumin amyloid-like nanofibers have been used as scaffolds for the synthesis of
Au nanoclusters. These amyloid fibril-stabilized Au nanoclusters possess strong red
fluorescence and have been used for cysteine detection within living cells [102].

One-dimensional protein nanofibers have been used as templates for nanomaterial

assembly. For example, silk fibroin fibers have been used as templates for preparation of
mechanically stable, flexible and biocompatible ZnO nanotubes. Gold NPs are subsequently
deposited on the surface of the ZnO nanotubes via electrostatic absorption [103]. The
AuNP/ZnO nanotube assemblies are capable of catalyzing the reduction of H2O2 (Figure 8c).
The efficacy of the electrochemical sensor is attributed to the electro-catalytic property of ZnO
and the high electron transfer capability of the AuNP/ZnO nanotube assembly.

Two-dimensional protein macromolecules assembled in the laboratory have also been used
as mineralization templates. Elastin-like recombinamers are recombinant macromolecules
based on a recurrent amino acid motif in natural elastin. These biopolymers are biocompatible,
biodegradable and resemble proteins present in biominerals (IDPs, previously described in
section 2.2). The degree of disorder and order of elastin-like recombinamers may be controlled
to design supramolecular matrices that generate new functionalities. A 2D protein-mediated
mineralization process has been developed that harnesses the disorder–order interplay of
elastin-like recombinamers to program organic–inorganic interactions into hierarchically-
ordered mineralized structures [104]. The formed materials consist of elongated HAp
nanocrystals that are aligned into microscopic prisms (Figure 8d). The latter grow into
spherulitic structures that are hundreds of micrometers in diameter and further coalesce to fill
macroscopic spaces. These structures are potentially useful as acid-resistant membranes or
coatings in hard tissue repair with tunable hierarchy, stiffness and hardness.

Three-dimensional protein scaffolds have been used in biomedical engineering as artificial

implantable extracellular matrices (ECM) for supporting osseous growth in bone repair [105].
A novel 3D scaffold has been prepared using alternate layer-by-layer assembly of 10 layers
graphene oxide (GO) nanosheets and 10 layers of fibrinogen nanofibers on a silicon substrate.
The layer-by-layer assemblies are used to create a 3D HAp scaffold via biomimetic
mineralization in simulated body fluid [106]. The mineralized scaffold is biocompatible and
21
promotes the proliferation of L929 fibroblasts in in vitro cell cultures.

Ferritin, a 3D iron storage protein NP with a hollow interior cavity, may be chemically- or
genetically-modified to impart surface functionalities to encapsulate drugs or probes within the
nanocages via controlled and reversible assembly/disassembly [107]. Ferritin that does not
contain iron is referred to as apoferritin. Electrostatic attraction and specific amino acid-
inorganic binding present inside the interior cavity of apoferritin are essential for inorganic NP
growth [108]. Because the apoferritin protein cage can accommodate metal ions other than Fe,
Au/Pd core shell NPs and CeO2 NPs with controlled sizes have been produced within the
protein cages and used as catalytic nanoreactors [109]. To date, nanocrystals of a wide range
of materials have been synthesized using apoferritin cages as nanotemplates. For example,
CuS-apoferritin has been prepared using the interior cavity of apoferritin to control the size of
the CuS NPs. A water-soluble near-infrared dye is then conjugated to CuS-apoferritin, to
produce a CuS-apoferritin-dye nanocomplex with greatly-enhanced photothermal conversion
efficacy [110]. The nanocomplex is readily taken up by tumors because of the enhanced
permeability, retention effect and active targeting of apoferritin, and finds use in imaging-
guided photothermal therapy in vivo. Tumors can be ablated in vivo by combining CuS-
apoferritin-dye with irradiation of an 808 nm laser (Figure 8e). Other examples of
nanomaterials synthesized within apoferritin protein cages include metals (e.g. Cu [111], Au
[112], Ag-Au hybrid [113] and Pd [114]), metal/transition metal oxides (e.g. MnO [111],
Co(O)OH, Co3O4 [115] and Fe3-xCoxO4 [116] ), as well as semiconductors (e.g. CdS, CdSe,
CdTe [117] and ZnSe [118]). Apart from using the interior of the apoferritin cages for
preparation of inorganic NPs, hollow NPs may also be synthesized by coating the external
surface of the protein cages with metal ions. For example, apoferritin is first used for
encapsulating doxorubicin, an anti-cancer drug. The surface of assembly is subsequently
coated with a Au nanoshell to produce a nanoplatform that has photothermal properties because
of the unique surface plasmon resonance properties of the Au nanoshell. This nanoplatform
forms a multi-stimuli responsive drug release system, in which doxorubicin is released under
acidic and high temperature conditions to reduce the side effects associated with the anti-cancer
drug [112].
22
4.1.3 Chitin-templated materials
Chitin is derived from seafood wastes such as crab, shrimp and lobster shells. It is
abundant and renewable, and is an important chemical raw material. Chitin is poly[(1→4)-
linked N-acetyl-D-glucosamine] and is the second most abundant natural polymer after
cellulose. The degree of acetylation of chitin is typically around 0.90, because of the presence
of large amounts of 2-acetamido-2-deoxy-D-glucopyranose. The latter contributes to the strong
hydrogen bonds among chitin chains [59]. Chitin-based biomaterials are much sought after in
the field of tissue engineering and regenerative medicine because of their biocompatibility and
degradability by human lysozymes [119]. An important feature of chitin is its relatively high
thermal stability, which opens venues for its use in hydrothermal synthesis reactions [120].
Chitin possesses high crystallinity and does not dissolve into high temperature water, which
often results in decomposition of less stable compounds via hydrolysis, deacetylation or
dehydration during hydrothermally processing [121].

With increase in concentration, chitin nanocrystals self-assemble into a chiral liquid

crystal phase, which may be used as a template for the synthesis of nanoscopic silicon with
liquid crystal structure. Chitin-silicon composite materials have been prepared using chitin
nanocrystals as templates, through sol-gel processes involving reactive siloxane oligomers [56].
Using solvent exchange, chitin nanocrystals are stably dispersed in siloxane oligomers to form
ordered structure under electric [56] or magnetic induction [122,123]. Mesoporous silica is
produced after calcination of the chitinous template.

Chitosan is a deacetylated product of chitin. Adsorbent hybrid organic-inorganic

composite membranes suitable for ultrafilteration, catalysis and pervaporation have been
produced by depositing inorganic silica within the pores of chitosan scaffolds via sol-gel
reaction [124]. The chitosan scaffolds are freeze-dried and crosslinked with genipin prior to
the incorporation of silica. The short chains of genipin act as crosslinking bridges between the
two amino groups of chitosan. Tetraethylorthosilicate (TEOS) and 3-
glycidoxypropyltrimethoxysilane (GPTMS) are used as silica precursors. The GPTMS also
functions as a coupling agent between the inorganic network and the hydrogel. When examined
by scanning electron microscopy, the silica phase appeared as a continuous phase that covers
23
the walls of the chitosan pores but does not alter the porosity of the scaffold (Figure 9a). The
porosity and mechanical characteristics of the composite membranes may be tailored by
changing the TEOS:GPTMS ratio.

The properties of the chitin–nanooxide organic-inorganic hybrid composites may be tuned

by varying the chitin volume fraction. By adjusting the volume fraction of chitin nanocrystals,
mesoporous materials with low surface Si/Ti ratio, high specific surface areas and porous
volumes are produced, which may be used as heterogeneous catalysts for the sulfoxidation of
bulky compounds such as methyl-phenyl sulphide and dibenzothiophene [125]. Similarly,
mesoporous SiO2-TiO2 microparticles are obtained by mixing Ti4+ monomer precursors with
an ethanolic suspension of α-chitin nanorods. The siloxane oligomers are added in the second
step (Figure 9b). The chemical groups on the surface of the chitin crystals (hydroxyl and de-
acetylated amino groups) are used to complex Ti4+ prior to the formation of the siloxane
network. This favors the location of Ti sites on the pore surface, after removal of chitin by
calcination [126].

Because chitin is a hierarchical polysaccharide with a carbon backbone, it may be used as

a natural precursor for the fabrication of porous carbon materials. Chitin-related nano-carbon
materials include graphene, carbon nanotubes, carbon dots and carbon fibers [127]. Chitin
aerogels and chitin nanofibers have been used to fabricate carbon fibers with large specific
areas after pyrolysis and carbonization, for potential applications as filter media, electric
double-layer capacitors and highly-efficient catalysts [128]. Because chitin is a nitrogen-rich
compound (nitrogen content 6.9 wt%), there is potential in using it for synthesizing nitrogen-
doped carbon materials. Nitrogen-doped mesoporous carbon nanofibers have been synthesized
using crab shells [129] and chitin nanocrystals [130] as templates. Some of these nitrogen-
doped carbon materials are hierarchically-porous and demonstrate high capacitance and
excellent cycling stability, with the potential to be used as supercapacitors (Figure 9c) [131].

Because of its abundant hydroxyl and acetyl groups and the small number of amino groups,
chitin can form strong chelation interaction with metal ions. Thus, chitin
nanocrystals/nanofibers have also been fabricated for the adsorption of heavy metal ions in
bioremediation [132] and as templates for the construction of ceramic-containing (ZrO2; Figure
24
9d) and metal-containing composites [133,134]. Metal materials, including quantum dots and
those with hierarchical sub-micrometer structure or photoanodic structure, have been
fabricated using the chitin backbone from butterfly wings as templates [135]. At least seven
metals have been successfully used to replicate the original morphology of the butterfly chitin
skeleton, including cobalt, nickel, copper, palladium, silver, platinum, and gold (Figure 9e).
Such a method provides a general strategy for replicating chitin-based structures with fine,
hierarchical 3D morphology, and enables the conversion of sophisticated natural 3D bioorganic
structures into various otherwise unavailable metal structures with optical, electronic, magnetic,
thermal or catalytic applications [136]. Metal–organic frameworks (MOFs) are a new class of
high-performance materials with specific surface areas up to 7000 m2/g. These materials have
great potential to be used for gas separation, and as nonlinear optical materials heterogeneous
catalytic materials and energy storage materials. However, the majority of MOF synthesis
involve preparation of small- or medium-sized crystallites, resulting mostly in powders.
Suitable supporting materials need to be shapeable, cost-efficient and chemically inert. In 2015,
MOFs have been synthesized for the first time using chitin fibers as the supporting matrix [46].
Hollow chitin microfibers are extracted from dry marine sponges and Cu2+ are loaded on the
chitin microfibers for homogeneous deposition of Cu3BTC2. The MOF loading content reaches
53 wt%, exceeding most synthetic polymeric supports. The MOF crystals are mainly
concentrated in the internal part of the hollow fibers, indicating that the MOF is effectively
protected by chitin fibers from mechanical stress and abrasion. This composite has a
hierarchical pore system with high surface areas and pore volume, with excellent potential to
be used for filtration of toxic industrial gases.

4.1.4 Lipid-templated materials

Carbohydrate amphiphiles and phospholipids are basic building blocks of biomembranes
in living systems. By the same fundamental principles, lipid molecules self-assemble in
aqueous medium into aggregates with diverse microstructures. The morphology of these
microstructures depends on both the shape of the molecules and solution conditions, such as
lipid concentration, pH value and temperature. Among these morphologies, electrolyte vesicles,
ultrathin membranes, nanotubes, helical ribbons and helical tubes have been utilized as
25
templates to create nanosized and microstructured inorganic materials. Microscale lipid-
templated materials discussed in the present section will not be repeated in section 5.

Solid lipid nanoparticles (SLN) are biocolloidal dispersions that can be loaded with
hydrophilic or hydrophobic ingredients such as low molecular weight drugs or high molecular
weight proteins. They are useful in materials design for templating inorganic materials or
creation of functional hybrid organic-inorganic materials with further applications. For
example, hierarchical porous silica may be produced using SLN as templates. Such a
templating method combines the unique properties of mesostructures such as high surface area
and controllable sized pores, with those of macropores with high diffusion and high throughput
rates. Typical applications of these materials are separation, catalysis, sensing and tissue
engineering [137]. They also have potential applications as reservoirs in drug delivery systems
[138] or as inclusion cavities for macromolecules [139]. The strategy for preparation of SLN-
templated porous silica involves addition of a silica source (tetramethoxylsilane, TMOS) to
SLN dispersions at neutral pH [137]. The mixture is kept in an autoclave at 70 °C to enable
hydrolysis/polycondensation of the silica. Removal of the organic phase by
ethanol/dichloromethane extraction results in silica beads that contain 0.5–1.5 μm diameter
spherical macropores (Figure 10a). The morphology and the structure of SLN-templated
hierarchical meso–macroporous silica may also be tuned [140]. By optimizing the reaction
conditions such as hydrothermal temperature, TMOS amount or surfactant concentration, silica
capsules are obtained with polyoxyethylene sorbitan (Tween 20 and 40) imprinting of lipid
NPs, whereas block silica is obtained with Pluronic P123. Mesopore diameters of about 3 nm
are obtained with Tween 20, 5 nm with Tween 40 and 9 nm with Pluronic P123. The size of
the mesopores increases with the size of the starting micelles, from Tween 20 to P123. The
ordering at the mesoscale also increases with mesopore size: only wormlike silica is obtained
with Tween 20. Wormlike silica embedding hexagonally-ordered microdomains is produced
with Tween 40. Hexagonally-ordered silica with circularly-ordered mesoporosity is created
with the use of P123 as a porogen (Figure 10b).

Synthesis of mesoporous silica with four different morphologies, helical ribbon, hollow
sphere, circular disk and helical hexagonal rod is accomplished simply by changing the
26
synthesis temperature from 0 ºC to 10, 15, or 20 ºC [141]. Formation of mesoporous silica tape
and helical ribbon is shown in Figure 10c. Upon decrease in temperature to 0 ºC, partially-
neutralized chiral amphiphilic carboxylate molecules self-assemble into flat tapes with a
bilayer structure. This is achieved through hydrophobic interaction of the hydrocarbon chains,
in which the chiral molecules are packed parallel to their nearest neighbors at a zero-twist angle
with respect to their nearest neighbors. Silica microparticles may also templated from the lipid
bilayer of HeLa cells or human red blood cells and loaded with cytokines for paracrine cytokine
release [142]. As shown in Figure 10d, artificial antigen-presenting cells (aAPCs) may be
created using supported lipid bilayers on various cell-templated silica microparticles with
defined membrane fluidity and stimulating antibody density.

There are many protocols developed with other amphiphiles (lipids) for these types of in-
situ reactions with the primary focus on silica deposition and the secondary focus on metallic
or metallic oxide deposition. Some successful examples include evaporation-induced self-
assembly, liquid crystal templating of oxides, and electro-deposition of metals. For example,
ordered 3D metal-nanowire network films have been produced using a coating of lipid inverse
cubic phase as the template for electrodeposition of metal ions. Using such a method, platinum
films with previously unreported “single diamond” nanoarchitecture have been synthesized
inside the water channels of the bicontinuous cubic lipid phase [143]. The new methodology
represents a facile route for synthesis of a wide range of metal and semiconductor materials
with 3D cubic nanostructures. Shear flow-induced lipid vesicles and tubules have also been
exploited as templates for fabricating hollow platinum nanospheres and nanotubes as catalysts
for hydrogen evolution reaction [144].

4.1.5 Virus-templated materials

In the 18th century, the term “virus” was defined as a poisonous substance produced in
the body as a result of some disease. With the advent of virology as a scientific discipline, the
definition of virus was changed to a small, non-cellular obligatory parasite carrying non-host
genetic information. This advance not only improves our knowledge about the nature of viruses,
but removes the negative connotation [145]. The first milestone of virus benefiting human
beings was realized by phage display technology, which will be discussed in section 5. Another
27
milestone was reached around the year 2000, when viruses were recognized as nanomaterials
with the ability to encapsulate molecules within their capsids, to template biomineralization of
inorganic materials and to form self-assembled 2D/3D nanostructures. Although animal viruses
are widely recognized as delivery vehicles or ‘vectors’ for gene therapy, their use as
nanocarriers or nanotemplates has remained relatively limited because of safety concerns. For
this reason, plant and bacteria viruses have received considerably more attention than animal
viruses as mineralization templates.

One of the most attractive features of plant viruses is that their coat proteins can self-
assemble around synthetic materials and break down on raising the temperature beyond a
certain threshold. This feature offers a stable and biodegradable delivery platform or
mineralization template for the synthesis of various compounds. For example, hollow
mesoporous silica nanocapsules have been synthesized using unmodified cowpea mosaic
viruses as templates and used for controlled drug delivery [146]. Capsid proteins of the viruses
are denatured by increasing the temperature. After diffusion of the denatured capsid proteins
from the core, the pores that remained within the silica nanocapsules are used for loading
medicine (Figure 11a). Tobacco mosaic virus (TMV) with its rigid rod-like structure has been
used as a template for the deposition of various inorganic materials (metals and semiconductors)
on the exterior or interior surface of the capsid to form hybrid nanowires or films [147,148].
By coupling magnetosomes with TMV particles, “drumstick”-like TMV–magnetosome
complexes are formed (Figure 11b), which have broad application potential in the biomedical
and biotechnological fields [149]. Two-dimensional compartmentalized thin films with
thicknesses varying from a monolayer to submicron dimensions have been produced through
interfacial cross-linking of cowpea chlorotic mosaic virus protein cages [150]. Functional
cargos such as AuNPs, quantum dots and the enzyme horseradish peroxidase can be loaded
separately into these protein cages prior to their cross-linking (Figure 11c). These
compartmentalized thin films not only ensure that the cargoes are homogeneously dispersed,
but also display good catalytic activity. Using the sample principle, more complex hybrid
systems may be constructed from viral protein cages that have been preloaded with different
cargo or structures.
28
 Controlled self-assembly of virus shell proteins into hierarchically-ordered structures with
high surface area-to-volume ratios is employed for the synthesis of oriented, high surface area
nanomaterials for applications as electrodes, catalyst supports, sensor arrays, thermal barriers,
and energy storage devices [151]. Early in 2011, field-effect transistors based on TMV-
templated ZnO (a semiconductor) exhibit high electron mobility and sensitivity, transparency
in the visible light region and consume little power [152]. More recently, viruses and their
hybrid materials have found application in construction of functional devices such as
semiconductors [153] and sensors [154–156], as well as components in Li-ion batteries [157].
Electroconductive materials have been generated by making use of the electrostatic interactions
between TMV and the polymers polyaniline and polypyrrole, which enable in-situ
polymerization of the polymers on the TMV surface. Recently, it was found that covalent
attachment of hydrophobic polymer molecules prevents viruses from subsequent
mineralization [158]. In addition, the degree of the virus hydrophobicity, determined via a ZnS
mineralization test, may be tuned by the polymer properties. This strategy provides clues for
quantitative or intermittent mineralization (such as block compositions) of viruses in the future.

Another feature of bacteria and viruses is their cell-targeting functionality. This

characteristic has been harnessed for the synthesis phage-templated Au clusters as a
photothermal therapy treatment platform to kill prostate cancer cells in vitro [159]. The phage-
templated Au clusters are capable of maintaining their cancer cell-targeting functionality and
kill the cancer cells via localized heating in minutes upon very low light irradiation (Figure
11d). Because these phages are artificially-modified by peptides as templates, they are not
strictly natural and unprocessed bio-templates. Other related studies on phage-templated
materials will be elaborated in section 5.

From a chemical point of view, the principle of using plant or bacteria viruses as templates
resides is their supramolecular structure with a diverse variety of shapes, sizes and highly
symmetrical protein architecture. Viral particle-based templates consist of protein shells which
separate the interior volume and protect the cargo (i.e. the genome, enzymes or other molecules)
from the exterior environment. The protein shells are usually 2-5 nm thick and may have
selective and/or non-selective pores [160]. Further modifications of these shell proteins enable
29
other materials to be deposited. Genetic and/or chemical modification may be performed on
three surfaces: the exterior surface of the protein cage, the inter-surface between protein
subunits, or the inner surface of the protein shell (Figure 11e). The inner cavity of the protein
cage can deliver the genome, selectively store and protect ions, molecules, or encapsulate other
particles for drug delivery or other use. Many protein cages are robust enough to tolerate
genetic modifications without affecting the properties of self-assembly [161]. Detailed review
of these methods of modification is available from recent literature [150,162]. Although
functionalization via bioconjugation provides many possibilities, modification of protein units
through chemical reactions often results in protein denaturation or viral particle disassembly
and aggregation [163].

4.2 Microscale templates

Materials found in nature possess many inspiring properties such as sophistication,
miniaturization, hierarchical organizations, hybridization, resistance and adaptability. These
properties are acquired after billions of years of stringent selection [164]. Synthetic materials
have been created using templates derived from microorganisms such as diatom, fungi and
bacteria, plants such as wood, leaves, corn stalks and pollen grains, and animals such as
butterfly wings, compound eyes, hair and silk fibers. After mineralization, these templates
endow the inorganic or hybrid materials with sophisticated morphologies on length scales that
range from micrometer to millimeter, and even centimeter. Essentially, the structures of as-
obtained biotemplated materials mentioned in the section 4.2 and 4.3 may be divided into two
categories: 1) hierarchically- or periodically-porous structures, using diatoms, corn stalks,
peacock feathers, pollen grains, wood, green leaves, or butterfly wings as templates; and 2)
hollow structures (spheres, tubes or squares), using hairs, egg membranes, flagella or bacteria
as templates.

4.2.1 Hierarchically- or periodically-porous structures

The design and synthesis of hierarchically-porous and periodically-porous materials are
spurred by the immense potential of these materials in energy conversion and storage, catalysis,
photocatalysis, adsorption, separation and life science applications. The hierarchy of porosity
in natural materials enables the production of inorganic materials or organic-inorganic hybrid
30
materials with porosities at different length scales, including those with dual porosities (micro–
micropores, micro–mesopores, micro–macropores, meso–mesopores, meso–macropores) and
multiple porosities: micro–meso–macropores and meso–meso–macropores) [165]. Similarly,
natural materials with periodically-arranged structures or porosities have also been adopted as
templates for the fabrication of novel inorganic and hybrid materials with periodic-ordered
components [166]. While ample examples prevail, only a few will be illustrated here.

Diatoms are photosensitive freshwater organisms containing hydrated amorphous silica.

Almost 110,000 species have been discovered, ranging from 2 μm to 2 mm in size with
thousands of different structure and morphologies [52]. The outer surface of diatoms have well-
arranged areolae and a myriad of sieve pores (~40 nm) for exchanging nutrients and gases
[167]. They play an essential role on earth by producing 20% of the oxygen through capture of
atmospheric carbon. Inspired by their unique porous structure, favorable mechanical properties,
larger inner space and low cost, functionalized diatom biosilica have been used for drug
delivery [167]. Surface functionalization of diatom frustules and their impact on drug loading
and release characteristics of water-insoluble drugs have been recently studied [168]. Because
hydrophobic drugs exhibit poor solubility and may not effectively reach their destined sites,
diatom biosilica is utilized as natural drug carriers to facilitate drug loading. Surface-
functionalized diatom biosilica with dopamine-modified iron oxide NPs are loaded with
indomethacin, a common anti-inflammatory drug, to generate a non-invasive platform for
targeted drug delivery [169]. Graphene oxide has also been combined with diatom biosilica for
drug delivery applications. A novel pH-sensitive nanohybrid material (biosilica-GO) has been
produced by electrostatic or covalent coupling of the carboxyl groups on GO to the amine
terminal groups of 3-aminopropyl-triethoxysilane (APTES)-functionalized diatomaceous earth
particles [170] (Figure 12a). A higher indomethacin-loading capacity is achieved with the
covalently-attached biosilica-GO compared to that of biosilica-APTES. Other studies have
demonstrated the effectiveness of chemically-modified diatomite biosilica in the transportation
of anticancer molecules through the cell membrane [171], as well as its use as a non-toxic drug
carrier of small interfering RNA (siRNA) for cancer cell delivery [172]. Drug release is
dependent on the pore size and architecture of the biosilica structure [168].
31
 Diatom biosilica, which possesses peculiar morphological and chemical features, creates
new prospects for the development of biosensors [52]. Gold-silica nanocomposite synthesized
using diatom biosilica bind DNA effectively and is readily applicable in the biomedical field;
the diatoms are used as support material for AuNPs and used as catalyst for oxidation of d-
glucose to d-gluconic acid [173]. The nanostructural arrangement enhances light emission by
quantum confinement and supports label-free biomolecule detection. The highly porous
surface chemistry of diatom biosilica also facilitates conjugation with organic and inorganic
dyes and with other biomolecules for biosensor applications [174]. For example, AgNPs have
been deposited through photo-induced reduction on the surface of diatom biosilica for
biosensing of ammonia [175].

Corn stalks have been utilized as precursors to prepare two-dimension hierarchically-

porous carbon composites for high performance battery anodes and cathodes, in which the
porous carbon nanosheets serve as host carbon matrices for functional nanoparticles [176]. The
corn stalks are chemically-activated to obtain the 2D carbon-based materials with hierarchical
pores and high specific surface areas. Afterwards, TiO2 particles are embedded into the porous
carbon sheets via infusion, followed by calcination in an inert atmosphere (Figure 12b). The
resulting TiO2/carbon composite is utilized as high performance anodes in Li-ion batteries,
with excellent cycling stability, high specific capacity and rate ability.

Nature is abound with materials that contain periodically-distributed components. The

iridescences in peacock feathers are caused by 2D photonic crystal structures composed of
periodically-arranged melanin rods that are connected by keratin. The melanin rods form
different lattice constants which tune the reflective light via multiple mechanisms [177]. These
periodic photonic crystal structures have been replaced by semiconductor nanoparticles via
biomineralization methods. Zinc oxide [177] and alumina photonic crystal structures [178]
with high-temperature resistance have been successfully synthesized using peacock tail
feathers as templates via an immersion and two-step calcination process (Figure 12c).

Pollen grains are cheap and ubiquitous natural products that are easy to harvest and store.
The grains are relatively uniformly sized with high specific surface areas. Because of their
unique structures and morphologies, pollen grains have been adopted as templates for
32
synthesizing novel materials. Examples include the formation of ferroelectric BaTiO3 porous
ceramics with a broad range of technological applications [179], a core-shell nano-ZnO/pollen
grain biocomposite for adsorptive removal of organic dyes from water [180], synthesis of
zeolites with significantly improved catalytic activity [181], hollow zirconia microspheres with
dye adsorption removal capability [182], CoFe2O4 pollen replicas with long-range (magnetic)
adhesion forces [183], and silica–nickel shell prepared by coating rapeseed pollen templates
for catalytic hydrogenation [184]. Combining a soft template with pollen grains further endows
the materials with well-defined hierarchical porosity. For example, pollen grains (the hard
template) have been combined with a triblock copolymer, P123 (a soft template) to form a dual
template. By combining the two templates, uniform mesopores can be introduced to the walls
of the pollen grain-derived microporous morphology through silicification, producing pollen-
structured, hierarchically meso/macroporous silica spheres (PHMSs) [185]. The PHMSs are
further used as support for AuNPs to impart catalytic activity. Pollen grains may also be used
as sacrificial templates in the biomedical arena. For example, biocompatible, hierarchical
macro–nano porous bioactive glass particles have been synthesized by a facile sol–gel process
using pollen grains as the sacrificial templates (Figure 12d). These hierarchically-porous
bioactive glass particles have potential to be used for bone regeneration and local drug delivery
[186]. Rapeseed pollen with periodic, interconnected honeycomb porosities have been used to
synthesize a cheap and environmental-friendly material for metal oxide affinity
chromatography by simultaneously coating TiO2 and ZrO2 onto the surface of the pollen grains
(denoted as PGs@(Ti-Zr)O4) [187]. The bionic composite has been used experimentally for
detection and enrichment of phosphopeptides from nonfat milk, human serum and the mouse
liver.

4.2.2 Hollow structures

Hollow nanostructures, a class of NPs with empty spaces inside solid shells, have attracted
growing attention in recent years because of their unique properties that are associated with
their hollow morphology [188]. The intrinsic features of hollow nanostructures, such as the
large surface area, low density and abundant inner void space, have been harnessed in many
energy-related applications such as batteries, supercapacitors and catalysts [189]. These novel
33
materials may be employed as nanoscale containers to load small organic molecules such as
pharmaceutical compounds, proteins, enzymes, DNA or even NPs within the void space
[190,191]. The shell can protect these active materials against external chemical interference.
When the shells are made porous, the loaded active materials can be released controllably to
achieve the desired therapeutic effect. In chemical synthesis, the void space enclosed by the
shells has been used as nanoscale reactors for space-limited reactions, which are vastly
different from macroscale reactions because of the confining effect and the change in micro-
environment [192].

Bio-shells derived from fungi, bacteria or flagella are also used as templates for
biomineralization. Bacterial flagella/pili are naturally-occurring, self-assembling protein
nanofibers present on the surface of motile bacteria. A strategy for silicification has been
developed using bacteria pili as biotemplates for directing the assembly of silica nanomaterials
[193]. Highly-ordered 3D lattice structures are fabricated from rod-like bacteria pili in the
presence of inducer molecules for molecular recognition-based self-assembly (Figure 13a).
Inducer molecules are used to tune the self-assembled pili structures. The so-formed free-
standing pili bundles, double-layer lattices, and multilayer lattices serve as biotemplates for the
synthesis of many other inorganic nanomaterials. In another study, bacteria flagella are
employed as templates for synthesizing environmentally-benign, cost-efficient, morphology-
controlled silica nanotubes [194]. The surface and morphologies of flagella-templated silica
nanotubes may be tuned by simply adjusting the flagellar surface chemistry via peptides or pH.
Bacteria utilize flagella to propel themselves through seemingly inertia-less environments by
rotating chiral filaments, breaking the time reversal symmetry of Stokes flow to generate thrust.
A porous hollow biotemplated nanoscale helix that serves as a robotic swimmer with low
Reynolds number has been designed for biomedical applications such as in vivo
imaging/sensing, targeted drug delivery, assisted fertilization and minimally-invasive surgery
[188]. The nanorobot utilizes re-polymerized bacteria flagella from Salmonella typhimurium
as a nanotemplate for biomineralization [195]. Using uniform rotating magnetic fields to mimic
the motion of the flagellate motor (Figure 13b), these flagella-templated silica are found to
possess swimming characteristics that may be wirelessly monitored to control their trajectories.
34
The biotemplated siliceous nanoswimmer represents a cost-effective alternative to current top-
down technologies for produce helical nanorobots.

Self-assembly of NPs on living biotemplate surfaces is an exciting route for designing

nano- or microstructured materials with high efficacy. Fungi thrive in diverse environments
and survive well in extreme conditions that are usually beyond the tolerance of most other
organisms. Fungi are known to induce precipitation of a wide range of minerals in different
environments. Various species of fungi have been shown to facilitate CaCO3 mineralization
[196]. In addition to utilizing inactivated fungus to synthetically induce precipitation of CaCO3
needles [196], researchers employ living filamentous fungi to fabricate microtubules of AuNPs
[197], SeNPs [198] and various carbonate minerals [199]. Fungal interactions with metals and
minerals can alter their physical and chemical states. These interactions are important for
environmental element biotransformation and cycling, and may be used to improve the
electrochemical performance of supercapacitors [199]. Novel electrochemical materials have
been synthesized using a fungal-magnanese biomineralization process based on urease-
mediated Mn carbonate bioprecipitation on filamentous fungal mycelia derived from the
urease-positive fungus Neurospora crassa [200]. The carbonized fungal biomass-mineral
composite provides a novel strategy for the preparation of sustainable supercapacitors for
incorporation into Li-batteries (Figure 13c).

Magnetotactic bacteria produce chains of magnetic iron oxide or iron sulfide NPs [201].
They use the magnetic NPs as biological geomagnetic sensors that help them navigate and
survive in their habitats. Novel structures, biological molecules and mineralization principles
have resulted from studies of the mechanisms of magnetic material formation in these
organisms. These findings are attractive to chemists, materials scientists and engineers in the
design of advanced magnetic materials. Magnetic materials are extensively used in the field of
electronics, mechanical engineering and biotechnology. Magnetic nanomaterials are important
for ultrahigh density magnetic recording media. They are also used for biomedical processes
such as magnetic resonance imaging, cell separation, environmental inspections, drug delivery,
and hyperthermia [202].

The magnetic particles in magnetotactic bacteria are housed in an organelle known as the
35
magnetosome and are configured from a magnetite core covered by a lipid bilayer membrane
vesicle (liposome) and specific membrane proteins. The proposed mechanism for magnetic
particle synthesis is as follows [203,204]: (1) the cytoplasmic membrane invaginates and forms
liposomes arranged in a chain; (2) iron ions are taken into the liposomes; and (3) the iron
concentration in the liposomes increases, causing crystallization to form Fe3O4 magnetite.
Proteins such as Mms5, 6, 7 and 13, which bind strongly to magnetite, have been shown to be
involved in magnetite crystal growth. Based on the cognition that proteins can be specifically
targeted onto magnetic particles, these particles may be used as “anchor molecules” for a
variety of target proteins. Researchers have developed a “magnetosome display system,” which
creates functional magnetic particles by transporting target proteins to the surface of the
magnetic particles using Mms13 (Figure 13d) [205]. Such a process enables precise control of
the magnetic particle surface. For other metals, a large number of bacterial species including
magnetotactic bacteria have been used with green nanotechnology for NP production.
Microorganisms have acquired various strategies (metabolic pathways) to survive in the most
extreme environmental conditions on earth. Many organisms have acquired tolerance for toxic
molecules, and some are able to convert various toxic targets to relatively non-toxic molecules.
For example, gold, silver, platinum, palladium, titanium, CdS and Fe3O4 have been synthesized
using various bacterial species [206,207]. A recent work fabricated core–shell microhelical
robots composed of iron oxide@titanium dioxide (Fe3O4@TiO2) for UV-visible light driven
degradation of organic pollutants in a cost-effective manner [208]. As show in Figure 13e, the
bio-templating approach takes advantage of the helical shape of the microalgae sub-species,
Spirulina platensis. Bio-templating and sol–gel synthesis are used to batch-fabricate magnetic
photocatalysts. These hybrid microrobots are capable of removing 97% of rhodamine B dye
from contaminated water in 75 minutes using UV-visible light.

4.3 Macroscale templates

Similar to section 4.2, this section will be divided into two parts according to the
morphology. In addition, a new sub-section entitled “protein-templated gradient materials” in
included in section 4.3 because macroscale gradient materials have extensive applications in
biomedical materials engineering.
36
4.3.1 Protein-templated gradient materials
In the translation of design motifs into synthetic materials, a spectrum of feasible pathways
is available for the development of unprecedented properties and functionalities that are
favorable for practical uses in a variety of engineering and medical fields. Incorporation of
gradients and heterogeneities into synthetic materials improves properties such as load bearing
and support, contact damage resistance, interfacial strengthening and toughening [7]. For the
repair of osteochondral defects, interfaces invariably play a dominant role in determining the
overall continuous gradient property of the bone repair scaffolds. To imitate the bone-cartilage
junction used for tissue engineering, researchers have developed composite osteochondral
scaffolds that are organized into different integrated layers, with features which are biomimetic
for articular cartilage and subchondral bone and can differentially support formation of such
tissues [209]. This multi-layered scaffold is composed of three layers with different portions
of type I and II collagen and HAp. After several freeze-drying processes and addition of
crosslinkers, a seamless integration between layers is achieved with highly-interconnected pore
structures (Figure 14a). The collagen-based, multi-layered osteochondral defect repair scaffold
has been used in vivo for repair of a critical-sized defect in the rabbit knee.

Apart from collagen, silk fibroin (SF) extracted from silk has also been employed as a
graded template to mimic natural bone. A graded graphene oxide-HAp-SF (cGO-HAp/SF)
scaffold has been fabricated by biomineralizing carboxylated GO sheets, blending with SF and
freeze-drying [210] (Figure 14b). The cGO-HA/SF composite stimulates mouse MSC adhesion
and proliferation, alkaline phosphatase secretion and mineral deposition more strongly than
HA/SF and pure HA scaffolds. Silk fibroin can also act as a sacrificial biotemplate for the
preparation of hierarchical porous silica monoliths for random laser applications (Figure 14c).
The template is removed by thermal treatment and the silica-based materials displayed surface
area values ranging from 704 to 1057 m2g-1 and a maximum pore volume of 0.621 mLg-1 [211].
Currently, researchers have been focusing on biomimetic synthesis of chiral mineral
architectures, similar to what is observed in nature’s biominerals [23]. Biomineralization-
related proteins, which are remarkably rich in acidic amino acid residues, are highly influential
on biomineral formation, growth and assembly. Specifically, they are important in terms of the
37
transfer of chiral information, where acidic enantiomers (negatively-charged that bind calcium)
possessing different chiralities are involved in the transfer of chiral character to inorganic
crystals. Previous work describes the use of small, simple chiral biomolecules such as amino
acids or small peptides to induce chiral shapes in biomimetic biominerals [212]. Recent works
utilize considerably more complex and bulky biomineralization-related proteins to transfer
chirality across their respective systems.

4.3.2 Hierarchically- or periodically-porous structures

Wood is readily available in large volumes at low cost, and is the most widely used
biological material for load-bearing structures. The unique characteristics of wood, a biological,
renewable and mechanically-robust scaffold with hierarchical structure, make it possible to
produce macroscopic load-bearing materials with multiple levels of structural hierarchy [213].
Wood has large inner surface (300 m2g−1 for swollen cell walls) and is highly suitable for
nanotechnological processing via biotemplating or outer and inner surface functionalization
[214]. Historically, both wood preservation and fire retardancy treatments [215] are often based
on wood-templated inorganics. Nanostructured organic–inorganic wood hybrids may, however,
offer new possibilities both scientifically and in terms of industrial potential. An important
research goal is therefore to be able to control the nanoscale distribution of inorganic matter in
wood tissue, and to understand mechanisms for nanoparticle effects on wood properties [213].
Figure 15a illustrates exemplarily different types of wood–mineral hybrids, the structure of
which is dependent on the selected mineral component and functionalization treatment. Details
on the functionalization protocols may be found in studies conducted by Merk et al. [215–218].
Other organic–inorganic hybrids are often based on nano-structured and porous inorganic
scaffolds functionalized by organic molecules. These molecules are attached to the internal
surfaces of the porous scaffold. Wood scaffolds offer new possibilities as they consist of a
structural material of high stiffness and toughness. The specific surface area is also very high,
since wood nanocellulose aerogels can reach 500–600 m2g−1 [219]. One may consider wood
as low cost, nanostructured substrate for advanced hybrid applications such as catalyst supports,
sorption and purification of liquids, electrodes, insulating materials and photonic materials.
Inclusion of inorganic NPs is another route, which may provide additional possibilities beyond
38
existing hybrids [220]. Recently, Merk et al. [218] successfully prepared magnetic wood by a
precipitation approach. X-ray diffraction and Raman analyses showed the formation of
multidomain ferrite particles inside the wood structure, decorating the inside of the lumen walls
in an ordered fashion. In terms of structural control, this is in contrast to random filling of the
lumen space that is typical for conventional chromated copper arsenate-impregnated wood.
This magnetic wood illustrates the impact of the anisotropy of wood structure on the magnetic
properties of the hybrid material. Magnetization occurs predominantly along the axial direction,
in parallel with the direction of wood tracheid and vessels. As a result, the wood-based material
can be manipulated by magnetic fields for potential use in actuator applications or as magnetic
switches. Magnetic NPs may also be precipitated inside the wood cell wall [221]. Calcium
carbonate is also of interest as a more environmental-friendly alternative to tackle wood
flammability [222]. There are several studies where CaCO3 has been used to chemically-
modify the internal structure of wood [223]. More advanced approaches involve the use of
ionized surface groups of cellulose [224] or other carbohydrates [225] to crystalize CaCO3
within the bulk of the wood material. In the context of nanoscience, it is also desirable to
nucleate CaCO3 inside the wood cell wall rather than within the lumen space. This is achieved
using amorphous calcium carbonate (ACC) as a transient phase that is stabilized by ions,
biological polymers, or proteins. All precursors are present in solution in this procedure, and
they react to form ACC upon a given stimulus [223]. A delignified wood template with
hydrophilic characteristics is obtained by removal of lignin. The delignified wood template is
further functionalized by a reactive epoxy-amine system (Figure 15b). This wood/epoxy
biocomposite reveals hydrophobic/oleophilic functionality and has been used for separation of
oil-water mixtures [226]. Using collagen/HA mixture as 3D matrix for bone regeneration,
cooperative effects of 3D matrix stiffness and oscillatory shear stress on the mesenchymal stem
cells (MSCs) survival, distribution, collagen secretion. [227].

Suppressing reflection and improving transmission of light are crucial for the development
of high-performance optical elements [228]. Anti-reflective surfaces have been used as a means
to enhance the optical performance of photovoltaic devices. One of the most well-known
example is the butterfly wing with multilayer nanostructures [228]. A high-transmission,
39
multiple anti-reflective surface has been constructed that is inspired by the bilayer 3D ultrafine
hierarchical structure in the butterfly Trogonoptera brookiana wing scales [229]. The
fabricated SiO2 biomimetic replicas possess excellent anti-reflective properties, which are
attributed to hierarchical structures of butterfly wing scales and the nano-ditch array structures
of the biomimetic replicas (Figure 15c). Apart from wood, leaves derived from the tree Populus
tomentosar Carr have been used as a templates for synthesizing hierarchical AgCl-Ag-ZnO
composites using Zn(NO3)2 and AgNO3 as precursors [230]. During the calcination of the
templates, Zn2+ ions react with oxygen to produce ZnO NPs. The Cl− ions in the leaf cells
combine with the external Ag+ ions to form AgCl, and Ag+ ions are reduced by reducing agents
in the leaf to Ag NPs (Figure 15d). The AgCl-Ag-ZnO composites exhibit strong photocatalytic
activity toward the degradation of rhodamine B dye when irradiated by visible-light.

Eggshell membrane is a segment of the poultry egg located between the eggshell and
albumin. It is generally regarded as waste material and can be readily obtained from canteens,
and the poultry industry. The proteins in the eggshell membrane contain abundant amino,
carboxyl and partial sulfhydryl groups, which can effectively adsorb metal ions. This property
is utilized for the fabrication of porous metal membranes with high loading of metal particles
and excellent uniformity [231]. A flexible nanocomposite membrane with interconnected pores
has been prepared for use in surface-enhanced Raman scattering. The membrane is obtained
via in-situ deposition of ~10 nm diameter AuNPs on an eggshell membrane. Abundant “hot
spots” are generated by the closely-arranged AuNPs, which enable rapid detection of
thiabendazole. In the medical arena, eggshell membrane/HAp composites have been prepared
using a biomimetic mineralization technique [232]. Both sides of the eggshell membrane
exhibit excellent mineralization capability. The hydrophilicity and thermal stability of the
eggshell membrane are improved by the introduction of HAp. With the use of the mineralized
eggshell membrane, the proliferation, adhesion and osteogenic potential of MC3T3-E1 cells
are significantly higher when compared to the original eggshell membrane. These findings are
indicative of the potential of mineralized eggshell membranes as a bone tissue repair material.

4.3.3 Hollow structures

Human hair, one of the keratin wastes, has been successfully used as raw material to
40
prepare activated carbon. Human hair-derived carbon (HHC) has been used as a carbon
template for synthesizing α-Fe2O3 NP/HHC composites [233]. The composite has been
employed as anodes for lithium ion batteries, with excellent cycling performance and rate
capability.

Inspired by the hollow structure of non-wettable hairs of polar bears, which help to keep
the animals warm in cold weather, a simple solution-based strategy has been designed to
fabricate a polar bear hair-templated, macroscale and lightweight carbon tube aerogel with
superelasticity and excellent thermal insulation property (Figure 16) [234]. The unique hollow
structure renders the aerogel highly porous and light weight, and with the ability to confine a
massive volume of air within the hollow fiber structure that can substantially decrease thermal
conductivity. Novel macroscopic mineralized hollow structures have continued to emerge in
recent years. For example, silk nanofibers have been utilized as biotemplates for preparation
of hierarchical porous silica monoliths for random laser applications [235]. Native spider silk
has been used as an organic template for controlled nucleation of a HAp nano-coating [236].
The biomineralized spider silk has potential to be used for bone tissue engineering.

5. Synthetic templates for materials manufacturing

Biomineralization in living organisms is due to the synergistic effect of a group of
biomolecules. Examples include the capsid protein in virus, ferritin in bacteria, cellulose in
fungi, chitin and chitosan in nacre, lignin and cellulose in wood, and collagen in bone. Synthetic
templates are fabricated by extracting and purifying them from raw materials. Post-extraction
modifications (such as interacting small proteins with chitin) may further improve the
performance of the final organic templates [237]. Conventional protein extraction from raw
materials is time-consuming and generates products that requires extensive purification.
Researchers now employed in vitro gene or protein engineering techniques to design the
desired peptide- or protein-based organic templates, thereby avoiding waste and impurity.
Biological self-assembly of peptides and proteins offers a versatile bottom-up approach for
construction of nanoscale materials that mimic the complex hierarchical order of natural tissues
[42]. Self-assembling templates are rapidly gaining in popularity over conventional

41
biodegradable polymeric templates for several reasons [238]. Firstly, the advent of advanced
molecular biology techniques allows recombinant production of self-assembling protein
templates in sufficient quantities and addresses homogeneity and standardization issues.
Furthermore, signaling and bioactive motifs such as cell-attachment motifs can be readily
combined with structural framework motifs through genetic engineering at the sequence level.
Finally, the combinatorial display of different bioactive motifs and enzymatic degradation sites,
as well as incorporation of soluble factors, is integral to designing scaffolds that recapitulate
the complex extracellular matrix microenvironment. Scaffolds with nanofibrillar topography
and porous microarchitecture, combined with biomolecules encapsulated in a hydrogel
environment, provides a multitude of approaches for enhancing cell proliferation and
differentiation in regenerative medicine. A brief introduction of phage display strategy as a part
of protein engineering is necessary for better understanding of the preparation of synthetic
templates.

5.1 Phage display strategy

Bacteriophage (phage) is a genetically-modifiable, nanoscale, filamentous
supramacromolecule. A phage may be visualized as a semi-flexible nanofiber (~900 nm long
and ~8 nm wide) that is composed of a DNA core and a protein shell, with the former
genetically encoding the latter. Although phage bioengineering and phage display techniques
were developed before the 1990s, they have not been extensively used in chemistry, materials
science and biomedical research until recently [239]. Because of their ability to bind to various
peptides and their self-assembling capability, phages are used for identifying specific peptides
that have the potential to template the growth of inorganic crystals and nanomaterials. Phages
can also fuse with crystal-nucleating peptides for construction of exotic nanomaterials and
nanostructures. They are excellent templates for material synthesis and assembly for several
reasons. First, different peptides may be co-displayed on the surface of a single phage, enabling
the phage to become a multifunctional nanofiber. Second, the phage itself is chemically stable
in acidic, basic and many organic solvents and remains intact up to 80 °C. Third, the biological
nature of phage replication guarantees error-free production of monodisperse phages. Fourth,
phages tend to self-assemble into different ordered structures by simply controlling factors
42
such as concentrations. Such a property may be utilized for the fabrication of hierarchical
structures such as bone [240].

Metalloid silicon [241], HAp [242] and ferroelectric metals [243] have been successfully
synthesized using phages as templates. The use of phages as templates makes it possible for
changing the morphology and composition of the synthesized materials. For example, scientists
have recently synthesized a germanium-tin oxide segregating-binary-alloy type, phase-change
material with controlled morphology, composition and functionality [244]. This is achieved
using phage template-driven nucleation that takes advantage of the electrostatic-binding
specificity on the surface of M13 phages (Figure 17a). By varying the amino acid composition
of the phage surface to increasing the electronegativity of the template surface, the composition
of the material may be precisely controlled. Wire-like materials are produced with controllable
and reliable phase-changing signatures that are capable of tens of nanoseconds switching times.
The use of phage templating technology addresses critical compositional and structural
constraints that restricts the use of phase-change materials in computer universal memory
systems that are capable of storing digital information on 10 ns time scales.

The use of phage templates enables synthesis of novel 1D materials at ambient temperature
and without the use of toxic reagents. One-dimensional MnO2 nanowires have been synthesized
with controlled structure and unique properties for electron transfer, using genetically-
engineered M13 phages as templates for precise nucleation and growth of MnO2 crystals [245].
These nanowires have potential applications as electrochemical glucose biosensors. One-
dimensional silica nanofibers have been created by expressing silaffin R5 peptides derived
from Cylindrotheca fusiformis on the surface of LAR5 phages [246]. The procedure can be
conducted without the use of APTES because of the presence of the R5 peptide on the major
coat of the phage used for templating of TEOS. Because silicon is essential in energy-related
devices such as solar cells and batteries, the phage-templated silica synthesized via
biomineralization can be further reduced to silicon via magnesiothermal reduction [241]. After
annealing at high temperature to decompose the template and sinter the nanomaterial, the
biotemplated silica is introduced into a magnesiothermal reactor along with Mg powder.
Within the reactor, silica reacts with Mg vapor and is reduced to silicon. After rinsing off the
43
MgO by-product, pure silicon structures with the same shape as the biotemplate-phage are
produced. The silicon structures can be porous or continuous depending on the shape of the
template and the silica mineralization conditions (Figure 17b). The phage display technique
has also been used to synthesize ferroelectric tetragonal barium titanate (BaTiO3) nanowires
for use in bioimaging and biosensing [243]. Because conventional methods for the synthesis
of BaTiO3 require toxic reagents and high temperature treatment, a short BaTiO3-
binding/nucleating peptide, CRGATPMSC is first identified from a phage-displayed random
peptide library. The binding/nucleating peptide is genetically fused to the major coat protein
(pVIII) of filamentous M13 phages to form pVIII-peptide phages. Using this method, uniform
tetragonal BaTiO3 nanocrystals are induced at room temperature without the use of toxic
reagents to produce 1D polycrystalline BaTiO3 nanowires (Figure 17c).

A notable feature of phages is their self-assembling ability. To date, all the aforementioned
phage-templated materials are 0 or 1D materials. That is, the morphology of those materials
only change in length or width irrespective of whether the phage is sacrificed; the resulting
material duplicates the original linear structure of the phage. Recently, phage NPs have
attracted significant attention as building blocks for the assembly of hierarchically-organized
nanostructures. This is because phages exhibit liquid-crystalline behavior in solution and can
be self-assembled into well-ordered 2D and 3D structures. In 2012, researchers prepared well-
ordered mesoporous silica fibers with hexagonally-arranged pores using ordered-arranged
filamentous phages as the biotemplate (Figure 17d) [247]. Inspired by the fact that the ECM of
bone is mainly composed of HAp crystallites embedded in self-assembled, highly-ordered
collagen fibrils, researchers more recently utilize phages to morphologically mimic collagen
fibrils. Apatite crystallites are embedded within the ECM-like matrix using 2 different
strategies [240]. In the first strategy, positively-charged calcium ions are used to trigger self-
assembly of negatively-charged phages (e.g. wild-type phages or phages displaying a cationic
peptide with a contiguous sequence of 8 Glu residues) into bundles. The self-assembled phage
bundles in turn serve as a calcium source to react with phosphate ions to form nanocrystalline
HAp with preferred crystal orientation along the phage bundles. In the second strategy, two
types of engineered HAp-nucleating phage nanofibers are fabricated with each displaying one
44
of the two HAp-nucleating peptides (QESQSEQDS and ESQES) derived from a HAp-
nucleating protein, Dentin Matrix Protein-1. The two HAp-nucleating phage nanofibers self-
assemble into bundles by forming β-structures between the two displaced peptides, which
promote site-specific nucleation of HAp with preferred crystal orientation. This is followed by
organization of the phages and HAp into an ECM-like matrix. Because phage nanofibers have
a higher degree of monodispersity than traditional polymer nanofibers, the resultant building
blocks self-assemble into scaffolds with more well-defined architectures than traditional
polymer-HAp composites. The success in creating bone-mimicking materials ignite scientists’
desire to construct centimeter-scale 3D multilayered phage assemblies with potential
applications as scaffolds for tissue engineering, regenerative medicine and other functional
devices [248]. Such templates would need to imitate the native ECM environment, which is
composed of a fibrous protein mesh and provides cells with physical support, guidance by
chemical signaling and directional alignment. Spatial control of dense chemical signaling
arrays is desirable for controlling cellular activity. This is accomplished on virus particles by
genetic modification of the designated virus coat proteins. Phage replication through E. coli
bacteria provides an easy and cost-effective method for obtaining a large, monodisperse
population of the basic building units for use as templates. The ability of the phages to self-
assemble into directionally-organized networks provides the cells with the physical and
directional guidance required for many biological systems.

5.2 Synthetic organic templates

Apart from peptides, synthetic organic molecules such as co-polymers and dendrimers
have also been employed as templates for biomineralization. To achieve more complex
morphologies, these synthetic molecules are modified with functional ligands prior to self-
assembled into 0-3D structures. Table 1 summarizes the recent achievements in using synthetic
molecules for templating the synthesis of inorganic or hybrid materials.

45
Table 1. Comparison of the use of synthetic molecules as templates for the synthesis of inorganic or hybrid materials

Synthetic Inorganic
Morphology Fabrication processes Proposed interactions Applications Merits Ref.
molecules composition

Oligonucleotides carbon 2 nm diameter NP chemical vapor deposition; π–π stacking and π–HN biosensors, biocompatible, [316]
oligonucleotides as ‘bio- bonding with sp2 transfection intrinsic fluorescence
solvent’ for isolation and as carbon atoms reagents or real- without undesirable
ligands for functionalization time imaging photo-bleaching effect
of carbon NPs
50-guanosine carbon blue-emitting chiral G-dots utilize the inherent Stacking of guanosine cell tracking, drug biocompatible, [317]
monophosphate (50- carbon dots (G-dots) self-assembly property of 50- quartets enable self- delivery biodegradable
GMP) GMP to form fluorescent assembly; the quartets
hydrogels further cross-linked by
orthophosphate diester
bonds
Adenosine 5’- amorphous ACP porous surfactant-free microwave- ATP biomolecules anticancer drug facile, rapid, [318]
triphosphate calcium nanospheres (238 nm) assisted hydrothermal acting as stabilizers for delivery surfactant-free and
disodium salt (ATP) phosphate synthesis ACP environmentally
(ACP) friendly fabrication

ATP Eu3+-doped mesoporous rapid microwave-assisted ACP nuclei forming by pH-sensitive drug high specific surface [319]
ACP microspherea (10-20 solvothermal method the reaction between release, bioimaging areas,biocompatible,
nm) calcium ions and pH-responsive drug
phosphate ions release, in vitro/in vivo
fluorescent imaging
ATP ACP vesicle-like sonochemical method in ACP nuclei formed by anticancer drug inappreciable cell [320]
nanospheres (150–240 mixed solvents of water and the reaction between nanocarriers, pH- toxicity
and 500–1100 nm) ethylene glycol calcium ions and responsive drug
phosphate ions release behavior
using doxorubicin
as model drug

Guanosine 5’- silica hierarchical sodium citrate reduction hydrogen bonds and not mentioned Preparation of [321]
monophosphate mesoporous method electrostatic adsorption nanotubes with
(GMP) nanotubes (4- 22 nm) mesopores in the outer
wall and add colors
GMP silver 5 nm long sol–gel reaction metal ion-linked H- nanocomposite readily prepared by [322]
nanofilaments bonded architectures supramolecular prolonged exposure to
constructed from producing enolate-like hydrogels with light.
helically stacked, tautomers potential plasmonic
chiral arrays of Ag- and catalytic
GMP dimers properties

GMP Tin sulfide spherical particles (5- sol–gel reaction coordination interaction optical and 3-month aging of [323]
quantum dots 10 nm) between the N(7) of electronic GMP-mediated Q-CdS
pyrimidine, the >C=O properties resulting in nanorods
and –NH2 of purine and
P-O-5’-sugar

47
Hydrogels of silver 3D fibrous network sol–gel method coordination interaction antimicrobial not mentioned [324]
adenine, cytosine, between Ag+ ions and properties
thymine and uracil N9 of adenine

Adenosine, gold micrometer-sized citrate and light-assisted sol- intermolecular fluorescent citrate and light [325]
deoxyadenosine, particles (2.2 m) and gel reaction multivalent materials with exposure or heating to
AMP and ATP molecular clusters coordination tunable sizes, produce fluorescence
applications in
analytical
chemistry, drug
delivery and
imaging
Nucleoside copper nanoclusters (1-4 nm) ascorbic acting as stabilizer not mentioned discrimination of water-soluble and [326]
and citrate as reducing agent nucleosides fluorescence

Cytidine hybrid gold and nanoclusters (50±0.3 citrate and incubation coordination interaction fluorescence identification of [327]
silver nm) properties, good disease-related changes
dispersibility, in blood serum
water solubility,
bioanalysis and
biomedical
diagnosis
Hydroxyl- palladium 2 nm diameter NPs sol–gel reaction not mentioned NP catalysis Investigation of [328]
terminated surface behavior of
poly(amidoamine) metal NPs
(PAMAM)
dendrimers

48
6th generation gold 2-4 nm diameter NPs sol–gel reaction CNC-PAMAM as superior catalytic pH adjustment of the [329]
PAMAM nanoreactor and property system causes the
dendrimer-grafted reducing agent catalyst particles to
cellulose phase separate out of
nanocrystals solution
(CNCs) (CNC-
PAMAM)
Hydroxyl- platinum Pt NPs immobilized sol–gel reaction not mentioned superior catalytic uniform dispersion and [330]
terminated 4th on mesoporous property small size
generation PAMAM alumina
(G4-OH PAMAM)
dendrimers
PAMAM yttria-stabilized YSZ power, 8–10 nm sol–gel reaction metal ions and not mentioned not mentioned [331]
zirconia (YSZ) dendrimer forming a
complex via coordinate
bond formation between
tertiary nitrogen atom
of the dendrimer and
metal ion
Serine-containing silica Nano to micro- sol–gel reaction, not mentioned drug delivery and mild reaction [332]
self-assembling structured assemblies polymerization/electrostatic controlled release, conditions and
octapeptide depending on the adsorption/H- enzyme simultaneous
precipitating peptides bonding/hydrophobic encapsulation encapsulation of cargo
and synthetic interaction (biocatalyst) during silica formation
conditions (spheres,
fibers, sheets,
hexagons, clusters,
dendrites)

49
Negatively-charged hydroxyapatite calcium phosphate noncovalent intermolecular not mentioned biomineralized enhance osteogenic [333]
self-assembling (HAp) nucleation on the interactions and electrostatic scaffolds in differentiation
peptide amphiphile surface of a adsorption regenerative
molecules negatively-charged medicine
peptide nanofiber
scaffold
Peptide-based HAp nanofibrillar network noncovalent intermolecular not mentioned functional high mechanical [334]
hydrogels composed decorated with HAp interactions and electrostatic biomaterials for strength, support cell
of fluorenyl-9- adsorption improved bone adhesion
methoxycarbonyl regeneration
diphenylalanine
Peptide (mineral HAp asymmetrical β- non-specific interactions not mentioned tissue engineering peptide attachment [335]
directing gelator)- hairpin β-sheet applications controls crystal
based hydrogels structures morphology and phase
of the calcium
phosphate mineral
Arginine-rich Bisphosphonate positively-charged electrostatic adsorption not mentioned drug storage and stability, rapidly [336]
amphipathic peptide NPs (< 100 nm in delivery internalized by cancer
diameter) cells in vitro, anti-
tumor activity in vitro
Self-assembling Nano-HAp and interconnected porous electrostatic adsorption not mentioned composite scaffold good mechanical [337]
peptide chitosan fibrous nanoscale for repair of bone properties,
network defects biocompatibility,,
biodegradability,
β-sheet peptides HAp and ACP β-strand peptide noncovalent intermolecular not mentioned bone-filling controlling inorganic [338]
forms antiparallel β- interactions and electrostatic materials morphology and
sheet conformation adsorption crystalline phase in
mineralization
50
Graphene oxide HAp hierarchical 3D noncovalent intermolecular not mentioned biocompatible biocompatibility and [339]
nanosheets and scaffold with size interactions and electrostatic scaffolds for bone high mechanical
fibrinogen distribution from 300 adsorption regeneration strength
nanofibers on a nm to 5 μm
silicon substrate
Polystyrene-poly-4- carbon free-standing gyroid nanoporous templates are not mentioned nanoporous carbon high charging/ [340]
vinylpyridine block carbon network with filled with carbon precursor cathodes for Li-S discharging capacity,
copolymers highly-ordered and solution, cross-linked and batteries high cycling stability
interconnected carbonized high surface area and
mesopores to fabricate the uniform porosity with
gyroid carbon replicas interconnected 3D
networks
Amphiphilic carbon cylinder and gyroid mesoporous carbon are covalent intermolecular electrode materials more efficient transport [341]
poly(ethylene nanostructures of synthesized from resol interactions for supercapacitors channels and higher
oxide-block- mesoporous carbon phenolic resin as the carbon surface area for the
caprolactone) with large pore sizes precursor and using the storage of ions
(14–16 nm) copolymer as template
Self-assembled nicklel metallic nanoporous nanoporous templates electrostatic adsorption hydrogenation narrow pore size [342]
diblock copolymer spheres with single soaked in a Ni bath and catalysts distributions, high
with double gyroid gyroid structure washed to obtain the free- specific surface areas,
structure standing single gyroid- 3D curved surfaces,
structured Ni nanoporous high-efficiency
spheres recyclable catalyst
Poly(styrene-acrylic nickel oxide nano-sized NiO The corona domain electrostatic adsorption anode materials for high electrochemical [343]
acid-ethylene oxide) (NiO) hollow spheres stabilizes organic/inorganic Li-ion rechargeable performance excellent
with core-shell (28 ± 2 nm) composite particles batteries cycling stability
corona architecture

51
Amphiphilic block tungsten oxide crystalline monoclinic direct template- hydrogen bonds, ordered ordered mesostructure, [344]
copolymers with (WO3) WO3 with large carbonization covalent bonds, mesoporous thermal stability,
high content of sp2- mesopores electrostatic interactions semiconducting excellent gas sensing
hybridized carbon metal oxides for performance,
in the hydrophobic gas sensors outstanding mass
segments transport efficiency,
high specific surface
area
Poly(isoprene- homopolymer interconnected single sol–gel reaction and dense electrostatic adsorption cathode material of electrical conduction [345]
block-ethylene (carbon), crystalline carbon- agglomeration and covalent bond lithium-ion enhancement, excellent
oxide) block sol−gel coated NP (30 nm batteries rate capabilities
copolymer precursors (Li+, diameter, 3 nm thick) sufficiently porous to
Fe3+, PO43−) accept Li+ from the
electrolyte
PAMAM palladium 1.33 ± 0.15 nm and encapsulation of the metal electrostatic adsorption catalysts versatile method for [346]
dendrimers 1.66 ± 0.20 nm NPs ions within dendrimer synthesizing NPs with
well-defined sizes,
compositions and
structures
6th generation gold 2-4 nm diameter NPs dendrimers as nanoreactors electrostatic adsorption catalysts superior catalytic [347]
PAMAM and NaBH4 as the reducing properties for reduction
dendrimer-grafted agent of 4-nitrophenol to 4-
cellulose aminophenol
nanocrystals
PAMAM platinum 5 nm NPs Pt ions are reduced to form not mentioned electrocatalysts the eco-friendly and [348]
dendrimers PtNPs encapsulated in low cost synthesis
dendrimer procedure.

52
Hydroxyl- platinum 1.4 nm sol-gel process and electrostatic adsorption catalysts control over particle [349]
terminated monodispersed NPs calcination size distribution
PAMAM
dendrimers
Hydroxypropyl tin dioxide 5 nm NPs bonded coordinative interaction electrostatic adsorption SnO2-based excellent [350]
cellulose-graft- along bottlebrush-like between the -COOH groups electrodes for Li- electrochemical
poly(acrylic acid) polymer template, of poly(acrylic acid) blocks ion batteries performance, superior
forming a corn-like and SnO2 NPs long-term cycling
structure stability, excellent rate
capability
PAMAM palladium 6.7 nm diameter monitoring color change covalent intermolecular catalyst synthesis of well- [351]
dendrimers spherical template from yellow to dark brown interactions dispersed NPs
encapsulating upon addition of the
2 nm diameter Pd NPs reducing agent NaBH4.
PAMAM zirconia crystallite size 8–10 hydrothermal electrostatic adsorption oxygen sensors, control of particle size [352]
dendrimers nm solid oxide fuel
cell electrolyte

PAMAM alumina mesoporous alumina sol-gel process, hydrogen bonds industrial catalysis high surface area, large [353]
dendrimers nanofibers (500–`650 electrospinning and and environmental pore volume, uniform
nm) calcination purification (as pore size
adsorbents)

53
6. Applications of template-directed inorganic and hybrid materials
Template-directed synthesis of inorganic materials and hybrid composites has redefined
the direction of future technologies and influenced almost every aspects of our daily lives [249].
These materials have eminent applications in biomedical science [52], the chemical industry
[189] and environmental protection [250]. After calcination or chemical decomposition of the
organic templates, pure inorganic materials are produced that replicate the hierarchical
structures of their templates. Conversely, retention of the organic components can improve the
properties of hybrid materials. For example, electrochromic metal oxides based on conjugated
polymers exhibit novel properties such as multicolor, fast switching speed, flexibility and ease
of optimization through molecular tailoring [251].

6.1 Biomedical science

Biomedical applications of hybrid organic-metal materials include polyaniline-
encapsulated titania nanotube arrays as bone substitutes [252], sperm-templated magnetic (iron
oxide) microrobots as contrast agents in ultrasound or magnetic resonance imaging [253],
DNA‐templated magnetic NP‐quantum dot polymers for ultrasensitive capture and detection
of circulating tumor cells [254], protein-templated AuNPs for small molecule delivery [101],
and protein-templated highly-fluorescent Au nanoclusters for cysteine sensing [255].
Protein/peptide-templated metal nanoclusters (AuNCs, AgNCs, CuNCs), metallic oxide
(MnO2, Gd2O3) or metal sulfides (CuS, NiS, and CoS) are also useful for in vivo cancer
theranostics as well as bio-sensing, ion detection and bio-labeling [256]. Figure 18a shows the
timeline of bioinspired protein-templated metal NPs that have emerged since 2009. The
categories of bioinspired NPs and their applications are summarized in Figure 18b. Of note,
controllable synthesis of stoichiometric transition metal (Co, Ni or Cu) sulfide nanocrystals has
been conducted within various protein nanoreactors. These nanocrystals possess ultrahigh
photothermal conversion efficiency, and are easily functionalized with the imaging agents such
as near-infrared fluorescence dye and radionuclide through facile coupling, for multimodal
imaging and photothermal tumor ablation (Figure 19a) [257]. In another system, human serum
albumin (HSA) is modified with chlorine-e6, a photosensitizer, or c,t,c-[Pt(NH3)2-
(O2CCH2CH2COOH)(OH) Cl2] (cis-Pt(IV)SA), as pro-drugs of cis-platinum, and used as the
template and coating molecules to induce biomineralization of MnO2 nanoclusters.
Multicomponent HSA-MnO2-Ce6&Pt NPs are produced through these processes [258].
Within the acidic tumor microenvironment, these NPs are gradually degraded into individual
therapeutic albumin-drug complexes (Figure 19b). Because of their small size (<10 nm), the
complexes show greatly enhanced tumor permeability and improves the therapeutic outcome
of combined photodynamic and chemotherapy.

The use of nucleic acid templates for the preparation of metal NPs has produced exciting
novel materials for biomolecular sensing, nucleic acids/protein/drug delivery, single- or multi-
mode cell imaging and antibacterial applications [259]. A short BaTiO3-binding/nucleating
peptide has been identified from a phage-displayed library. The peptide is genetically fused to
the protein coat of M13 phages for inducing the nucleation of uniform tetragonal BaTiO3
nanocrystals at room temperature, without the use of toxic reagents, to form one-dimensional
polycrystalline BaTiO3 nanowires [260]. This approach enables the green synthesis of non-
toxic ferroelectric materials for bioimaging and biosensing. Genetically-engineered M13
phages have also been used as templates for nucleation and growth of MnO2 crystals. The
MnO2 crystals were uniformly distributed on the surface of genetically-modified phages,
forming nanowires The MnO2 nanowires exhibit peroxidase-like activity and are potentially
useful as electrochemical biosensors for glucose detection [245]. Ocean green tide waste
(Enteromorpha prolifera, EP) has also been used as a biotemplate to prepare MoO3 nanorods
supported on EP-derived carbon (MoO3/C) [261]. The MoO3/C nanorods exhibit peroxidase-
like activity that is superior to most of the peroxidases used for detection of blood glucose in
human serum.

Peptide- or protein-templated calcium phosphate (CaP)-based materials are widely used

as bone substitutes. Peptide nanosheets have been synthesized via self-assembly of a small
peptide fragment (LLVFGAKMLPHHGA) and conjugated onto a graphene support for
biomineralization of HAp (Figure 20a). This extra-light, highly-porous, biocompatible 3D
hybrid scaffold enables vascularization and nutrient transport in bone regeneration [262].
Another 3D hybrid scaffold is prepared by self-assembly of fluorenylmethoxycarbonyl-valine
(Fmoc-Val)-cetylamide nanofibrils. The nanofibrillar template is used for layer-by-layer
55
assembly of collagen, a sialophosphoprotein sequence derived from dentin, and the
osteoinductive growth factor BMP-4. The assemblies are incubated with HAp nanocrystals,
blended with TiO2, and coated with alginate to form biodegradable and antibacterial 3D hybrid
scaffolds (Figure 20b). The ECM-mimicking scaffold induces attachment and proliferation of
mouse MC3T3-E1 cells and promotes their differentiation into osteoblast-like cells [263].
Phospholipid vesicles have been used as templates for preparation of CaP nanostructures that
promote adhesion and proliferation of osteoblast-like cells [264]. Strontium-doped CaP NPs
produced by DNA templates are used for targeted gene transfer in treating bone diseases; the
efficacy of gene transfer and alkaline phosphatase activity in human fetal osteoblastic cells are
dependent on the Sr2+ content within the NPs [265].

Proteins, peptides, oligonucleotides and filamentous biomacromolecules such as flagella

and bacteriophages have been used to nucleate and synthesize silica materials (Figure 21).
Silica matrices are valuable for incorporation of functional components in the biomedical arena
because they are water-soluble, chemically-inert, thermally-stable, biocompatible, have
negligible absorption from the ultraviolet to near-infrared wavelength range and are unaffected
by magnetic fields [52].

6.2 Chemical industry

Graphitic carbon nitride (g-CN) is a semiconductor containing only carbon and nitrogen.
It has important energy applications such as photo-electrochemical conversion of solar energy
into chemical fuels. As a promising candidate for sustainable photocathodes, g-CN has
advantages such as low cost, visible light sensitivity and excellent chemical stability [266]. To
date, the performance of g-CN has been limited because conventional synthesis methods
produce relatively dense materials with low surface areas. Many bio-templating strategies are
currently available for changing the structure and morphology of g-CN and introducing
porosity. Both polysaccharides and polypeptides have been used to introduce porosity into g-
CN. Alginate and gelatin are mixed with aqueous dicyandiamide and heated to prepare g-CN
with sponge-like nanostructure [267]. Compared with pristine and bulk g-CN, the sponge-
structured g-CN enhances diffusion, mass transfer and improves optical adsorption during
photocatalytic reactions. Another example of the use of biological templates for synthesis of
56
g-CN is diatoms [268]. Diatoms are combined with cyanamide to synthesize a g-CN material
with diatom frustule structure and excellent photocatalytic property. Photocatalytic
enhancement is attributed to the diatom structure in enabling light trapping and scattering.

Biomolecule-templated nanomaterials have shown potential for light-harvesting in solar

cells and photocatalysis [66]. Peptides and metalloporphyrins can self-assemble into high
quality nanofibers for use as light-harvesting systems. For example, a peptide sequence has
been combined with zinc protoporphyrin to form a long peptide–metalloporphyrin fiber with
stable β-sheet structure and good photocatalytic activity [269,66]. Chromophores and DNA
have also been assembled by covalent and noncovalent interactions for preparation of light-
harvesting materials [270]. Although noncovalent self-assembly may be utilized to fabricate
light-harvesting materials, covalent DNA systems based on DNA base substitution and
modification produce materials that are more stable [271]. Supramolecular light-harvesting
antennae have been synthesized using solid-phase “click” chemistry to produce fluorescent
AuNP-decorated DNA-oligo(p-phenylene-ethylene) hybrid amphiphiles with tunable emission
(Figure 22a) [272]. Likewise, viruses have also been used as templates for assembly of
porphyrins into light-harvesting nanoantennae [273].

Peptides have been used as templates for the development of dye-sensitized solar cells
[274,275]. Hollow TiO2 nanoribbons are produced by depositing a TiO2 layer on self-
assembled aromatic dipeptide nanoribbons followed by pyrolysis (Figure 22b) [275]. These
nanoribbons may be used as photoanodes to improve the power conversion efficacy of dye-
sensitized solar cells. As a good semiconductor and photocatalyst, TiO2 NPs have been self-
assembled on a DNA template to form a linear structure through electrostatic interaction and
covalent modifications [276]. The obtained DNA-TiO2 1D nanowires are used as anodes for
solar cells with a high cycle life. Genetically-engineered M13 virus has been used to synthesize
single-wall CNT (SWCNT)-TiO2 core-shell nanocomposites [277]. This system maintains the
original structure of each component part, exhibits high electron mobility and improves the
power conversion efficiency of dye-sensitized solar cells (Figure 22c).

Self-assembled peptide superstructures are ideal templates for synthesis of photocatalytic

nanomaterials. Positively-charged dipeptides and negatively-charged porphyrins have been co-
57
assembled by electrostatic interaction to synthesize porous, water-rich, light-stable and light-
resistant microspheres [278]. Three-dimensional TiO2 and ZnO semiconductor nanoscopical
networks have been synthesized using self-assembled mussel-inspired dopamine-peptide
amphiphiles as templates [279]. The TiO2 and ZnO NPs are deposited on the peptide nanofibers
by atomic layer deposition. After removing the peptide template, 3D TiO2 and ZnO networks
are formed with excellent photocatalytic activities and controlled band gap energies. Proteins
can also serve as templates for producing TiO2-decorated silicatein/silintaphin photocatalysts.
This kind of photocatalyst solves the problem of post-treatment recovery [280].

Lithium-ion batteries are attractive because of their long service lives and low maintenance.
However, they suffer from drawbacks such as low power densities, long charging times and
poor cycle stability compared with supercapacitors. To address some of these issues, M13
phages have been used as a biological scaffold to develop 3D nickel phosphide nanofoams with
control over a wide range of phase compositions and structural elements [281]. These phage-
templated Ni5P4 nanofoams are used as thin-film anodes in Li-ion microbatteries (Figure 23a).
Self-assembled peptide superstructures can form stable nanostructures with other materials
through molecular interactions such as electrostatic, hydrophobic and hydrogen bonds [282].
Because of their structural diversity and biocompatibility, self-assembled peptide
nanomaterials may be used in energy storage and conversion equipment [283]. Although
graphitic materials possess stable structures, their specific capacity are relatively small;
conversely, metal oxide is considered as a high specific capacity anode material with
remarkable performance [284]. Biosynthesis of Co3O4 electrode materials for Li-ion batteries
has been accomplished by peptide and phage engineering [285]. Apart from Co3O4, TiO2 has
also been used for synthesis of electrodes. A 3D network of TiO2 hollow nanoribbons has been
synthesized using lysozyme self-assembly via heat denaturation [286]. This highly-ordered
network structure facilitates electronic transmission and improves electron conductivity. Wood
may also be utilized as templates for the synthesis of Li-ion battery anodes [287]. A rigid and
electrically-insulating wood membrane is converted into a flexible and electrically-conductive
material via delignification and coating with CNT/Ru NPs (Figure 23b). The resulting material
comprises cellulose nanofibers with abundant nanopores, which are ideal for Li+ ion transport.
58
 Biomolecules may be combined with other nanomaterials to fabricate secondary batteries
such as Li–S and Ni–Zn batteries. Self-assembled peptides have been designed for coating of
active sulfur NPs in Li-S batteries. The recyclability of Li–S batteries is increased when self-
assembled peptide superstructures are incorporated into sulfur NPs. This property enhancement
is ascribed to the strong combination of the peptide with sulfur via hydrogen bonds [288].
Proteins are also used for the preparation of multifunctional electrode materials. For example,
Li–S batteries have been produced by using a polysulfide nanofilter, through combination of
self-assembled proteins with conducting particles to form a stable Li2Sn conductive layer [289].
The bioinspired material has a 3D porous structure and functional layer-like surface, which
may be used to capture sulfide in Li–S batteries and facilitate the transport of Li ions between
two electrodes to improve electron conductivity (Figure 23c). In another example, Ni-plated
TMV (viruses) are self-assembled into nanorods on a gold coating to produce a 3D layered
electrode [290]. This TMV-templated hierarchical Ni/NiO electrode greatly increases the
charge storage capacity of the battery and stability of electrochemical cycling. Bioinspired
synthesis methods may also be used to improve the performance of Na-ion batteries. For
example, self-assembled M13 viruses are combined with SWCNTs to produce templates for
synthesizing FePO4 cathodes to increase the power and capacity of Na-ion batteries [291].

Supercapacitors based on carbon nanomaterials and metal oxides have been produced via
templates created from self-assembled biomolecular superstructures. Carbon nanotubes are the
most popular materials for energy-storing electrodes because of their unique pore structure and
excellent electrical performance, mechanical performance and thermal stability. The CNTs
may be combined with DNA to improve the performance of supercapacitors. For example,
porous DNA hydrogels are good templates for electrodeposition of CNT layers and polyaniline
layers (Figure 23d). The insulating DNA hydrogel is transformed into a conductive material
through electrostatic deposition of poly(allylamine), CNT and polyanaline within the hydrogel
[292]. The so-formed supercapacitors exhibit good biocompatibility and circulation stability.
Negatively-charged DNA has also been used as templates for assembly of TiO2 NPs into wire-
like clusters for supercapacitor applications (Figure 23e) [276]. Similarly, MnO2 may be
combined with biomolecules to produce supercapacitors. For example, a DNA-assisted
59
assembly approach has been utilized to combine DNA, CNTs and MnO2 to produce a porous
supercapacitor (Figure 23f) [293]. Another DNA-assisted approach has been used to prepare
flake-like and wire-like MnO2 supercapacitors [294].

Catalysts are much sought after in the rapidly-developing field of green chemistry.
Combining self-assembled biomolecules (or raw nature materials such as leaf) with other
materials is an alternative way to obtain effective catalysts. Self-assembled metallocatalysts
have been produced from small self-assembled peptides via non-covalent interactions [295].
An active nickel electrocatalyst with a structured peptide outer coordination sphere has been
synthesized that transforms electrons more efficiently to improve catalytic efficiency [296]. In
addition to Ni, Pt nanocomposites have also been used for developing green energy materials.
For example, Co-deposited teeth-like virus-platinum nanohybrids have been synthesized using
M13 phages as templates for methanol oxidation catalytic reactions [297]. Peptide-based
nanomaterials can also be combined with bimetallic NPs for electro-catalytic applications. This
is exemplified by the development of peptide-FlgA3-based gold palladium bimetallic NPs for
catalyzing oxygen reduction in alkaline solutions [298]. Nanomaterial-based catalysts also play
important roles in hydrogenation reactions, as illustrated by the attenuated reactivity of peptide-
templated Pd nanomaterials in olefin hydrogenation [299].

6.3 Environmental protection

Nanomaterials created with biotemplates find use in the purification of wastewater and
polluted air, as well as environmental monitoring of pollutants. Water purification includes the
removal of dyes, pathogenic microorganisms and toxic metal ions from water systems. Metal–
biomolecule 2D frameworks have been produced by controlling the self-assembly of DL-
glutamic acid–copper ion hybrid building blocks [300]. Self-assembly of this supramolecular
nanofibers can be fine-tuned by adjusting the chirality of the ligands employed. Uniform 1D
and 2D nanomaterials are produced for removing anionic dyes such as Congo red from water.
Similarly, graphene oxide-enzyme hybrid nanoflowers have been synthesized via a facile one-
pot strategy under mild conditions for removal of water-soluble dyes [301]. In another example,
two lignin sources (kraft and alkali lignins) are used as templates for the green-synthesis of
hollow metal-phenolic capsules [302]. The wall of the capsules is prepared by self-assembly
60
of tannins and Fe3+ ions around the lignin particle templates (Figure 24a). The lignin template
particles are degradable when exposed to aqueous or organic solvents under ambient conditions.
The synthesized hollow capsules may be used for environmental remediation of organic dyes
from contaminated water.

An important part of environmental remediation involves the removal of pathogenic

microorganisms from water. Colistin-functionalized AuNPs have been synthesized for rapid
capture of Acinetobacter baumannii, a Gram-negative bacterium [303]. Likewise, thin film
membranes have been prepared using palm fruit stalk cellulose nanofibers, oxidized carbon
nanofibers and activated carbon for removal of Escherichia coli bacteria from water [304]. The
prepared hybrid membrane effectively removes E. coli (96–99%) and is highly resistant against
the growth of E. coli and Staphylococcus aureus bacteria. In another study, antibody-
conjugated Fe3O4-Ag@APTES hetero-nanocomposites have been prepared using a two-step
synthetic technique consisting of co-precipitation and hydrothermal reaction. This is followed
by functionalization with APTES and antibodies against Salmonella enteritidis. The
nanocomposite selectively captures and rapidly removes S. enteritidis from contaminated
aqueous solutions [305].

Bioinspired 2D nanomaterials have also been used for removing metal ions from water.
Inexpensive hybrid membranes have been synthesized from self-assembled amyloid protein
fibrils and activated porous carbon for removing heavy metal ions from water (Figure 24b).
The concentration of heavy metal ions is reduced by 3-5 orders of magnitude per passage
during the adsorption process [306]. Gold nanoclusters embedded in bovine serum albumin
nanofibers-graphene hybrid membranes have recently been synthesized for detection and
separation of Hg2+ in water [307]. The membranes exhibits excellent selectivity (94%) toward
Hg2+ separation.

Detection of pesticide residues is of practical significance in environmental monitoring. A

highly-sensitive acetyl-cholinesterase biosensor nanospheres has been developed based on
modification of a glassy carbon electrode with chitosan-adsorbed hollow Au nanospheres [308].
Acetylcholinesterase is immobilized on the modified electrode for specific binding of pesticide
residues. A highly-sensitive method for visible detection of bacteria without the need of a
61
readout device has been reported in another study [309]. Biotinylated antibacterial antibodies
are used as bifunctional linkers to mediate the aggregation of streptavidin-functionalized
AuNPs. Visually-recognizable color change is produced based on surface plasmon resonance
(Figure 24c). The assay improves the detection limit of live E. coli and Salmonella down to 10
colony forming units/mL. Decomposable quantum-dots/DNA nanospheres have been
developed for rapid and ultrasensitive detection of extracellular respiring bacteria [310]. These
nanoprobes are prepared by self-assembly of streptavidin-conjugated quantum dots and Y-
shaped DNA nanostructures (Figure 24d).

7. Conclusions and outlook

Recent advances in biological and synthetic template-directed synthesis and applications
of inorganic and hybrid materials have been covered in the present review. Hopefully, the
information provided will ignite the passion of readers to design more sophisticated materials
for applications in nanotechnology, materials science, analytical science and biomedical
engineering. Despite significant progress in the fabrication of bioinspired materials and
structures, there are still many challenges that need to be addressed. Firstly, the complex
mechanisms employed by nature for synthesis of natural materials need to be further perused
for the design of bioinspired structures that can be used in engineering systems. Nature’s
creations occur relatively large time-scales; bone growth, for example, takes years to complete.
In contrast, in vitro biomineralization of organic templates is a synthetic manufacturing process,
the production cycle of which is expected to be completed in hours or days. It is important to
understand the mechanism of the material formation in nature and identify the reasons for the
necessity of a long time-scale. This may inspire scientists to find alternative tracks to mimic
the natural growing process but with shorter time-scales.

Secondly, all biological structures derived from nature are multi-scale (from nano to
macro) and multifunctional (e.g. biological, mechanical, optical, electrical). Multiscaling of
biological materials plays important roles in achieving functional integration. For example, the
nanostructures of butterfly wings provide colors as well as superhydrophobicity for conveying
self-cleansing properties. Reproduction of these multiscale and multifunctional biological

62
structures with impressive efficiency is still far beyond current manufacturing processes.
Advances in nanomechanical characterization, structural investigation, computer simulation,
and manufacturing are required.

Thirdly, most of the bioinspired materials reported in the present reviews involved
benchtop experiments performed in test tubes. A critical bottleneck is harnessing the benefits
of template-directed mineralization is the translation of advances in scientific knowledge, often
performed in the laboratory scale, to tangible technological applications that have to be scaled
up to the industrial level. One of the problems associated with such an issue is that the level of
control that is exerted at the single-object level tends to wane with scale-up attempts to address
a large number of objects. It is important to assure that the biological systems involved do not
change significantly when moving from the laboratory scale experimental conditions to the
industrial-relevant production level. In this regard, producing materials using simple
components under ambient processing conditions is especially desirable.

To solve the aforementioned problems and explore further development of bio-inspired

materials, future studies have to be performed in the following aspects. Firstly, additive
manufacturing (3D printing) has created new opportunities for manipulating and mimicking
the intrinsically multiscale, multi-material and multifunctional nature of organic templates
derived from nature. Such manufacturing practices are only at their infancy of
commercialization and need to be exploited further [311]. Secondly, functional tailoring of
biomolecules should be done to improve the performance of organic templates, This may be
accomplished via fine-tuning the design of biomolecules at the molecular level. For example,
functional peptide sequences may be designed by motif-tailoring to mediate the specific
molecule-molecule and molecule-material interactions on the one hand, and to inspire the
growth and binding of the desired nanoscale building blocks (silica-based, calcium-based,
metal NPs, CNTs and quantum dots) on the other hand. Molecular dynamics simulations are
ideal techniques for exploring and validating the feasibility of molecular design. Thirdly, more
attention should be focused on the fabrication of 2D and 3D hybrid bioinspired nanomaterials
for energy applications. For instance, self-assembled peptide nanomaterials may be used for
light-harvesting systems, especially solar cells. Metal oxides such as SnWO4, Nb2O5 and
63
SrTiO3 are expected to combine with biomolecular superstructures to improve the performance
of supercapacitors. Hybrid nanomaterials based on biomolecular self-assembly and bio-
inspired synthesis of transition metal (Co, Fe, Ni, Mn) oxides/sulfides/nitrides/phosphides for
high performance catalytic hydrogen production (hydrogen evolution reaction) are also highly-
desired. In addition, self-assembled highly-ordered peptide nanofibers for piezoelectric and
triboelectric energy generators have to be further explored. To date, only a few studies are
available on the fabrication of power generators by self-assembled peptide nanostructures
[312,313]. Last, but not least, extensive in vitro and in vivo studies will be required to improve
biocompatibility issues, for augmenting the targetability of these novel materials in different
tissues/cells. Taking silica-based materials as an example, in vivo theragnostic practice should
achieve characteristics/performance that are comparable to synthetic silica materials, to
facilitate future bench-to-beside translational applications [314,315].

In the grand scheme of things, biological or synthetic-templated materials will become

more prevalent in the biomedical, semiconductor and energy sectors, despite the potential
challenges associated with their design, manufacture and use. The unique properties derived
from the nanoscale structure of these materials will enable new and useful products to be
produced on increasingly larger scales (micro or macro scale) as the field develops. The ability
to precisely template inorganic nanomaterials will be the key to developing next-generation
nanomaterials. Complex nanostructures are anticipated to demonstrate better performance than
the simple 1D and 2D architectures employed at present. Biotemplates, inspired from
biomineralization in nature, will provide multifaceted control over inorganic nanomaterial
synthesis. Evidence have emerged for the potential of biotemplates to control the shape and
size of nanoparticles, their molecular recognition capabilities for selective binding to specific
inorganic species, their ability to spatially localize inorganic materials to specific underlying
patterns, and their 3D self-assembly capabilities. The integration of these control strategies in
the nanoscale, such as in next-generation biotemplates, may yield unprecedented control in
synthesizing hierarchical nanostructures. While a great deal of progress has been made in the
past decade to elucidate design principles and explore potential applications, bioengineered
templating of inorganic nanomaterials is still an immature field with considerable untapped
64
potential.

Acknowledgments
This work was supported by grants 81722015, 81870805, 81671012, 81870787 and
81720108011 from the National Nature Science Foundation of China and by the Youth
Innovation Team of Shaanxi Universities.
Author contribution
Chen-yu Wang, Kai Jiao, Franklin. R Tay and Li-na Niu contribute to the original draft writing.
Lorenzo Breschi, Ji-hua Chen, Franklin. R Tay and Li-na Niu contribute to the revising. Jian-
fei Yan, Mei-chen Wan and Qian-qian Wan contribute to the data collecting and table
formatting.
Declaration of Interest statement
There is no conflict of interest.

65
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Figure Legends
Figure 1 Structural hierarchy of hard tissues derived from different organisms. A: Nacre exhibits
suture and layer designing elements. It’s mineral platelets provide strength while proteins account for
ductility and toughness. Each aragonite mineral platelet consists of millions of nanograins (~30 nm)
templated by protein and chitin. B: Fish scales exhibit helical and overlapping designing elements. They
provide multiple layers of defense. Firstly, the overlapping pattern provides flexibility through bending
of multiple scales. Secondly, each scale has graded material properties consisting of a highly-
mineralized outer shell to provide hardness and an inner core of collagen fibril lamellae (scale bar: 500
μm). Thirdly, the lamellae are arranged in a twisted plywood pattern, such that the fibrils within
neighboring lamellae are rotated by various angles. Each lamella is composed of mineralized collagen
fibrils with a predominantly parallel orientation (diameter of single fibril: 100 μm). C: Bone exhibits
fibrous and layer designing elements. Macroscale arrangements involve cortical bone at the surface and
trabecular bone (~100 μm-thick struts) in the interior. Compact bone is composed of osteons and
Haversian canals, which surround blood vessels. Osteons have a lamellar structure with individual
lamella consisting of fibers arranged in geometrical patterns. The fibers comprise mineralized collagen
fibrils that are composed of tropocollagen molecules and HAp nanocrystals, linked by an organic phase
to form fibril arrays. D: Bamboo exhibits gradient and cellular designing elements. It is composed of
cellulose fibers embedded in a lignin-hemicellulose matrix. The latter is shaped into hollow prismatic
cells of varying wall thickness. Flexural rigidity is increased by combining a radial density gradient
with a hollow-tube cross-sectional shape. E: Dentin exhibits fibrous and tubular designing elements.
Collagen fibrils that surround dentinal tubules are ~1.5 μm in diameter with HAp nanocrystals deposited
both around and within the gap zones of the collagen molecules.
Figure 2 Gradients and chirality in biological materials. a) Local property profiles and basic forms
of gradients: (a) Local properties change gradually (I) or in a stepwise manner (II) through the entire
material volume; (b) Local properties vary continuously (III) across the interface between dissimilar
components; (c–g) Gradients may be associated with changes in chemical compositions/constituents
(c), structural characteristics that include arrangement (d), distribution (e), dimensions (f) and
orientations (g) of building units; (h) Gradient interface in biological materials. b) Forms of chirality
in biological materials from nanoscale to macroscale. (A) Model of a biogenic calcium oxalate
monohydrate single crystal (left) and its theoretical enantiomorph (right) superimposed on a
centrosymmetric single crystal grown in vitro. (B) Characteristic crystals extracted from the leaves of
Solanacea plants (C) Macroscopic spiraling morphology of the pteropod shell Limacina helicina. (D)
3D model of typical right-handed helical assembly structure of curved fibrous building blocks in the
pteropod shell. (E and F) 3D-rendering and scanning electronic microscopy of the helical assembly with
a vertically-cut section of the pteropod shell (C. pyramidata). (G) Narwhal whales with their chiral,
spiraling tusks (inset). (H) Rounded, chiral (clockwise, arrow) pathologic calcium carbonate vaterite
otoconia from the inner ear of an elderly patient suffering from vertigo. (I) Synthetic, chiral
superstructure (clockwise, arrow) showing hierarchically-organized, rounded vaterite forms induced by
L-aspartic acid. Image from a) was reproduced from Ref. [7], copyright 2017, with permission from
Elsevier. Image from b) was modified from Ref. [20], copyright 2019, with permission from Royal
Society of Chemistry.
Figure 3 Research in nature-inspired engineering is initially focused around three themes,
corresponding to three fundamental mechanisms that are perceived as the most timely for exploration:
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(level 1) hierarchical transport networks, (level 2) force balancing and (level 3) dynamic self-
organization. Each level contains examples from nature, experimental realization and results. a) and b)
was reproduced from Ref. [287], copyright 2019, with permission from Wiley-VCH Verlag. c) was
reproduced from Ref. [227], copyright 2016, with permission from Royal Society of Chemistry. d) was
reproduced from Ref. [67], copyright 2018, with permission from Wiley-VCH Verlag.
Figure 4 Biomineralization process and schematic of molecular dynamics prediction during
biomineralization. a) Physicochemical process of mineral deposition. (i) Schematic illustrating how
ions in solution can form linear chains of ions with critical nucleus (the classical concept of nucleation)
or unstructured (amorphous) clusters. The critical nucleus continues to accumulate ions and develops
into a crystal. The clusters may also associate to form a “critical nucleus”. Proteins can interact with
any of these forms to facilitate or inhibit the subsequent step. (ii) The major expenditure of energy is in
the formation of the critical nucleus, as illustrated by a plot of activation energy vs time. b) Peptides
increase their secondary structure when bound to the hydroxyapatite (HA) surface. Phosphorylation
(P5P) causes a shift to more helical structures. Images from a) and b) were reproduced from Ref. [4],
copyright 2016, with permission from Elsevier.
Figure 5 Interfaces in nature materials. a) Schematic of the brick-and-mortar structure of nacre.
ⅰ) Deformation of nacre under tension is dominated by sliding of mineral tablets over one another. ⅱ)
Scanning electron microscopy (SEM) of the fracture surface of abalone nacre. ⅲ) Tablets separated in
the out-of-plane direction reveals a highly-deformable matrix. ⅳ) The ligaments can elongate to great
lengths. In this transmission electron microscopy image, the ligaments are up to 500 nm long, which is
more than 10 times the initial thickness of the interface. ⅴ) Schematic of the interface in nacre. b)
Schematic of the building blocks and interfaces in bone. ⅰ) Bone has hierarchical structure with
building blocks that range from nanometers to hundreds of micrometers: fibril, fiber, cross-ply and
osteon. ⅱ) The interfaces within each hierarchical structure depicted at different length scales. These
interfaces differ in composition and size, but they all function in transferring mechanical stresses
between building blocks and across length scales. c) Schematic of structure and mechanics of wood.
ⅰ) SEM of poplar wood depicting tracheid. ⅱ) Hierarchical structure of an individual wood tracheid.
ⅲ) Experimental stress–strain curve for spruce wood, showing large nonlinear strains and a progressive
change in microfibril angle with deformation. ⅳ) Deformation mechanism of a wood tracheid under
axial tension, resembling that of a spring. Change in conformation of the spring-like tracheid involves
shear deformations at the interface. Zoomed-out schematic shows the key components of the
interfibrillar interface and its Velcro-like behavior. Image from a), b) and c) were modified from Ref.
[6], copyright 2016, with permission from Macmillan Publishers Limited.
Figure 6 Bioinspired synthesis strategies for hybrid nanomaterials.
Figure 7 DNA-templated 0D-3D nanostructures. a) Schematic of AuNPs immobilized on a DNA-
grafted supramolecular nanoribbon. b) Schematic of multi-helical DNA-silica fibers (MHDSFs) and
non-helical DNA-silica fibers (NHDSFs). ⅰ) Interaction of 3-aminopropyltrimethoxysilane (APS)
with DNA triggers DNA condensation. ⅱ) During synthesis, APS co-condensed with TEOS to form a
silicatropic DNA liquid crystal phase. ⅲ) APS lowers the tension produced from silica condensation
over DNA and induces higher-ordered asymmetric packing structures with opposite handedness. c)
Arrangement of 2D mesostructured DNA-silica platelets (DSPs) on silicon substrates. 2D-square p4mm
mesostructured DSPs are horizontally deposited on unpatterned surfaces (a). The DSPs are selectively
organized in grooves (b), on protuberances (c) and deposited in parallel columns near the edges (d) on
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patterned surfaces. d) Formation of oriented chiral DNA-silica films (OCDSF). i) DNA molecular layer
formed on the surface of Mg2+-anchored mica sheets by a quartet-templating mechanism. ii) DNA
chiral-packing aggregates induced by N-trimethoxysilylpropyl-N,N,N-trimethylammonium chloride
(TMAPS) and Mg2+. iii) Growth of mesostructured chiral DNA-silica assemblies with long-range
horizontal parallel arrangement. e) Folding of a circular single-stranded DNA with helper strands to
generate a rigid tetrahedral DNA origami cage containing two sets of sticky-ended DNA strands. One
set (green) is projected from the inner faces of the edges, functioning as anchor to encapsulate and hold
the guest particle inside the cage; another set (red) is installed at each vertex of the tetrahedral cage,
acting as a sticky patch to provide binding to the basis particles. The guest and basis particles coated
with corresponding complementary DNA either interact with the tetrahedral cages to form tetravalent
caged particles and FCC superlattices (route A, empty cages), or hybridize with the tetrahedral cages to
create diamond crystals (route B, with caged particle). f) Schematic of TileB-TileA-TileB (BAB)
complex with two different sticky ends pointing up (bright red and green). Gold NPs conjugated with
complementary DNA strands (dark red and dark green) are attached to these sticky ends and serve as a
chain of isolated islands for single electron transistor (SET). C is the capacitance of the tunnel junctions
formed between the AuNP and electrode by a tiny gap filled with single-strand DNA and air. g) Top.
Workflow for preparing AuNP lattices. 1) Folded DNA origami triangles are incubated with Au
particles and purified. 2) Addition of polymerization oligonucleotides initiates lattice growth. 3)
Incubation for 3–4 days yields assembled host-guest lattices. Bottom. Model views and TEM images of
DNA origami lattice hosting 10 nm AuNPs. Image a) was reproduced from Ref. [79], copyright 2018,
with permission from Royal Society of Chemistry. Image b) was reproduced from Ref. [84], copyright
2013, with permission from Royal Society of Chemistry. Image c) was reproduced from Ref. [86],
copyright 2013, with permission from Wiley-VCH Verlag, and modified from Ref. [72], copyright 2014,
with permission from Wiley-VCH Verlag. Image d) was reproduced from Ref. [88], copyright 2016,
with permission from Wiley-VCH Verlag. Image e) was reproduced from Ref. [91], copyright 2016,
with permission from American Academy of Arts and Sciences. Image f) was reproduced from Ref.
[92], copyright 2016, with permission from American Chemical Society. Image g) was reproduced from
Ref. [93], copyright 2018, with permission from Wiley-VCH Verlag.
Figure 8 Self-assembled 0D-3D protein supramolecular nanostructures as templates for
mineralization. a) Chimeric molecular templates prepared with silk fibroin (SF) and albumin-silk
fibroin (ALB-SF), which serve as promoter and inhibitor for hydroxyapatite (HA) formation,
respectively. These templates are used to produce 0D HA nanospheres (using ALB-SF template), and
1D HA nanorods (using SF template only). Nanoparticle shape plays a vital role on cellular uptake by
rat mesenchymal stem cells (MSCs). b) 0D FBG-Au NCs (nanoclusters) fluorescent probes developed
using fibrinogen (FBG) as protein template. Red florescence (“Signal on”) is quenched in the presence
of cysteine (Cys) and Hg (II) (“Signal off”). c) 0D silk fibroin fibers (SFF) are used as sacrificial
templates, after calcination, for preparation of ZnO nanotubes. Poly(diallyldimethylammonium
chloride (PDDA) functionalized ZnO nanotubes electrostatically attracted Au nanoparticles (AuNPs).
The AuNPs/ZnO-NTs (nanotubes) are deposited on glassy carbon electrode (GCE) surface for non-
enzymatic sensing of H2O2. d) Hierarchical apatite mineralization on 2D protein template is achieved
in 2 steps: (i) elastin-like recombinamer (ELR) matrix assembly by disorder–order interplay, and (ii)
calcium phosphate (CaP) nucleation and growth on the ELR membranes into spherulitic structures that
coalesce to fill macroscopic spaces. e) Synthesis of 3D CuS-apoferritin-MBA (a kind of dye) and the
experimental scheme for evaluating the anti-tumor effect of CuS-apoferritin-MBA. Carbodiimide
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(EDC) and N-hydroxysuccinimide (NHS) are used to immobilize MBA on CuS-apoferritin. Image from
a) was adapted from Ref. [100], copyright 2015, with permission from American Chemical Society.
Image from b) was reproduced from Ref. [101], copyright 2019, with permission from Springer. Image
from c) was reproduced from Ref. [103], copyright 2018, with permission from Elsevier. Image from
d) was reproduced from Ref. [104], copyright 2018, with permission from Springer Nature. Image from
e) was reproduced from Ref. [110], copyright 2018, with permission from Royal Society of Chemistry.
Figure 9 Chitin-templated inorganic and hybrid materials. a) Synthesis of adsorbent composite
membrane from chitosan. Genipin crosslinked chitosan scaffolds are treated with tetraethylorthosilicate
(TEOS) and γ-glycidoxy-propyl trimethoxysiloxane (GPTMS) as silica precursors. Silica deposits via
sol-gel reaction with the pores of the scaffold. b) Synthesis of mesoporous silica-titania microparticles
with Ti sites preferentially located at the mesopore surface. Chemical groups on the chitin crystal
surface are used to complex with Ti4+ prior to the formation of the siloxane network, so as to favor the
location of Ti sites at the pore surface after removal of chitin by calcination. c) Conversion of chitosan
hydrogel to nitrogen-doped hierarchical porous carbons (NHPCs) for production of high-performance
supercapacitors. The loose spatial structure of chitosan hydrogel facilitates reformation of dense,
compact carbon materials during carbonization. After impregnation of ZnCl2, the chitosan hydrogel-
ZnCl2 complex is converted to NHPC-ZnO complex via rapid microwave carbonization. d) Possible
mechanism of chitin–zirconia interactions under hydrothermal conditions, based on interactions of
zirconia hydroxyls with the C=O, NH and OH groups of chitin. e) Left: gold replica of a butterfly wing
chitin skeleton. Middle: Cross-section SEM image of the main ridges and struts of the chitin skeleton
that is replaced by Au. Right: high magnification of the ribs within the Au replica. Image a) was
reproduced from Ref. [122], copyright 2016, with permission from Taylor & Francis. Image b) was
reproduced from Ref. [124], copyright 2019, with permission from Elsevier. Image c) was reproduced
from Ref. [131], copyright 2017, with permission from Elsevier. Image d) was reproduced from Ref.
[133], copyright 2013, with permission from Springer. Image e) was reproduced from Ref. [136],
copyright 2011, with permission from Wiley-VCH Verlag.

Figure 10 Lipid-templated inorganic and hybrid materials. a) SLN (solid lipid nanoparticle)
formation and templating of macroporous silica beads. SLN-templated porous silica is prepared by
allowing tetramethoxylsilane (TMOS) to condense on a SLN dispersion and removing the organic NPs
by solvent extraction. b) Hierarchical meso-macroporous silica obtained through a dual templating
mechanism that combines micelles (CTM) and SLN. c) Formation of mesoporous silica tapes and
helical ribbons by self-assembly of partially-neutralized chiral amphiphilic carboxylated lipid
molecules, and hydrolysis/condensation of a silica source consisting of 3-aminopropyltriethoxysilane
(APES) and tetraethoxylsilane (TEOS). d) Platform technology for cell-templated supported lipid
bilayer activation particles. Artificial antigen presenting cells (aAPCs) are successfully created using
supported lipid bilayers 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and 1,2-distearoyl-sn-
glycero-3-phosphocholine (DSPC) on various cell-templated silica microparticles with defined
membrane fluidity and antibody density. 18 particle formulations used for T cell outgrowth and
differentiation studies are shown. Image a) was reproduced from Ref [137], copyright 2011, with
permission from Royal Society of Chemistry. Image b) was reproduced from Ref [140], copyright 2012,
with permission from Royal Society of Chemistry. Image c) was reproduced from Ref [141], copyright

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2008, with permission from Wiley-VCH Verlag. Image d) was reproduced from Ref [142], copyright
2018, with permission from Wiley-VCH Verlag.
Figure 11 Virus-templated materials. a) Synthesis of hollow mesoporous SiO2 nanocapsules using
cowpea mosaic viruses (CPMV) as templates. Steps I and II: Unmodified CPMV is mixed with silica
precursors (APTES and TEOS). A network of silicate is formed around the virus because of electrostatic
interactions between the carboxyl/carbonyl or amine groups of CPMV and the –NH2 groups of silicates.
Step III: A hollow cavity is created in the siliceous particle after denaturation of the CPMV in phosphate
buffer saline at elevated temperature. b) Schematic and TEM micrographs showing the coupling of
tobacco mosaic virus (TMV) particles and functionalized magnetosomes to form magnetic
biocomposites. c) Synthesis of compartmentalized thin films with customized functionality using
cowpea chlorotic mosaic viruses (CCMV) as templates. AuNPs or the enzyme horseradish peroxidase
are pre-loaded as cargoes into individual protein cages after RNA removal from the viruses. The cargo-
loaded protein cages are interfacially-crosslinked at the oil–water interface using trimesoyl chloride to
produce a continuous film. d) Use of genetically-engineered phages with Au-binding peptides and
prostate cancer cell-targeting peptides conjugated to the viral surfaces (GP-Phages) for the deposition
of AuNPs. The GP-Phage-coupled Au-NPs (GP-Phage@AuNPs) are used for cancer-selective
photothermal therapy by targeting prostate cancer cells specifically. Application of very low light
irradiation on the targeted AuNP clusters results in killing the cancerous cells in minutes without
affecting other cell types. e) Schematic representation of the three surfaces of protein cages, each of
which may be modified by functionalization. The three distinct surfaces are: the inner surface that
projects into the central cavity, the outer surface that faces the exterior of the cage, and the inter-subunit
surfaces that form the protein–protein interfaces in the assembled cage. Image a) was reproduced from
Ref. [146], copyright 2015, with permission from Royal Society of Chemistry. Image b) was
reproduced from Ref. [149], copyright 2018, with permission from American Chemical Society. Image
c) was reproduced from Ref. [150], copyright 2018, with permission from Wiley-VCH Verlag. Image
d) was reproduced from Ref. [159], copyright 2015, with permission from American Chemical Society.
Image e) was modified from Ref. [160], copyright 2016, with permission from Wiley-VCH Verlag.
Figure 12 Microscale templates in nature for fabrication of hierarchically- or periodically-porous
structures. a) Synthesis of graphene oxide-diatomaceous earth (GO–DE) nano-hybrids through
electrostatic and covalent attachment routes. (ⅰ) Plain DE silica particles (ⅱ) organo-silane
(APTES:3-aminopropyl-triethoxysilane) functionalized DE particles (ⅲ) O–DE nano-hybrids
fabricated via covalent attachment, and (ⅳ) electrostatic attachment of graphene oxide (GO) sheets. b)
Synthesis of 2D hierarchical nanoporous carbon composites from corn stalk precursors. These
precursors are chemically activated to create 2D nanostructural carbon-based materials with
hierarchical pores and high specific surface area. Functionalized particles are subsequently embedded
into the porous carbon sheets via infusion, followed by calcinations in an inert atmosphere. c)
Biomineralization process for producing alumina nanorods using peacock tail feathers as templates.
Individual barbs of the peacock tail feather are activated in ethylenediaminetetraacetic acid-N,N-
dimethylformamide to produce E/D feathers. Activated E/D feathers are then immersed in Al3+
precursor solution; the immersed feathers are calcined to remove the template, producing alumina
replicas with well-aligned nanorod structures. d) Synthesis of hierarchically macro–nanoporous
bioactive glass particles (BGPs) and the process of drug loading. Image a) was reproduced from Ref.
[170], copyright 2013, with permission from Royal Society of Chemistry. Image b) was reproduced

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from Ref. [176], copyright 2016, with permission from Elsevier. Image c) was reproduced from Ref.
[178], copyright 2018, with permission from Elsevier. Image d) was reproduced from Ref. [186],
copyright 2015, with permission from Elsevier.
Figure 13 Microscale templates derived from nature for fabrication of hollow structures. a) Self-
assembly of bacteria pili into 1D bundles, 2D lattices and 3D lattices. (ⅰ) Illustration of a bacterium
with many pili protruding from its surface. (ⅱ) An individual pilus. (ⅲ) Pili bundles. (ⅳ) Double-
layer pili lattices. The two neighboring layers of pili have a fixed angle of 42o. (ⅴ) Four-layer pili
lattices. A layer of parallel pili was formed initially (red), with subsequent assembly of another layer of
pili (blue) on top of with a twist angle of 42o. Similarly other layers (black and yellow) are deposited,
twisted at the same angle of 42o, to produce a four-layer pili lattice. b) (ⅰ) Schematic of flagellar
repolymerization and sol-gel silicification. The repolymerization process consists of harvesting sheared
flagella from bacteria, depolymerization to flagellin, and repolymerization of the flagellin, first into
short flagellar seeding fragments and subsequently into long flagella, (ⅱ) thermal evaporation of a thin
nickel film onto a substrate coated with silica-templated flagella, (ⅲ) magnetization of thin nickel
coating using a uniform magnetic field. c) Use of carbonized fungal biomass for urease-mediated
manganese carbonate precipitation for the synthesis of novel electrochemical materials. d) Schematic
of a “magnetosome-display” system. A host-vector system is formed using an oxygen-tolerant AMB-1
magnetotactic bacterial strain as host and a plasmid from another magnetotactic MGT-1 strain as vector.
This technology creates functional magnetic particles by transporting target proteins to the surface of
the magnetic particles using Mms13 gene introduced into the plasmid, enabling free control of the
magnetic particle surface. e) Fabrication of hybrid Fe3O4@TiO2 microhelices. (a) Fabrication scheme
for developing hybrid microrobots. (b) SEM image of overlapping biotemplates. (c) High magnification
of the rough morphology (arrow) on the template surface. (d and e) SEM images showing coated Fe3O4
biotemplates. (f) and (g) SEM images of Fe3O4@TiOx coated biotemplates. (h) SEM image showing
overlapping hybrid Fe3O4@TiO2 microhelices after annealing. Inset shows formation of hollow
microhelices after annealing. (i) High magnification of the rough and irregular morphology of the
hybrid Fe3O4@TiO2 microhelices. Scale bars: (b) 20 mm; (c) 1 mm; (d) 30 mm; (e) 3 mm; (f) 30 mm;
(g) 4 mm; (h) 20 mm; inset 1 mm; (i) 1 mm. Image a) was reproduced from Ref. [193], copyright 2011,
with permission from Wiley-VCH Verlag. Image b) was reproduced from Ref. [195], copyright 2017,
with permission from American Institute of Physics. Image c) was reproduced from Ref. [200],
copyright 2016, with permission from Elsevier. Image d) was reproduced from Ref. [205], copyright
2018, with permission from Springer. Image e) was reproduced from Ref. [208], copyright 2019, with
permission from Royal Society of Chemistry.
Figure 14 Protein-templated macroscale gradient materials. a) Schematic showing (ⅰ) the
superficial, intermediate and deep layers of the osteochondral region, and (ⅱ) A multi-layered scaffold
fabricated using three distinct collagen-based slurries that are freeze-dried sequentially to produce a
highly-porous, seamlessly-integrated, multi-layered scaffold (SEM, extreme right) that mimics the
composition and microstructural properties of the osteochondral region. b) Mechanisms of HAp growth
in the presence of chitosan and graphene oxide (GO). Carboxylated GO (cGO) is mineralized in
simulated body fluid. The resulting material is blended with silk fibroin and freeze-dried. c) Self-
assembly of fibroin nanofibers during sol-gel synthesis of silica gels. Subsequent calcination of the
fibroin nanofibers produces porous silica. Image a) was reproduced from Ref. [209], copyright 2015,
with permission from Elsevier. Image b) was reproduced from Ref. [210], copyright 2017, with

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permission from Elsevier. Image c) was reproduced from Ref. [211], copyright 2018, with permission
from Royal Society of Chemistry.
Figure 15 Use of macroscale templates derived from nature for fabrication of hierarchically- or
periodically-porous structures. a) Distribution patterns of different minerals in wood cells and cell walls
illustrated by schematics and SEM micrographs. b) Structural design of porous and functional wood
materials for selective separation of oil-water mixtures. (i) native balsa wood, (ii) delignified wood
template, (iii) delignified wood/epoxy biocomposite. c) Left: photograph and high-magnification field-
emission SEM image (inset) of a biomimetic replica of butterfly wing that exhibits delicate blue color
and a pore-free surface. Right: anti-reflective mechanism of biomimetic replica. N is a normal, θ1 and
θ2 (θ2 = θ1) are the angles of incidence and reflection, respectively; n1 (1.00) and n2 (1.45) are the
refractive indices of air and SiO2, respectively. d) Leaf-templated synthesis of hierarchical AgCl-Ag-
ZnO composites with enhanced visible-light photocatalytic activity. There is a number of thylakoids in
the chloroplasts derived from leaves. Chlorophylls are converted to pheophytins by substituting Mg2+
with Zn2+ in the porphyrins with H+ provided by diluted HCl, and dipping of the leaves in zinc nitrate
solution. Image a) was modified from Ref. [213], copyright 2018, with permission from Wiley-VCH
Verlag GmbH. Image b) was modified from Ref. [226], copyright 2018, with permission from
American Chemical Society. Image c) was reproduced from Ref. [229], copyright 2015, with
permission from Wiley-VCH Verlag GmbH. Image d) was reproduced from Ref. [230], copyright 2015,
with permission from Elsevier.
Figure 16 Bioinspired macroscopic carbon tube aerogel (CTA) materials. a) Photographs and SEM
image of polar bear hair. b) Steps in the synthesis of a CTA. c) Transmission electron microscopy image
of the CTA. Inset: optical image of the CTA. d) Stress-strain curves of CTA-25 at 90% strain for 10,000
cycles. Insets: photographs recording the compress-release of CTA-25 during the first cycle. e)
Thermographic image of a cylindrical CTA positioned on a hot plate with surface temperature
maintained at ~400oC. Image was reproduced from Ref. [234], copyright 2019, with permission from
Elsevier.
Figure 17 The use of bacteriophages as templates for mineralization. a) Binding, synthesis, and use
of nanoscale, wire-like phase-change materials (PCMs) with phages. (i) Schematic illustrating the
atomic binding of materials during synthesis with and without phage. Red and green atoms represent
two different species of a segregating binary alloy. Yellow filaments denote the phage. (ii) TEM images
of suspensions with no phage (top) and E3 phages (bottom). (iii) Schematic of the test structure and
photograph of the structure made of gold/nickel-on-copper electrodes patterned on plastic-laminated
substrates. (iv) Time evolution of the current that passes through structures prepared without phages or
wild-type (WT) phage during pulsed excitations. b) Silica biomineralization and magnesiothermal
reduction into metallic silicon. Silica NPs are nucleated on a phage template. After annealing at high
temperature to decompose the template and sinter the NPs, the biotemplated silica is introduced into a
magnesiothermal reactor along with Mg powder. The reactor vaporizes magnesium, which reacts with
SiO2 to produce pure Si and MgO. The MgO is removed with acid rinse. c) Use of engineered phages
for synthesis of barium titanate (BaTiO3) polycrystalline nanowires at room temperature. (i) Selection
of BaTiO3-binding peptides via biopanning, and (ii) Use of the bioengineered phage with binding
peptide for nucleation of BaTiO3 on the phage surface to form polycrystalline nanowires. d) Phage-
directed formation of hexagonal mesoporous silica. The magenta spots denote mono- and oligo-
hydrolyzed APTES molecules which are anchored to the phage surface and function as nuclei for

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condensation of hydrolyzed TEOS into a silica network (blue). Image a) was reproduced from Ref.
[244], copyright 2018, with permission from American Chemical Society. Image b) was reproduced
from Ref. [241], copyright 2015, with permission from American Chemical Society. Image c) was
reproduced from Ref. [243], copyright 2016, with permission from American Chemical Society. Image
d) was reproduced from Ref. [247], copyright 2012, with permission from Wiley-VCH Verlag GmbH.
Figure 18 Protein/peptide-templated synthesis of inorganic NPs. a) Timeline in the development of
various bioinspired NPs from 2009. b) Application of these materials in various biomedical fields.
Image was modified from Ref. [256], copyright 2016, with permission from Royal Society of Chemistry.
Figure 19 Biomedical applications of hybrid organic-metal materials. a) Synthesis of transition
metal sulfide nanocrystals via the protein-nanoreactor approach for multimodal imaging and
photothermal tumor ablation. A protein such as bovine serum albumin (BSA) was mixed with a
transition metal salt such as Cu2+ in water under vigorous vortexing. Subsequently, Na2S was
introduced into the mixture for triggering the nucleation of CuS through reaction between Cu2+ and S2−
in the nanoreactor. These nanoreactors possess ultrahigh photothermal conversion efficiency, and are
easily functionalized with the imaging agents including a near-infrared-fluorescent (NIRF) dye (Cy7.5)
and a radionuclide (99mTc). In 4T1 breast cancer cells, the nanocrystals exhibit the potent hyperthermia
upon irradiation, resulting in effective tumor ablation. b) Synthesis and application of human serum
albumin (HSA)-MnO2-chlorine e6 (Ce6)-Pt (HMCP) nanoparticles. (i) Synthesis of HMCP NPs. (ii)
Intratumoral penetration of the “smart” HCMP nanoparticles. Dissociation of HCMP NPs in the tumor
microenvironment enables deep interstitial penetration of therapeutic albumin complexes (HSA-Ce6
and HSA-cis-Pt(IV)) via diffusion. Image a) was reproduced from Ref. [257], copyright 2016, with
permission from Wiley-VCH Verlag GmbH. Image b) was reproduced from Ref. [258], copyright 2016,
with permission from Wiley-VCH Verlag.
Figure 20 Use of peptides or proteins as templates for preparation of hydroxyapatite-based minerals.
a) 2D peptide self-assembly and biomimetic fabrication of 3D graphene foam-peptide nanosheets-
hydroxyapatite (GF-PNSs-HA) minerals. First, GF is synthesized by pyrolysis of GO-coated
polyurethane foam (PUF). The PNSs are subsequently loaded through π–π stacking onto the surface of
GF to obtain GF-PNSs. The hybrid GF-PNSs are used for biomimetic mineralization of HA to form a
3D scaffold (GF-PNSs-HA). b) Preparation of fluorenylmethyloxycarbonyl-valine-cetylamide-
collagen-peptide sequence (EDPHNEVDGDK)–bone morphogenetic protein-4 (Fmoc-Val-
Cetylamide-collagen-DT-BMP-4) biocomposites using layer-by-layer assembly. The assemblies are
used to bind HAp that have been doped with varying mass percentages of TiO2 nanoparticles, and
coated with 1% alginate to create scaffolds for bone tissue regeneration. Image a) was reproduced from
Ref. [262], copyright 2018, with permission from Wiley-VCH Verlag GmbH. Image b) was reproduced
from Ref. [263], copyright 2015, with permission from Elsevier.
Figure 21 Overview of biological and synthetic template-directed syntheses of mineralized hybrid
and inorganic materials and their biomedical applications.
Figure 22 Examples of the applications of templated inorganic and hybrid materials in the chemical
industry. a) Top: use of solid-phase “click” chemistry for the synthesis of 3 hybridized DNA (with
different conjugation lengths of oligo(p-phenylene-ethynylene) (OPE) segment amphiphiles). Bottom
center: self-assembly of the hybridized DNA into surface-engineered vesicles with enhanced light
emission. Bottom left: surface decoration of vesicles with Au-NPs. Bottom right: a fluorophore for the

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design of light-harvesting antenna through sequence-specific DNA duplex formation. b) Preparation of
highly-entangled hollow TiO2 nanoribbons and dye-sensitized solar cells (DSSCs). (ⅰ) Molecular
structure of diphenylalanine. (ⅱ) SEM image of 3D xerogel consisting of peptide nanoribbons. SEM
images of the entangled TiO2 nanoribbons (ⅲ) before and (ⅳ) after the calcination of the peptide
template. (ⅴ) A cross section of a DSSC made from peptide-templated hollow TiO2 nanoribbons. Scale
bars: 1 μm. c) Virus-enabled single-walled carbon nanotube (SWNT)/TiO2 DSSC. (ⅰ) Process of M13
virus/SWNT complexation and biomineralization of TiO2 on the surface of the complex. (ⅱ) Scheme
of DSSC incorporating the SWNT/TiO2 complex. Image a) was reproduced from Ref. [272], copyright
2014, with permission from Wiley-VCH Verlag. Image b) was reproduced from Ref. [275], copyright
2010, with permission from IOP Publishing. Image c) was reproduced from Ref. [277], copyright 2011,
with permission from Nature.
Figure 23 Applications of templated inorganic and hybrid materials as supercapacitors and batteries
in the chemical industry. a) Synthesis of virus-templated nickel phosphide nanofoams. M13 virus
displaying the negatively-charged peptide sequence E–E–A–E are crosslinked with glutaraldehyde to
form a virus hydrogel. An alloy of nickel and phosphorus (Ni–P) is deposited on the crosslinked scaffold.
The Ni–P nanofoam is heat-treated to produce nickel phosphides. b) Tree-inspired tri-pathway design
for flexible Li–O2 cells. (ⅰ) Multiphase transport of water, ions, and nutrients is essential for
photosynthesis in trees. (ⅱ) A tri-pathway structural design is realized by chemically treating natural
wood to remove lignin and hemicellulose (endowing it with flexibility) and subsequent carbon nanotube
(CNT)/Ru coating to provide electron conductivity and catalytic activity to enable triphase transport of
Li+ ions, electrons and oxygen gas. c) Synthesis of polysulfide nanofilters (PSNF) based on self-
assembled protein@carbon black (CB). (ⅰ) PSNF interlayer for filtration of polysulfides in Li-S cells;
(ⅱ) Critical properties for achieving a high-performance PSNF; (ⅲ) Fabrication of PSNF with 3D
porous structures and functional surface via protein-directed self-assembly. d) Assembly of a DNA
hydrogel (Dgel)-based supercapacitor. (ⅰ) Supercapacitor immersed completely in the electrolyte
solution. (ⅱ) Conversion of insulating Dgel into a conductive Dgel by electrostatic deposition of
poly(allylamine hydrochloride) (PAH), single-wall carbon nanotubes (SWCNT) and polyaniline
(PANI). (ⅲ) DNA building block (X-shaped DNA) present in the Dgel. e) Wire-like TiO2 clusters
formed on DNA scaffold. In the presence of ethanol, water and heating, Ti4+ ions first formed
Ti(C2H5O)4 and subsequently TiO2 on DNA to generate nanomaterials with different wire-like
morphology. f) DNA-assisted assembly of CNTs and MnO2 nanospheres for the fabrication of
CNTs@DNA and CNTs@DNA–MnO2 supercapacitor electrode materials. Image a) was reproduced
from Ref. [281], copyright 2019, with permission from Wiley & Sons, Inc. Image b) was reproduced
from Ref. [287], copyright 2019, with permission from Wiley-VCH Verlag. Image c) was reproduced
from Ref. [289], copyright 2018, with permission from American Chemical Society. Image d) was
reproduced from Ref. [292], copyright 2013, with permission from Royal Society of Chemistry. Image
e) was reproduced from Ref. [276], copyright 2014, with permission from Royal Society of Chemistry.
Image f) was reproduced from Ref. [293], copyright 2014, with permission from Royal Society of
Chemistry.
Figure 24 Environmental protection applications of templated inorganic and hybrid materials. a)
Formation of metal-phenolic network (MPN) nanocoating on a lignin particle ① using Fe(III) and
tannins for film formation ②. Dissolution of the lignin particle template ③ results in hollow, high
surface area MPN capsule ④. b) Synthesis of activated carbon–amyloid fibrils adsorber membrane and

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its use for purifying heavy metal ions from polluted water. (ⅰ) Structure of the β-lactoglobulin protein
with the strongest heavy metal-binding motif, 121-cys, highlighted with an attached lead ion. (ⅱ)
Amyloid-forming 121-cys-containing fragment from β-lactoglobulin with docked Pb ions. (ⅲ) Heavy
metal ion purification by the amyloid–carbon adsorber membrane. c) Detection of target bacteria using
streptavidin-coated AuNPs (st-AuNPs) (pink particles) and biotin-labeled bacteria antibodies which
serve as bifunctional linkers. Target recognition occurs via antibody-antigen immunoreaction (function
1) and signal indication occurs via the aggregation of st-AuNPs (function 2). The biotin-streptavidin
binding reaction causes visible color change due to localized surface plasmon resonance of the AuNPs.
d) Schematic of the detection method described in “c”. Target bacteria are enriched and separated from
the environmental sample by immunomagnetic separation (IMS). IMS employs antibody-coated
magnetic beads (IMB)-captured bacteria combined with desthiobiotin-modified antibody, which then
reacts with quantum-dots (QDs)/DNA nanospheres. The QDs-desthiobiotin-streptavidin (SA) in the
IMB/bacteria/QDs complex are released into solution via biotin displacement and determined by
fluorescence measurement. Image a) was reproduced from Ref. [302], copyright 2013, with permission
from Royal Society of Chemistry. Image b) was reproduced from Ref. [306], copyright 2016, with
permission from Macmillan Publishers Limited. Image c) was reproduced from Ref. [309], copyright
2017, with permission from Elsevier. Image d) was reproduced from Ref. [310], copyright 2017, with
permission from Elsevier.

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