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3 Applying Lessons from Nature: Synthesis of Biomimetic and Bioinspired Materials

3 Applying Lessons from Nature: Synthesis of Biomimetic and Bioinspired Materials

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APPLYING LESSONS FROM NATURE



147



aspect of the biomaterial (i.e., morphology, mechanical, optical, or magnetic

properties) are to be reproduced, and in what length scale.

6.3.1



Biomimetic Bone Materials



Biologically inspired materials have a great potential in the fields of regenerative

medicine and biomedical engineering.44 In this case, most approaches focus on

reproducing the overall properties of the biomineral in order to restore its function in the body. One biological tissue that has been the subject of research for

biomimetic replacement materials is bone. Bone is a tissue that provides structural support for our bodies and has unique mechanical properties that arise from

its hierarchical structure and may vary according to the function that a particular

bone performs at a particular location in the body.16 Although bone is capable of

self-repair, this capability is limited to small defects and further decreases with

age and is affected by diseases. In case of severe traumas, the tissue needs to be

replaced using artificial materials in order to restore its function. Thus, there is

great interest in developing bioinspired materials that possess osteoinductive properties, being capable of inducing bone regeneration and eventually being resorbed

by the organism and replaced by bone, or that can directly be used as replacement

material.

Biogenic calcium carbonate, as found in coral skeletons and sea urchin spines,

was found to be a promising material for bone replacement and regeneration, since

it can easily be resorbed by osteoclasts and be replaced by native bone.44, 45 Furthermore, nacre was shown to have osteoconductive properties, meaning that it

stimulates the activity of osteoblasts and induces the formation of new bone. Therefore, synthetic, bioinspired organic–inorganic composites are emerging as new

materials for bone regeneration and offer more possibilities to tune biocompatibility, biodegradability, and mechanical properties.44, 46 Based on the osteoconductive

properties of biogenic calcium carbonate, synthetic calcium carbonate has been

investigated as a material with potential application in bone regeneration. Indeed,

it has been shown that thin films of crystalline CaCO3 can be used as substrates for

cell culture, being capable of supporting rat bone marrow stromal cell attachment

and differentiation into osteoblast- and osteoclast-like cells.47 These films were

prepared on a patterned block copolymer film consisting of alternating of mineralized and nonmineralized regions (Figures 6.5a and 6.5b). Furthermore, polyacrylic

acid was used to stabilize an amorphous CaCO3 precursor phase, which is important in that the amorphous material can easily be molded into any shape before

it crystallizes. Thus, it is possible to generate different patterns of CaCO3 in a

variety of substrates. While these results were obtained on two-dimensional (2D)

substrates, a follow-up investigation was performed, using the same methodology,

on three-dimensional (3D) polymer scaffolds (Figures 6.5c–e).48 The jump from a

2D to a 3D scaffold is an important step since biological tissues have a complex 3D

architecture that is crucial not only for its mechanical properties, as is the case of

bone, but also for providing spatial and organizational cues toward morphogenesis.

Bone cells are sensitive to the physical properties of their environment, such that the



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BIOINSPIRED MATERIALS CHEMISTRY II



composition, topography, and roughness are key determinants in osteogenesis.49, 50

The deposition of calcium carbonate on 3D scaffolds allows the construction of

hybrid ceramic scaffolds with controllable architecture, porosity, and mechanical

properties, which allows their application in bone tissue engineering.

It is evident that an ideal biomimetic scaffold should be as close to the biological tissue as possible, in terms of composition, structure, and properties. Although

designing and producing such a scaffold is still a challenge, a large step was made

a few years ago, when it was demonstrated that collagen mineralization could

be mimicked in vitro by substituting the noncollagenous proteins by a synthetic

polymer, polyaspartic acid (Figure 6.6a).51 For the first time, intrafibrillar mineralization of collagen was achieved under artificial conditions, where the apatite

crystals formed inside the collagen fibrils had the same morphology and orientation

as in bone (Figures 6.6c and 6.6d).51, 52 These findings open new possibilities in

developing bone-replacement scaffolds composed entirely of mineralized collagen,

with optimal osteoconductive properties.

In a similar approach, collagen–apatite composites were prepared using a neutralization reaction, where Ca(OH)2 was directly mixed with a phosphoric acid

solution containing disassembled collagen.53 This reaction yielded calcium phosphate in the form of apatite crystals, which nucleated in close association to the

collagen, while its assembly into fibrils occurred, triggered by the increase in pH.

Based on this methodology, a three-layered scaffold was constructed, consisting

of a layer of mineralized collagen, mimicking subchondral bone; an intermediate

layer also of mineralized collagen, however, with lower mineral content, simulating the tidemark layer, which separates hyaline cartilage from subchondral bone;

and a layer of hyaluronic acid–collagen, reproducing the cartilage.54 Tissue culture tests were done, where it was shown that articular chondrocytes loaded into

the three-layered scaffold yielded cartilaginous tissue formation selectively in the

cartilage-mimicking layer. Additionally, the scaffold was seeded with stromal cells

and implanted in mice, resulting in bone formation within the layer of mineralized

collagen and loose connective tissue in the cartilaginous layer. Thus, even though

one could argue that this scaffold mimicks the biological tissue in composition but

not in structure (i.e., the apatite crystals are most likely outside the collagen fibrils

and not as well organized and oriented as in bone), it still has very good potential as an implant material with osteoconductive properties. This methodology for

collagen mineralization was further developed to allow the incorporation of magnetite nanoparticles during the stage of apatite nucleation and collagen assembly,

with the aim of improving the stability, biocompatibility, and mechanical properties

of the scaffold.55 Indeed, the authors observed that the stiffness of the composite

material when under compression increased, even with a higher collagen/apatite

ratio; its cytotoxicity decreased, and it was able to support cell growth. Last, the

magnetization properties can be exploited for further applications.

In addition to being able to induce osteogenesis and eventually be replaced by

bone, a scaffold also mimics the hierarchical structure and mechanical properties

of the biological tissue. Although we still lack the knowledge to produce such

materials, an interesting approach recently developed is to modify wood templates



APPLYING LESSONS FROM NATURE



(a)



(c)



149



(b)



(d)



Figure 6.6 (a) Scanning electron microscopy image of collagen fibrils mineralized with

hydroxyapatite, using polyaspartic acid as a directing agent. (b) Higher magnification

of (a). (c) Cryo-transmission electron microscopy image of a collagen fibril mineralized with hydroxyapatite, using polyaspartic acid as a directing agent. (d) Slice from

a section of the three-dimensional reconstruction of a mineralized collagen fibril, after

cryo-electron tomography. Crystals are viewed edge on (insets 1 and 2, white arrows).

Note how the long axis of the crystals is aligned parallel to the long axis of the fibril.

Black circle: amorphous calcium phosphate infiltrating into the fibril. Scale bars: 100 nm.

(Panels (a) and (b) adapted with permission. Copyright Elsevier: Ref. 51. Panels (c) and

(d), reproduced with permission. Copyright Macmillan Publishers Ltd, Nature Materials,

www.nature.com/nmat: Ref. 52.)



to obtain an organic–inorganic composite scaffold containing a three-dimensional

morphology and hierarchical architecture (Figure 6.7).56 The development of such

a scaffold was achieved by using a multistep process, involving (1) pyrolysis

of the wood specimens to decompose mainly the cellulose, hemicelluloses, and

lignin and produce a carbon template; (2) carburization to transform the carbon

template into calcium carbide; (3) oxidation of the calcium carbide template to

yield calcium oxide; (4) carbonation to convert the calcium oxide into calcium



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BIOINSPIRED MATERIALS CHEMISTRY II



(a)



(b)



500 μm

(c)



(d)



(e)



(f)



50 μm



Figure 6.7 Scanning electron micrographs depicting the different stages in converting

pine wood into an organic–inorganic composite of native pine wood. (a) Native pine

wood. (b) Wood after pyrolysis. (c) Calcium carbide obtained from pyrolyzed pine wood.

(d) Pine wood-derived calcium oxide. (e) Pine wood-derived calcium carbonate. (f) Pine

wood-derived hydroxyapatite. Note how the natural wood microstructure is preserved

throughout the procedure, culminating with parallel fastened hydroxyapatite microtubes.

(Adapted with permission. Copyright the Royal Society of Chemistry: Ref. 56.)



carbonate; and (5) phosphatization to transform the calcium carbonate template into

hydroxyapatite. After this process, the obtained biomaterial preserved the structure

and morphology of the original wood template. The hierarchical structure of this

scaffold, combined with the hydroxyapatite constituting phase, is very valuable.

First, it ensures a multilevel organized morphology characterized by unidirectional

oriented pore structures that is necessary for cell-in growth and reorganization and

provides the necessary space for vascularization. Second, the fascicular matrix

may be able to satisfy biomechanical requirements, providing the mechanical

properties that are required for the tissue. This process is highly versatile and can



APPLYING LESSONS FROM NATURE



151



be adapted to a number of different organic structures found in Nature, allowing

the production of scaffolds with different three-dimensional architectures.

Ultimately, an ideal biomimetic scaffold should be able to reproduce the composition, three-dimensional structure, and overall properties of a biological tissue

and thus be able to restore its function. However, since biological tissues, and bone

in particular, have quite complex architectures that are directly correlated to their

function and overall properties, producing such a scaffold is still a challenge. Nevertheless, a biomimetic approach, namely, to finding new approaches to understand

and mimic the way that mineralized biological tissues are designed and formed,

has provided significant advances in the design of bioinspired materials that have

great potential for tissue engineering.

6.3.2



Semiconductors, Nanoparticles, and Nanowires



At the nanoscopic scale, mimicking the ability of organisms to tune the size

and morphology of crystals is relevant to a number of synthetic materials. One

example is of semiconductor materials, which have unique optical, electrical, and

optoelectrical properties that can effectively be controlled by tuning the size, composition, and crystal structures of the nanocrystals.57 Indeed, over the last decade,

methodologies have been developed to use organic templates for the molecular

manipulation of semiconducting microstructures, such as CdS and CdSe.57 For

example, organic surfactants have been used to produce II–VI semiconductor

nanocrystals that were highly monodisperse and regular in shape.58 – 63 In this case

the organic template ensured not only the formation of nanocrystallites that were

homogeneous in size and morphology, but also the surfactant formed molecular monolayers around the nanocrystals, preventing the formation of disordered

structures. The result was the self-organization of the quantum dots in superlattices that formed two- and three-dimensional networks. Langmuir monolayers

have also been used as templates for semiconductor growth, resulting in nanocrystals with different morphologies, such as rods, triangles, or a continuous network

(Figures 6.8a and 6.8b).64 Another approach is to produce a polycrystalline semiconducting continuum with periodic nanometer-sized cavities, directly templated by

assemblies of organic molecules.65, 66 The nanometer-sized cavities are an interesting feature in semiconducting materials because, for instance, their presence

could produce a periodic array of antidots that could modify the electronic properties of the material.67 – 69 A further possibility is to use the cavities to selectively

adsorb, transport, or transform molecules diffusing through the cavities according

to the electronic and photonic properties of the semiconductor.57 There are also

reports where the self-assembly properties of large molecules and subsequently

their supramolecular structure were exploited to directly template the formation of

the semiconductor following the morphology of the template. In this case, CdS

nanoribbons could be produced, which were composed of polycrystalline domains

of 4–8 nm (Figures 6.8c and 6.8d).70

More recently, core–shell CdSe/ZnS nanocrystals were synthesized using

bifunctional peptides composed of two different domains, one containing a



152



BIOINSPIRED MATERIALS CHEMISTRY II



(a)



(c)



(b)



(d)



Figure 6.8 (a) Transmission electron microscopy image of a film of particulate PbS

formed by the infusion of H2 S to a monolayer of arachidic acid. Scale bar: 200 nm. Inset:

Electron diffraction of a PbS domain. (b) Transmission electron microscopy image of a

film of particulate PbSe formed by the infusion of H2 Se to a monolayer of arachidic acid.

(c) Transmission electron microscopy image of CdS helixes precipitated in a suspension

of dendron rondcoil nanoribbons71 in ethyl methacrylate. (d) Schematic representation of

a possible templating mechanism, in which a coiled CdS helix (in light gray) is produced

from a twisted helical template through growth along one face of the template (in dark

gray). (Panels (a) and (b) adapted with permission. Copyright Wiley-VCH Verlag GmbH

& Co. KGaA: Ref. 64. Panels (c) and (d) adapted with permission. Copyright Wiley-VCH

Verlag GmbH & Co. KGaA: Ref. 70.)



APPLYING LESSONS FROM NATURE



153



CdSe-binding domain and the second comprised of a ZnS-binding domain.71

By using this method, it is possible to modulate the thickness of the shell using

another peptide capable of controlling the growth of the ZnS shell. In addition,

since it is the peptide sequence that guides the formation of the nanocrystals, it

can be selectively fine-tuned to control and direct the formation of other inorganic

materials and structures. Recently, new methods to produce nanoshells were

developed using enzymes as a template and nanoreactor for the reaction. In this

example, ZnO nanoshells were produced using urease as a catalytic template.72

This enzyme has an overall negative charge and thus can electrostatically interact

with zinc precursors, and the ammonia generated by the enzyme through the

hydrolysis of urea increases the pH, which is suitable for the formation and growth

of ZnO. The procedure used allows the synthesis of semiconductors at room

temperature, under mild conditions, and can be extended to other materials such

as ZrO2 , SnO2 , Ga2 O3 , WO3 , IrO2 , NiO, and TiO2 . Furthermore, since the size of

the nanoshells is determined by the size of the enzyme core, their diameter can

be tuned by employing isoenzymes of different molecular weights. Viruses have

also been exploited as scaffolds for semiconductors. Peptides that control the size,

composition, and phase during the nucleation of nanoparticles were expressed on

the capsid of the virus and served as templates for the formation of ZnS and CdS

nanocrystals 3–5 nm in size that were in close contact and preferentially aligned.73

Upon annealing, the removal of the organic template allowed the polycrystalline

assemblies to form single crystal nanowires of high aspect ratio, being several

hundreds of nanometers in length and only about 20 nm in width (Figure 6.9).

By changing the substrate-specific peptide, nanowires of ferromagnetic FePt and

CoPt were also produced, highlighting the versatility of this system.

Biomimetic systems have also been applied to the synthesis of silver nanoparticles and nanowires. Drawing inspiration from the biosynthesis of silver nanoparticles by bacteria,74 Naik et al.75 have used a phage display library to select peptides

capable of precipitating flat silver crystals, 60–150 nm in size and about 15–18 nm

in thickness. By patterning the adsorption of the peptides on a substrate, they could

also form ordered arrays of nanoparticles. However, although the peptides could

induce nucleation of crystals, they could not precisely control their morphology. Silver nanowires could also be produced, using amyloid-based polypeptides.76 These

polypeptides self-assembled into hollow nanotubes that were a few micrometers

in length and could subsequently be filled with silver nanoparticles (Figure 6.10).

Upon reduction of the silver with citric acid, the amyloid nanotubes served as

molds for casting the metal. After degradation of the polypeptide chains with proteases, discrete nanowires with high persistence length were obtained. Contrary to

what we have discussed so far, where organic macromolecules directly control the

nucleation and growth of nanoparticles, the key function of the amyloid fibers is

to template the morphology of the silver deposits simply by providing a casting

mold. Therefore, controlling the self-assembly of the polypeptide chain into higher

structures is the crucial step in order to template the deposition of the metal into

desired morphologies.



154



BIOINSPIRED MATERIALS CHEMISTRY II



(a)



(b)



(c)



(d)



Figure 6.9 Electron microscopy of both the pre- and postannealed ZnS and CdS viral

nanowires. (a) Dark-field diffraction-contrast imaging of the preannealed ZnS system using

the (100) reflection, showing the crystallographic ordering of the nucleated nanocrystals, in which contrast stems from satisfying the (100) Bragg diffraction condition. Inset:

Electron diffraction pattern of the polycrystalline preannealed wire showing the wurtzite

crystal structure and the single-crystal type [001] zone axis pattern, suggesting a strong

[001] zone axis preferred orientation of the nanocrystals on the viral template. g = (100)∗

denotes the reciprocal vector of (100) crystal planes, which is perpendicular to the (100)

planes and has a length inversely proportional to the interplanar spacing of the (100)

planes. (b) Bright-field TEM image of an individual ZnS single-crystal nanowire formed

after annealing. Inset: (Upper left) Electron diffraction pattern along the [001] zone axis

shows a single crystal wurtzite structure of the annealed ZnS nanowire. Inset: (Lower

right) Low-magnification TEM image showing the monodisperse, isolated single-crystal

nanowires. (c) HRTEM of a ZnS single-crystal nanowire showing a lattice image that continually extends the length of the wire, confirming the single-crystal nature of the annealed

nanowire. The measured lattice spacing of 0.33 nm corresponds to the (010) planes

in wurtzite ZnS crystals. (d) HAADF-STEM image of single-crystal ZnS nanowires.

(e) HAADF-STEM image of CdS single-crystal nanowires. (f) A HRTEM lattice image of

an individual CdS nanowire. (Adapted with permission. Copyright American Association

for the Advancement of Science, AAAS: Ref. 73.)



APPLYING LESSONS FROM NATURE



(e)



155



(f)



Figure 6.9 (Continued )



(a)

Ag+



Sodium

citrate



Proteinase K



+

Ag+ Ag



~20 nm



Ag+

Silver-filled nanotube



(b)



(c)



Silver nanowire



(d)



Figure 6.10 (a) Schematic representation of the casting of silver nanowires using the

peptide nanotubes as templates. (b) Transmission electron micrograph of peptide tubes

filled with silver nanowires. (c) and (d) Transmission electron micrographs of the silver nanowires after digestion of the peptide tubes with proteinase K. (Adapted with

permission. Copyright American Association for the Advancement of Science, AAAS:

Ref. 76.)



The potential for such methodology for the construction of functional nanometerscale electronic devices has already been demonstrated. Braun et al.77 used DNA

strands to connect two gold electrodes, which was followed by selectively depositing silver on the DNA molecules through Ag+ /Na+ ion exchange and formation of complexes between the Ag ions and the DNA bases. The silver ions

were then reduced to form nanometer-sized metallic silver aggregates, bound to

the DNA backbone, forming a conductive metal wire connecting both electrodes

(Figure 6.11).



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BIOINSPIRED MATERIALS CHEMISTRY II



100 μm

Ag+/OH–

12-16 μm

(c)

50 μm

Ag+



+



Ag



+



Ag



Ag+



+



Ag



+

+

Ag+ Ag+

Ag+ Ag Ag



Oligo B

′R–S–S–R



Oligo A

′R–S–S–R

(a)



–S–R



–R–S–



–S–R



–R–S–



–S–R



–R–S–



–S–R



–R–S–



Hydroquinone/OH–

(d)



+

Ag



+

Ag



+

Ag



Ag



+



+

Ag



+

Ag



Ag+ lons + Hydroquinone/OH+

+



Ag



DNA

2Ag+ + Hq

(b)



–S–R



–R–S–



–S–R



–R–S–



–S–R

–S–R



DNA



–R–S–



(e)



Ag+ Ag+

+



Ag



–R–S–



2Ag0 + Bq + 2H+



+



Ag



+



Ag



Ag+

Ag+



Ag+



Conductive silver

wire



Figure 6.11 Schematic representation of the construction of a silver wire connecting

two gold electrodes. (a) Oligonucleotides with two different sequences are attached to the

electrodes. (b) A DNA bridge connects both electrodes. (c) The DNA bridge is loaded

with silver ions. (d) Metallic silver aggregates and binds to the DNA backbone. (e) Silver

wire fully formed on the DNA substrate. (Adapted with permission. Copyright © 1998

Macmillan Publishers Ltd, Nature, www.nature.com: Ref. 77.)



APPLYING LESSONS FROM NATURE



(a)



(b)



10–4



Pt-NP-only device



TMV-pt device

1st scan

2nd scan



10–5

Current (A)



157



3rd scan



10–6

10–7



TMV-only

device



10–8

10–9



AI



AI

TMV–Pt



50 nm



10–10

–6



–4



–2



0

2

Bias (V)



4



6



Figure 6.12 (a) Transmission electron micrograph of a tobacco-mosaic virus (TMV)

impregnated with Pt nanoparticles. (b) Current–voltage (I -V ) characteristics of the

TMP–Pt composite. Filled circles represent the first bias scan and show that the device

switches to the ON state at 3.1 V and stabilizes (empty circles). A reverse scan (squares)

shows that the device switches back to the OFF state at 22.4 V. No conductance switching was observed for TMV-only (triangles) and Pt nanoparticles-only (diamonds) devices.

Inset: Schematic representation of the device structure, with an active layer of dispersed

TMV–Pt nanowires. (Adapted with permission. Copyright Macmillan Publishers Ltd,

Nature Nanotechnology, www.nature.com/nnano: Ref. 79.)



Further works exploited this idea, for example, depositing the DNA strands in

ordered arrays that were used as a substrate to form parallel one-dimensional and

two-dimensional crossed-metallic nanowire arrays of Pd.78 In these cases, however,

the DNA not only templates the morphology of the nanowires but its interaction

with the metal ions during the metal deposition process also assists in controlling

the formation of the nanowires. Also in the field of nanoelectronics, tobacco-mosaic

viruses were used as substrates for the incorporation of Pt, yielding nanowires with

remarkable nonvolatile memory properties that are the result of the combination of

the platinum nanoparticles and the virus (Figure 6.12).79 Here, the virus serves not

just as a scaffold for the organization of the nanoparticles but also plays an integral

role in the process as a charge donor and in stabilizing the charges and creating a

repeatable memory effect.

6.3.3



Biomimetic Strategies for Silica-Based Materials



Another class of materials that have attracted interest in bioinspried design is silica.

Silica and silica-based materials are widely used in industrial and technological

applications.80 A few examples of such applications include (1) zeolites, which are

products of silicalites or aluminosilicates that are applied as thermostable catalysts

in chemical reactions; (2) molecular sieves in separation, purification, and ion

exchange, including (3) as carriers of detergents in washing powders, (4) absorbents



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