Re-designing materials for biomedical applications: From biomimicry to nature-inspired chemical engineering

Abstract

Gathering inspiration from nature for the design of new materials, products and processes is a topic gaining rapid interest among scientists and engineers. In this review, we introduce the concept of nature-inspired chemical engineering (NICE). We critically examine how this approach offers advantages over straightforward biomimicry and distinguishes itself from bio-integrated design, as a systematic methodology to present innovative solutions to challenging problems. The scope of application of the nature-inspired approach is demonstrated via examples from the field of biomedicine, where much of the inspiration is still more narrowly focused on imitation or bio-integration. We conclude with an outlook on prospective future applications, offered by the more systematic and mechanistically based NICE approach, complemented by rapid progress in manufacturing, computation and robotics.
This article is part of the theme issue ‘Bioinspired materials and surfaces for green science and technology’.

Full text

royalsocietypublishing.org/journal/rsta
Review
Cite this article: Perera AS, Coppens M-O.
2019 Re-designing materials for biomedical
applications: from biomimicry to
nature-inspired chemical engineering. Phil.
Trans. R. S oc. A 377: 20180268.
http://dx.doi.org/10.1098/rsta.2018.0268
Accepted: 30 October 2018
One contribution of 14 to a theme issue
‘Bioinspired materials and surfaces for green
science and technology’.
Subject Areas:
materials science, green chemistry, biomedical
engineering, chemical engineering, materials
science, fractals
Keywords:
nature-inspired engineering, biomedicine,
biomedical materials, biomimetics,
bioinspired
Author for correspondence:
Marc-Olivier Coppens
e-mail: m.coppens@ucl.ac.uk
Re-designing materials for
biomedical applications: from
biomimicry to nature-inspired
chemical engineering
Ayomi S. Perera1,2 and Marc-Olivier Coppens1
1Centre for Nature Inspired Engineering, Department of Chemical
Engineering, University College London, Torrington Place, London
WC1E 7JE, UK
2Department of Chemical and Pharmaceutical Sciences, Kingston
University London, Penrhyn Road, Kingston upon Thames KT1 2EE,
UK
M-OC, 0000-0002-1810-2537
Gathering inspiration from nature for the design
of new materials, products and processes is a topic
gaining rapid interest among scientists and engineers.
In this review, we introduce the concept of nature-
inspired chemical engineering (NICE). We critically
examine how this approach offers advantages
over straightforward biomimicry and distinguishes
itself from bio-integrated design, as a systematic
methodology to present innovative solutions to
challenging problems. The scope of application of
the nature-inspired approach is demonstrated via
examples from the field of biomedicine, where much
of the inspiration is still more narrowly focused on
imitation or bio-integration. We conclude with an
outlook on prospective future applications, offered
by the more systematic and mechanistically based
NICE approach, complemented by rapid progress in
manufacturing, computation and robotics.
This article is part of the theme issue ‘Bioinspired
materials and surfaces for green science and
technology’.
2018 The Authors. Published by the Royal Society under the terms of the
Creative Commons Attribution License http://creativecommons.org/licenses/
by/4.0/, which permits unrestricted use, provided the original author and
source are credited.

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1. Introduction
(a) Nature-inspired chemical engineering (NICE)
Nature is replete with examples of processes that, through evolution, have been perfected over the
ages, to effectively use energy, matter and space, and to sustain life. These processes have proven
resilient to time-tested environmental changes, and thus are able to recover and rebuild when
disturbed or damaged. An extraordinary feature of natural processes is their ability to transcend
barriers of scalability, while maintaining efficiency [1]. Together with other desirable traits, such
as robustness, dynamic self-organization and self-healing ability, these systems embody ideal
characteristics that man-made formations strive for, yet often fail to achieve.
The concept of drawing inspiration from nature for the design and engineering of new
materials and structures is not new. Since ancient times, man has been inspired by structural
wonders found in nature. Architecture is the most prominent field that benefitted from this
notion. The remarkable constructions by Eiffel [2], Gaudí [3] and Paxton [4] are examples where
natural structures have provided inspiration for unique and enduring man-made creations. Other
examples around the world include the lotus temple in India, The Gherkin in London, the Beijing
national stadium in China, the Olympic pavilion in Barcelona and the Eastgate development in
Zimbabwe, to name a few [5,6](figure 1). Some of these examples, like the lotus temple, however,
mainly mimic their biological counterparts in appearance, with less attention to nature-inspired
function.
In contrast, nature-inspired design goes beyond structural or aesthetic similarities, and delves
into the mechanistic and physico-chemical features of natural systems. The Centre for Nature
Inspired Engineering (CNIE) at UCL draws inspiration from such natural processes to create
innovative solutions to engineering challenges. In particular, we attempt to address some of
our grand challenges in energy, water, functional materials, health, and living space via nature-
inspired design [1]. Our research is currently based around three themes, corresponding to three
fundamental mechanisms, of wide applicability: (i) hierarchical transport networks, (ii) force
balancing and (iii) dynamic self-organization (figure 2).
The goals of this paper are to discuss key issues related to nature-inspired material and process
design: (i) Provide clarity on defining nature-inspired design, versus imitation (bio-mimicking)
and bio-integrated design, (ii) Offer perspective on the advantages of the NICE approach in (re-)
designing new and advanced materials, and (iii) Discuss the broad scope of application of this
approach, using examples from literature, with particular focus on biomedical applications.
(b) Inspiration, imitation and integration: three ways to connect nature to design
In recent years, there has been increased interest within the scientific community in redesigning
materials and processes, based on biological or other natural analogies. These studies belong
to three distinct categories, based on how the natural component is used: (i) nature-inspired,
(ii) nature-mimicking or (iii) nature-integrated design. As most of such studies centre around
biological organisms, these definitions also appear in the literature as ‘bio-inspired’, ‘bio-
mimicking’ or ‘bio-integrated’ design. The term ‘nature’ infers a broader definition, where
features of non-living natural systems are also included, in addition to living systems, for
materials and process design. It is important to understand the distinctions between these
terms, in order to effectively use each methodology, as the terms are often misrepresented
or misinterpreted. The following paragraphs attempt to define each distinct category, clarify
what nature-inspired engineering really entails, and why, we believe, it is more systematically
applicable in solving engineering challenges. The term ‘bio-inspired’ has been broadly defined
as the use of analogous biological systems to develop solutions for engineering problems
[7]. This can be expanded to include non-biological natural systems as nature-inspired
design [1].

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building inspiration
(a)
(c)
(d)
(b)
(e)
Figure 1. Buildings inspired by nature. (a) Thelotus temple in India, inspired by the lotus ower; (b)theGherkininLondon,UK,
inspired by gherkins; (c) the Beijing national stadium in China, inspired by birds’ nests; (d) the Olympic pavilion in Barcelona,
Spain, inspired by gold sh; (e) and the Eastgate development in Zimbabwe, inspired by termite structures. (Online version
in colour.)
By our definition, 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
fundamental mechanisms underlying desirable traits. These mechanisms are subsequently
applied to design and synthesize artificial systems that borrow the traits of the natural model [8].
Thus, nature-inspired designs may not even superficially or morphologically resemble their
natural counterparts, but rather function or behave as such. Such designs adopt some of the
features of the systematic model, after suitable adaptation to fulfil the different contexts of nature
and technology.

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Centre for Nature Inspired Engineering
Theme 1
Hierarchical transport
networks
Lung-inspired fuel cells Bio-inspired membranes Robust, adaptive, self-healing materials
Pattern formation in pulsed fluidized beds
Enzyme nano-confinement
Nano-confinement in catalysis
Hierarchical porous catalysts
Fractal injector for reactors
Theme 2
Force balancing
Theme 3
Dynamic self-
organization
Figure 2. The broad scope of application of the NICE approach, as demonstrated by some of the work conducted at the UCL
Centre for Nature Inspired Engineering (CNIE) [1]. (Online version in colour.)
Figure 2 lists examples of problems tackled by the NICE approach, within the UCL Centre
for Nature Inspired Engineering, organized by Theme, following a fundamental mechanism.
For example, as illustrated in figure 3, a polymer electrolyte membrane (PEM) fuel cell
was redesigned via inspiration from the human lung with its unique hierarchical transport
network, with a scalable architecture and dimensions optimized for minimal metabolic energy
consumption for breathing [9]. In the lung-inspired PEM fuel cell, the flow channel network
for gas transport in the bipolar (current carrying) plates is derived from the fractal geometry
of the upper airway tree of the lung, while the porosity distribution of the electrocatalyst
draws inspiration from the alveolar sacs, as convection-driven flow gives way to diffusion
as the dominant transport mechanism, from bronchi to alveoli, leading to minimal resistance.
Dimensions are based on fundamental thermodynamics and physico-chemical principles, rather
than straightforward imitation of the lung’s appearance. The design is realized using advances
in additive manufacturing and materials synthesis. This systematic methodology, from natural
model, to nature-inspired concept, design, and realization, is illustrated in figure 3. Compared
to traditional designs, this lung-inspired design has great potential for scale up, is more robust
and overcomes reactant homogeneity issues in PEM fuel cells. The method has shown to improve
energy efficiency and save on expensive catalyst material [10].
Similarly, the field of heterogeneous catalysis has also benefitted from nature-inspired design.
By using hierarchical transport networks such as those found in trees as inspiration, new types
of catalysts can be developed to overcome diffusion limitations and optimize transport, leading
to more efficient catalyst design [1,11,12]. Tree-inspired fractal injectors facilitate scale-up, and
uniformise the flow distribution in multiphase reactors [1,11,12]. The behaviour and properties
of wind-swept sand dunes have also been used as inspiration, to induce pattern formation
via a pulsed gas flow in fluidized beds, hereby structuring their dynamics, and avoiding
maldistribution [13–15]. It is important to note that neither the fuel cells, catalysts nor reactors
physically resemble their natural sources of inspiration, but rather express properties or functions
of them, and are hence, truly, nature-inspired inventions.
Nature-imitation or mimicking, on the other hand, refers to more straightforward copying
of physical and morphological features of organisms or natural systems in product or process
design, however it does not take, or insufficiently takes into account, mechanistic features.
Imitating nature tends to target a single feature of its natural counterpart, by mimicking its
characteristics. Biomimetic robot design is a prominent example, where movement of dogs, birds
and insects have been used as inspiration, to guide robot locomotion [16,17]. The behaviours
thus adapted include flapping-wing flight, jumping, crawling, wall climbing, and swimming.
Great progress has also been made in the development of artificial muscles, propellers and
actuators [17]. Other examples include the mimicking of pinecone structure for clothing design

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LUNGS
O2 or fuel distribution
(top view)
Alveoli
Flow
inlet
Multitude of outlets,
equidistant from inlet
Nanoporous catalyst
Uniform macro-porosity Catalyst nano-particles
Fractal distributor
Fractal distributor
Membrane
acini
Diffusion
and
Gas exchange/
reaction
Right main
stem
bronchus
Right
lobes
Trachea
Bronchioles
Left main
stem
bronchus
Bronchi
Left
lobes
Pleura
Pleural
fluid
Diaphragm
2
0.05
0
10
20
30
Pt utilization (kW/gpt)
High CO2
Low CO2
40
Cathode
Pt nanoparticles
Nanopores
Interconnected
macropores
GDL
O2 path Platinum Particle
Carbon Black
Electrolyte
Liquid Water
PEM
0.15 0.25
0.2
0.6
N = 2
N = 3
Pe~1!
Pe~1
N = 5
1.0
1.4
4
Pt loading (mg cm–2)
Branching generation (N)
Current density (A cm–2)
68
Natural model
Nature-
inspired
concept
Nature-
inspired
design
Possible
experimental
realization
Results
Pt NPs
(b)
(a)(c)(d)(e)
Figure 3. Lung-inspired fuel cell. Illustration of the NICE methodology, which uses fundamental mechanisms underpinning the scalability and eciency of transport in the lung (a) to inspire a concept for
transport in a fuel cell (b), which is fractal at the macro- to mesoscales of the ow plates (top) and uniform at the meso- to microscale of the porous catalyst (bottom) that is the basis for a new design (c), which
can be realized thanks to progress in additive manufacturing and chemical synthesis (d), which leads to exceptional improvement in fuel cell performance (e). This versatile methodology could be applied to
trigger innovation in biomedical applications as well. (Online version in colour.)

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to help regulate body temperature [18], the basilisk lizard to design micro-robots that can walk
on water [19], and the lotus leaf structure for design of superhydrophobic, self-cleaning coatings
[20,21], to name a few.
Nature-integrated or bio-incorporated design is yet another category, which includes living
organisms as part of a product or process. The best known cases are those where living
components are integrated into buildings to fulfil key functional purposes. Germany’s ‘algae
house’ or BIQ building in Hamburg is a well-known example, where living microalgae are
incorporated into the walls [22]. The microalgae are grown in transparent surfaces and harness
sunlight to provide renewable energy to the building. The Netherlands’ Sportplaza Mercator is
another example, which incorporates lush vegetation to create living walls on its breath-taking
façade [5].
(c) Why should we look to nature for answers?
Scientific research becomes increasingly challenging, as we attempt to tackle more and more
complex technical problems, and answer deeper scientific questions, regardless of the advances
made in synthesis and manufacturing. Often times, there are too many variables to consider for a
comprehensive analysis of the problem at hand, with limited time and resources. Developing
methodologies to optimize the management of time, materials, energy cost, man-power,
instrument availability and maintenance cost is crucial in research. Empiricism goes only so
far. Brute-force computational approaches have their limitations, and do not necessarily provide
understanding. If there were to be a blueprint or guideline of strategies and methodologies that
could increase the efficiency of research and development, and lead to more sustainable solutions,
its impact on scientific advancement would be immeasurable. That is where nature comes in.
Natural systems are full of characteristics and mechanisms that can be studied and used to give
us clues to the solution of critical problems [8,23,24].
Careful examination of natural systems reveals certain patterns that are key to underlying
structures, which, in turn, may relate to desirable properties. One example, arising from dynamic
self-assembly, consists of regularly striped patterns on dunes, altocumulus clouds and Rayleigh–
Bénard convection rolls. Another is related to the Fibonacci sequence and the golden spiral [25].
Fibonacci, a twelfth century Italian mathematician, described a sequence of numbers, now known
as the Fibonacci sequence. The sequence starts with 1, and each next number is the sum of the two
previous numbers, and, hence, goes as: 1, 1, 2, 3, 5, 8, 13, 21, 34, 55, 89, 144, 233, etc. [26,27]. The
ratio between subsequent numbers in this series approaches what is known as the golden ratio.
This ratio is believed by many to represent unique functional and aesthetic ideals in nature. It
corresponds to the ratio between the lengths of the larger and smaller sides of a rectangle, and
is approximately equal to 1.618. Such a rectangle is called a golden or a perfect rectangle. If a
perfect rectangle is divided into squares based on the Fibonacci numbers, and each square is
crossed with a tangential arc to connect them, a spiral takes shape, which is called the golden
spiral. It has been noted that the Fibonacci numbers, the golden ratio and the golden spiral
are universally ubiquitous in nature (figure 4)[25,28]. The nautilus shell, a galaxy, seeds of a
sunflower, cactus leaves, a storm formation, a fern bud, a sea wave and a fingerprint all contain
examples of the golden spiral in nature. Moreover, the branching of trees, leaves, riverbeds and
even the human lung contain fractal divisions that relate to the golden ratio. In many cases,
such features result from optimization processes of energy, matter and space in natural systems,
sometimes by self-organization, sometimes by evolution. Observing such patterns in nature helps
us to describe them mathematically, and start looking for underlying reasons (are they satisfying
some optimality criterion under constraints?) as a basis for developing a systematic approach to
understanding natural materials, and processes. Such deeper insight can lead to meaningful and
scientific, nature-inspired engineering solutions.
Cataloguing characteristics in the hugely diverse systems that constitute nature is not easy.
From a materials science viewpoint, according to Arzt and Meyers, biological systems have
six major characteristics that lead to remarkably advantageous properties: (i) self-assembly, (ii)

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(a)
(c)
(b)
Figure 4. Examples of patterns in nature, including the golden spiral, the golden ratio and frac tal self-similar structures. From
left to right, (a) a nautilus shell, a galaxy, a sunower, a desert plant; (b) a storm formation, a fern bud, an ocean wave, a
nger print; (c) fractal properties in a branched tree, a leaf, river bed formation, a cast of human lungs. (Online version in
colour.)
multi-functionality, (iii) hydration, (iv) evolution and environmental constraints, (v) synthesis
at ambient conditions, and (vi) hierarchical structures [29,30]. Each of these characteristics is
particularly prominent in biological systems, as opposed to most synthetic counterparts today.
For example, self-assembly in biological structures broadly refers to them being assembled from
the bottom-up, rather than top-down, as, e.g., in lithographic techniques. This ensures continuous
growth, as there is no overriding scaffold that terminates top-down growth.
Components of biological systems usually serve more than one purpose, so as to optimize
resources, and are, hence, multifunctional. The properties of such structures are drastically
influenced by the amount of water they contain, thus, hydration is a key feature. Some of the
most widely used elements in man-made materials are iron, aluminium and copper. All of
these require high temperatures for processing, leading to high production costs and energy
requirements. However, years of evolution, environmental constraints and limited resources
have constrained nature to build robust, functional biological structures with only a few
key elements, predominantly carbon, oxygen, hydrogen, nitrogen, calcium, phosphorous and
silicon. These elements are put together at ambient temperature and atmospheric conditions,
in building those structures. Finally, the property of hierarchy is omnipresent in biology,
where structures consist of multiple scales, each of which deliberates a distinctive feature,
as in bones or tendons. In some cases, the hierarchy contains a fractal scaling range,
in which features repeat themselves repeatedly under magnification, e.g. by self-similarity
(figure 4c).
Taking inspiration from such features can lead to the development of new materials and
technologies with minimal resource consumption and environmental impact. As a result, the

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reach of nature-inspired design in science and engineering is vast, and expanding. Herein, we
focus on one key area: that of biomedical applications.
2. Biomedical applications
In biomedical design, engineering principles are applied to medicine and biological systems for
the purpose of designing applications for healthcare. This includes diagnostics, therapeutics and
analysis. Not seeking to be comprehensive, but rather illustrative, the following sections will
discuss a few selected biomedical examples of nature-inspired design, including membranes and
coatings for tissue engineering scaffolds, as well as implants and support materials. Attention
will be given to a few key sources of inspiration, with particular focus on mollusc nacre, and
some other selected examples that were chosen because of their remarkable features, as well as
broad applications.
(a) Tissue regeneration, implants and support materials
(i) Nacre-inspired materials
As one would expect, the development of new types of materials for tissue engineering has
been significantly influenced by biological materials [30]. Bio-materials, such as mammalian
bones, crustacean shells and reptile skins have unique properties that are intimately associated
to their structure. These structures usually consist of elaborate, hierarchical arrangements and
interactions, across multiple length scales, giving them superior mechanical strength, adaptability
and self-healing ability [30,31]. Associated properties are often the result of a combination of two
distinct components: a ‘hard’ component, consisting of bio-minerals, such as calcium carbonate,
hydroxyapatite or silica, and a ‘soft’ component, consisting of organic matter, such as collagen,
elastin or cellulose.
Nacre, or the inner shell layer of molluscs, is an example of such a composite, hybrid structure
that has been widely used as inspiration in biomedicine [32]. The structure of the red abalone
(Haliotis rufescens) shell, in particular, has been studied extensively (figure 5)[35]. In general, nacre
consists of 95 wt% of aragonite, which is a crystalline form of CaCO3and 5 wt% organic materials,
which are proteins and polysaccharides. The aragonite is present as hexagonal plates in a layered
arrangement, and the organic matter is present in between the plates, acting as a glue to keep them
in place [37]. This arrangement of columnar sheets and tiles is spread across multiple length scales
in a hierarchical manner, from nanoscale to macroscale [38]. Moreover, features are also present
that enhance mechanical properties, such as mineral bridges [33] and an interlocking mechanism
in between plates [36], rotatable nanograins (or nano-asperity) [39], and plastic micro-buckling
to decrease strain energy. Due to this ingenious structure, nacre displays superior mechanical
properties compared to monolithic aragonite. These include high fracture toughness, high energy
absorption, and prevention of crack propagation, while being incredibly light-weight. Nacre also
displays continuous growth following a mechanism called the ‘Christmas tree’ pattern, and has
the ability to self-heal once damaged, being guided by the organic matrix (figure 6). A horizontal
view of the aragonite plates, together with the organic glue, bears a remarkable resemblance to a
brick wall, in both structure and function. Thus, nacre is often referred to as ‘nature’s bricks and
mortar’. These extraordinary features of nacre have attracted attention from material scientists,
for the development of novel composite and laminated materials, especially for biomedical
applications.
Production of nacre-inspired bioactive materials is a key research area in this field. Nacre-
inspired porous scaffolds for bone repair have been established via a combination of strategies,
including electrospinning, phase separation, and 3D printing [42]. A composite film consisting
of clay nano-platelets and polyimide has been fabricated via a centrifugal deposition process, to
form an alternating, layer-by-layer, nacre-like structure [43]. This material displays mechanical
properties comparable to bone and has potential applications as bioactive bone replacement or

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Red abalone
Haliotis rufescens
Variations
of nacre
Mesolayers Complex hierarchical
structure
Hard component
Aragonite (caco3)
Soft component:
Chitin fibrils + proteins
Chitin
Micro
Tiles
200 nm
0.1 mm
1 cm
0.2 mm
Figure 5. Various mollusc species containing nacre in their inner shell, and the complex and hierarchical structure of nacre, as
described via the red abalone shell [30,33,34]. Modied with permission from references [27,35,36]. (Online version in colour.)
Aragonite (CaCO3) tiles
held together by proteins
5 mm
200 nm
growth
surface
nacreous aragonite
spherulite calcite (5–25 mm)
green organic (5–15 mm)
blocklike calcite (10–15 mm)
prismatic calcite (0.5–3.0 mm)
periostracum (100–200 nm)
nacreous aragonite
Resembles “bricks and mortar”
Growth of Aragonite (CaCO3) in a ‘Christmas tree’ pattern
(a)
(c)
(d)
(b)
(e)
(f)
Figure 6. A closer look at the layer-by-layer arrangement of CaCO3plates and organic matrix in the nacre of the red abalone
shell. (a) Vertical section of the nacre outer edge of the shell and mantle [32], (b) SEM image of a growth surface of nacre,
showing the ‘Christmas tree’ growth pattern[32,40], (c) schematic representation of nacre depicting the growth pattern [32], (d)
SEM image depicting the layered aragonite platesheld together by proteins [36], (e) zoomed in SEM image of the cross section of
the aragonite plates and proteins [37], (f) image of a brick wall. Adapted with permission from references [29,31,37,41]. (Online
version in colour.)

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dental graft. A nacre-inspired, layered, freestanding membrane consisting of chitosan, hyaluronic
acid and bioactive glass nanoparticles, has been produced as another potential bone replacement
material [44]. This material displays enhanced mechanical and bioactivity properties, together
with highly tunable physical characteristics, controlled via altering the nanoparticle content.
Nacre’s property of combining hard and soft materials in a hierarchical manner has been
leveraged to create robust, artificial bone materials, via a sol-gel process [45,46]. In this case,
TiO2was polymerized with a flexible polymer (polydimethylsiloxane or polytetramethyloxide),
to deposit nano-sized apatite particles on a fine polymer matrix, which was subsequently textured
into an intricate 3D framework. These hybrid materials show a Young’s modulus and bending
strength similar to those of human cancellous bone, together with increased deformability,
making them attractive materials for bone grafting. The same inspiration has also been used to
create organic-inorganic hybrid ceramic-polymer and alumina-polymer materials with superior
mechanical properties [47].
Combination of magnetic nanoparticles (MNPs) with a polymeric matrix is an area that is
gaining increased interest for various biomedical applications [41,48,49]. Layer-by-layer assembly
of MNPs held together by chitosan and alginate, resembling the structure of nacre, was shown to
produce membranes with increased Young’s modulus and tensile strength [50]. These materials
display magnetic response and adaptive properties that can be triggered by hydration. They were
also shown to be more biocompatible compared to non-magnetic counterparts, with increased cell
viability, adhesion and proliferation. MNPs have also been used in combination with graphene, to
create hierarchical, soft, biocompatible materials, with potential applications as tissue engineering
scaffolds and artificial muscles [51].
The development of coatings for biomedical scaffolds and implants has also been inspired
by nacre. The main purpose of such coatings is to provide a means to functionalize the surface
of biomaterials, in order to induce desired biological responses [52,53]. Multilayered coatings
consisting of bioactive glass nanoparticles, chitosan, and catechol functionalized hyaluronic
acid, have been developed, inspired by marine mussel nacre [54]. These materials display
enhanced mechanical adhesion, and were shown to promote bonelike apatite formation, in vitro.
In addition, multilayer coatings combining chitosan and bioactive glass nanoparticles, developed
via sequential deposition display robustness, together with apatite forming ability, when
immersed in simulated body fluid [55]. This methodology has potential in creating scaffolds and
implants with complex geometries for orthopaedic applications. Moreover, the approach has been
further extended to include antibacterial properties, via incorporation of silver nanoparticles in
the coating, which reduces the possibility of infection in implants [56]. Fibres that resemble nacre-
like properties have been developed via shear-induced self-assembly of nanoplatelets, and have
shown potential in the field of optomechanics, with scalability [57]. It must be noted that there is
also a vast literature on synthetic strategies to develop nacre-inspired materials for applications
outside biomedicine [46,58–60].
(ii) Other bioinspired materials
Many other materials in biology have been used as inspiration to develop innovative, synthetic
analogues for biomedicine (figure 7). The gecko foot is a prominent example, studied extensively
by material scientists for its remarkable ability to attach strongly to various surfaces and yet
be adaptable and recover from mechanical stresses [66,67]. A gecko-inspired, biodegradable
and biocompatible adhesive was developed from surface modified poly(glycerol-co-sebacate
acrylate), in a nanoscale pillar arrangement, used in combination with a thin tissue-reactive
surface [68]. This material has displayed superior adhesion to porcine intestine tissue in vitro,
and to the rat abdominal muscle tissue, in vivo. It is also thought to have potential applications
in wound healing and replacement of tissue joints. The development of novel adhesives for
non-biomedical applications has also been inspired by the gecko-foot [65,69,70].
The unique structure of shark skin has been used as inspiration to fabricate functional surfaces
with advanced properties. An example is a material named as the Sharklet™ micropattern, which

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(a)
(c)(d)
(b)
(e)(f)
(g)(h)
500 nm
Figure 7. Examples of biological structures that provide inspiration for the design of biomedical materials.(a) The gecko’s foot,
inset—enhanced image of a gecko foot, (b) SEM image of the foot hairs of Tokay Gecko (Gekko gecko)[61], (c) the shortn
mako shark, (d) ESEM image of the bonnethead shark (Sphyrna tiburo)skinsurface[62], (e) star sh, belonging to the class
of echinoderms, (f) optical microscope image of the coelomic epithelium of starsh (Asterias rubens)[63], (g) the sandcastle
worm (h) SEM image of the adhesive precursor granules secreted by the sandcastle worm (Phragmatopoma californica)[64].
The microscopic images are adapted with permission from references [62–65]. (Online version in colour.)
has surfaces resilient to bacterial infections, without the addition of any antimicrobial agents
[71]. This material has shown potential for use in hospitals and other places where bacteria-
borne infections are likely to occur. A synthetic, flexible membrane, inspired by the shortfin
mako shark (Isurus oxyrinchus), has been developed via 3D modelling and printing [62]. Such

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discoveries open up possibilities to develop resilient materials for various applications. The
remarkable tissue regenerative abilities of Echinoderms have also provided inspiration to achieve
advances in the field of tissue engineering [72]. A bio-adhesive material capable of holding
bone fractions, and allowing 3D cell alignment, together with the growth of new bone cells,
has been developed based on a secretion produced by the sandcastle worm (Phragmatopoma
californica)[73]. Such adhesives are said to be particularly useful in treatment of craniofacial
injuries and trauma. The advanced mechanical properties of insect cuticles have also provided
inspiration for the development of a tough, yet lightweight material, which is also biocompatible,
biodegradable, and micro-mouldable [74]. This material named ‘shrilk’ has potential to be used as
a biodegradable alternative to plastics, replacing a wide range of non-biodegradable products. In
addition, the mechanical properties of biomedically important materials such as hydrogels have
been dramatically improved, by incorporation of biomimetic nanoparticles [75].
Going beyond the inspiration of animal tissues, technologies that involve customization of
living cells [76] or creating artificial cells [77], based on bioinspired methodologies, are emerging
as novel promising research areas.
(b) Drug delivery
The process of drug delivery consists of various engineered technologies for targeted and/or
controlled release of therapeutic agents. Traditionally, the main method of delivering drugs
to a desired area of the body has included pills taken orally, eye drops, ointments and
intravenous solutions. Later on, more sophisticated approaches, using polymeric materials
(hydrogels and fibres), vesicles (liposomes and micelles), and chemically modified drugs have
been introduced to achieve more target-specific delivery [78,79]. In recent years, with the
advancement of nanotechnology, major developments have revolutionized this field, with
nanoparticle and liposome loaded drugs that can precisely target specific regions or organs in
the body [80]. However, challenges still remain, as most of these new technologies fail to reach
clinical expectations. Novel approaches inspired by nature could provide alternative solutions,
and lead to precise and sustainable practices in drug delivery. A few relevant examples are
discussed below.
(i) Nature-inspired methodologies
Polydopamine (PDA) coatings are a key example of a nature-inspired compound, used in various
drug delivery applications [81]. These are synthetic pigments derived from a naturally occurring
pigment, melanin, and used in multiple biomedical applications. PDA-coated nanoparticles
[82,83] and emulsions [84] have demonstrated potential to be used as alternatives to the polymer
capsule production method. They have the advantages of being much easier to fabricate, while
being highly customizable in terms of physical–chemical properties, to suit specific target sites
[84,85]. A mussel-inspired PDA capsule has also been developed by a PDA coating method
[86]. These capsules have been used successfully in the intracellular delivery of the anti-
cancer drug, doxorubicin. This has been achieved by conjugating the drug with thiolated
poly(methacrylic acid) polymer and immobilizing it within the PDA capsule via carrying out
thiol–catechol reactions between polymer functional groups and the capsule walls. The system is
capable of sustained pH-induced drug release, leading to a stimulus-responsive, nature-inspired
methodology for drug delivery.
Recently, non-spherical polymersomes, inspired by the structure of cells, have been
synthesized using amphiphilic block copolymers, targeting drug delivery applications [87,88].
The polymers are capable of self-assembling into ellipsoidal shapes, resembling cells, and can be
directed to release toxins to cancer cells. The non-spherical shape is said to be far superior in such
applications, and previously has been a challenge to achieve, synthetically. With high stability,
responsiveness to chemical–physical stimuli, and ability to be functionalized with bio-receptors,

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these materials are expected to greatly improve the precision and efficiency of cancer targeted
drug delivery.
With the advancement of nanoparticles as effective drug carriers, various strategies to improve
their performance have also evolved. One critical method is to develop coatings or shields that
can improve their biocompatibility. Bioinspired coating strategies are emerging as a dynamic,
‘active’ way of shielding nanoparticles effectively, in vivo, rather than the conventional ‘passive’
methods [89]. This is achieved by employing carbohydrates, lipids and proteins, which are often
found as natural shields on cells. Hyaluronic acid, which is a polysaccharide, has been coated
onto liposomes and used as an intravenous drug carrier [90]. This system has displayed less
accelerated blood clearance and side effects in mice compared to conventional, polyethylene
glycol (PEG) coated liposomes. Nanoparticles consisting of polysialic acid and modified with
hydrophobic groups, as effective carriers of doxorubicin [91]. These particles have displayed low
toxicity on non-cancerous cells, yet as much toxicity on cancer cells as free doxorubicin. Sialic
acid is a monosaccharide that is found in the body as an amino acid modifier, and the superior
performance of the nanoparticle-drug system is attributed to its biocompatibility. The membranes
from red blood cells (RBCs) have also been investigated as an alternative to PEG coatings, with
various nanoparticles [92–95]. In these studies, the RBC membrane coated particles, through
a combination of bio-inspired and bio-integrated design, showed superior biocompatibility
properties, such as increased blood circulation and retention times [92,94], decreased macrophage
uptake, low toxicity, deceleration in blood clearance [93,95], and higher uptake by the tumour cells
[94,95], compared to PEG coated particles. This is owed to the structure of the RBC membranes,
resembling those on cells, with lipid bilayer feature and membrane proteins, thus improving the
biocompatibility of the delivery system. Drug-loaded nanoparticles coated with peptides derived
from the cell membrane glycoprotein CD47, have shown similar traits [96,97].
(ii) Biomimetic and bio-integrated approaches
The structures and functions of pathogens, including bacteria and viruses, have been used
extensively to develop new types of delivery techniques [98]. A nanogel with virus-like features
has been effectively used as a vehicle to deliver doxorubicin to tumour cells, in vitro [99]. This
system was pH sensitive, and consisted of a hydrophobic polymer core and two layers of
hydrophilic shells, in which the outer shell, made of bovine albumin serum, resembled a virus
capsid. The inner shell, formed of PEG, acts as glue, linking the core and the outer shell. The core
was loaded with doxorubicin, along with a polymer. This nanogel displayed a behaviour similar
to that of a virus, where it actively infects tumour cells in a receptor-dependent manner, then
destroys the cells, and migrates to neighbouring cells to repeat the process again. Polymer micelle
assemblies called ‘filomicelles’, which resemble filamentous viruses, have also been effectively
used to deliver the anti-cancer drug paclitaxel into mice tumours [100]. The filomicelles displayed
blood circulation times that were ten times longer than their spherical counterparts, and exhibited
high anti-cancer activity. This study provided further evidence that the shape of drug delivery
vehicles plays a role in their effectiveness, and that shapes mimicking those in natural biological
systems are more desirable.
Another approach is to use particles that mimic the shape, structure and functions of cells.
Synthetic particles that resemble RBCs are a growing area of interest in this field [101]. RBC-
mimicking particles with the ability to carry oxygen and move through capillaries smaller than
their own size, have been developed by using hollow polystyrene spheres [102]. These particles
are also able to encapsulate drugs and imaging agents, much like RBCs. Hydrogel microparticles
resembling RBCs in size, shape and elasticity, have also shown promise as highly stable and
biocompatible delivery vehicles [103]. The biodistribution and blood circulation properties
of these particles were increased significantly, compared to conventional microparticles, by
customizing their elastic modulus in the physiological range. A combination of mimicking both
the shape and structure of RBCs has also resulted in enhanced blood circulation times, found
by another recent study [104]. In this case, cellulose microparticles were coated with a natural

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RBC membrane, collected from mouse blood, as a method to enhance biocompatibility. These
studies indicate that combining the functions of natural RBCs, together with the versatility of
synthetic particles, can lead to the development of a highly effective class of delivery agents. A
better understanding of the underlying principles would help to move from biomimetic to truly
bioinspired designs, using the systematism of the NICE approach.
In some cases, genetically engineered pathogens have been used as biocompatible alternatives
to conventional drug delivery methods. A phase I clinical trial has been successfully conducted
using the genetically modified Lactococcus lactis bacteria for effective mucosal delivery of
immunomodulatory proteins [105]. Patients with a chronic intestinal disease called Crohn’s
disease were given the above remedy and showed far less systemic side effects, compared to a
placebo group. The same bacteria, engineered in a different way, have been used successfully
in a mouthwash solution, to treat oral mucositis [106]. Genetically modified Salmonella typhi
has also been used as a vector to target tumour cells and to effectively deliver a multidrug-
resistant gene, MDR1 siRNA [107]. This system has displayed efficient cytotoxicity in vitro,as
well as suppression of tumour proliferation in vivo, when administered orally, in mice. Similarly,
Salmonella typhimurium, genetically modified with the transcription factor STAT3 SiRNA, has
displayed significant anti-cancer activity in mice [108]. In this case, inhibition in tumour growth,
in the liver and spleen in mice, along with prolonging the lifespan of prostate tumour induced
mice, have been observed, and compared to those treated with the attenuated, unmodified
bacterial strain. Although all of the above studies have shown promise, the use of living
pathogens in vivo comes with inherent safety concerns, which must be carefully considered in
designing clinical trials. One objective could thus be to develop bioinspired designs that maintain
the biocompatibility of the bio-integrated approaches.
(c) Other applications: novel composite materials and robotics
Characteristics of biomineralization have been used to create synthetic microenvironments that
allow customization of artificial crystallization [109]. This development indicates that certain
aspects of crystallization that are generally difficult to influence, such as the precise localization of
particles, nucleation density, crystal sizes, crystallographic orientation, morphology, polymorph,
stability, and architecture, could be tailored via a nature-inspired approach. Alumina platelets
coated with MNPs, inspired by the layer-by-layer composite fabrication approach used by
cells, have been magnetically aligned to create highly customizable, robust materials for
biomedical and other applications [110]. Due to the advanced material properties, achieved by
this approach, such as locally controlled texture and high mineral content, various complex-
shaped composites can be created, which are otherwise impossible to engineer using conventional
technologies. Another example uses 3D printing to create complex structures of bone-inspired
materials with high energy absorption capabilities, targeting multiple applications. A hard
shell-soft core composite material (similar to bone) was moulded into complex architectures
using 3D printing, and shown to have enhanced, tunable mechanical properties to suit specific
applications [111]. Such materials have far superior mechanical strength, compared to pure stiff
polymeric composites. A robocasting 3D printing technique has also been used to develop nacre-
inspired ceramic composite materials with complex structures, paving a new way to obtaining
unprecedented scaffold microstructures [112].
Some of the most promising biomedical applications of nature-inspired engineering are in
the field of robotics. A recent issue of Nature Materials has been devoted to this [104–108]. 3D
printed soft robots are of particular interest, which can either be integrated with human tissues
or used as biomedical devices [113]. These can mimic the movements of animals, and allow
for responsive, adaptive deformation and movement, which are highly beneficial properties for
biomedical applications. Another category is origami robots, inspired by the natural folding
mechanisms seen in proteins, intestines, etc. [114]. These robots are built according to a top-down
approach, with smart material actuators embedded within, and are capable of folding, to achieve
a wide range of robot morphologies with complex functionalities. Origami robots embody many

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characteristics of living organisms, such as self-assembly, movement, shape change and sensing,
making them excellent candidates for future medical devices. For example, ingestible origami
pills have been developed that can deploy inside the stomach and perform various functions,
such as patch wounds, deliver drugs or remove foreign objects. Such technologies pave the way
towards non-invasive, incision-free techniques to perform surgery [115]. Locomotion has also
been the key focus in the development of magnetic micro-robots, inspired by the movements
of microorganisms [116]. The robots consist of soft polymeric materials, together with magnetic
micro- and nanoparticles, and use flagella and filament-inspired components to achieve self-
propulsion, in response to external stimuli, such as magnetic and electric fields. They can also
exhibit collective behaviour over longer periods of time. These have great potential in the
advancement of surgical techniques and targeted drug delivery.
Finally, hydrogel ionotronics is another rapidly evolving field, where hydrogels are
incorporated with mobile ions and electrons, and can act as hybrid, stretchable, transparent ionic
conductors similar to an ionotropic device [117]. These could serve to develop artificial muscles,
skins and axons, along with various other applications.
3. Outlook and conclusion
It is striking that many of the discussed examples are based on a combination of mechanistic
insights (bioinspired) with biomimicry, while the integration of biological components may
be chosen for reasons of biocompatibility or to directly use desired features of the biological
ingredients. Materials scientists continue to develop novel nature-inspired and biomimetic
materials with advanced properties, but the full potential of learning lessons from nature has
yet to be realized.
This is where, we believe, the nature-inspired chemical engineering (NICE) approach has
a lot to offer. It is systematic, versatile and based on fundamental mechanisms, rather than
superficial analogies. The versatility of the approach is partly due to the ability to translate a
validated application from one field to another, promoting lateral thinking. The systematism
is reflected in the step-by-step process of deriving mechanisms from the model natural system
(which underpins the desired properties) to create a nature-inspired concept, which leads to a
proposed nature-inspired design, and its implementation, cognizant of the differences between
the natural context and that of the engineering application. These unique characteristics of the
NICE approach, already successfully applied across many other application areas, suggest that
biomedical research could greatly benefit from it. Indeed, most examples discussed here do not
follow such a systematic methodology, and there is a gap between materials science, engineering,
and the medical context of the application. A product-oriented engineering mindset is required
to close this gap.
The NICE approach provides opportunities to redesign materials and processes, in a
capacity that supersedes conventional technologies, and leads to sustainable solutions to
engineering problems. It differs from nature-imitating (or biomimetic) and nature-integrated
(or bio-incorporated) design, in that, instead of copying nature out of context, or incorporating
living organisms, it focuses on using mechanistic features of natural systems, to create new
technologies that may not superficially resemble their natural counterparts. In On Growth and
Form, d’Arcy Thompson pioneered the vision that mathematics can serve as a language to
describe biology [118]. Nature is full of mathematically definable patterns and features, such as
logarithmic spirals, golden ratios, fractal geometry and Turing patterns, which are often related
to specific physical–chemical mechanisms that, then, can provide guidelines for engineering.
Living organisms have unique characteristics that lead to robust, adaptable properties with
optimal resource management, which can be used as a source of inspiration for materials,
product and process design. The biomedical field is only starting to benefit from nature-
inspired approaches, with a vast array of research being conducted in tissue engineering
and drug delivery [76], although most work still applies more narrowly biomimetic and
bio-integrated approaches. Certain natural materials, such as mollusc nacre, gecko feet and

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shark skin have already had a major impact in creating novel tissue engineering technologies.
The structures of natural membranes, cells and pathogenic microorganisms have provided
inspiration to advance the field of drug delivery. However, once we embrace a systematic,
mechanistic methodology, as advocated by the NICE approach, even more opportunities should
arise to innovate in biomedicine, complemented and aided by parallel advances in additive
manufacturing, computation and robotics.
Data accessibility. This article has no additional data.
Competing interests. We declare we have no competing interests.
Funding. The authors gratefully acknowledge the EPSRC for providing funding via a ‘Frontier Engineering’
award, EP/K038656/1.
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