SMP-Based Biomaterials for
Tissue Engineering
Generic SMP-Based Tissue Scaffolds
• enable their implan-tation via minimally-invasive surgical techniques
• biodegradable temperature-responsive SMPsthat were used as
sutures for wounds
• support the adhesion and proliferation ofhuman fibroblast cells over
a period of threeweeks.
• temperature-responsive SMPs based on poly-caprolactone have been
shown to support theadhesion and proliferation of human
bonemarrow-derived stem cells over a periodof 3 days
Instructive SMP-Based Tissue Scaffolds
• Films composed oftemperature-responsive caprolactone-basedSMPs
have been shown to support the adhe-sion and proliferation of
mouse fibroblastL929 cells over a period of one week.
• Body-temperature-responsive SMP-based materials that
areprogrammed to change surface topography can also be used
tocontrol cell morphology.
SMP-Based Vascular Tissue Scaffolds
SMP-Based Bone Tissue Scaffolds
www.advmat.de
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John G. Hardy,* Matteo Palma, Shalom J. Wind, and Manus J. Biggs*
in novel biomedical settings, particularly
as devices for minimally invasive surgery,
for the delivery of therapeutics and cells
and as responsive “smart” implantable
devices. Indeed, by comparison with traditional materials used in medical technologies (e.g., ceramics, metals, polymers)
that are morphologically static, SMPs offer
a number of potential advantages, the
clearest being a significant change in morphology following deployment by simple surgical procedures
as exemplified by the work of Lendein and Langer highlighted
above.[2] Critically, it can be inferred that SMP devices may be
implanted as a simple or densely packed structure which when
subjected to a physiological environment will adopt a complex
functional three-dimensional morphology. With the alarming
rise of antibiotic resistant strains of bacteria that may render
previously treatable infections deadly, the importance of simple
surgical procedures cannot be overstated both in the developed
and developing world, and SMPs offer a means to radically
reduce the frequency and severity of infections through the use
of keyhole surgery to implant them.
The unique chemical space that SMPs populate offers chemists and chemical engineers significant opportunities to tune
their properties to suit a specific application, and many years
of fundamental research into this class of polymers has yielded
fundamental insight into the structure-function relationships
underpinning their function. Indeed, the structure of the
polymer backbone plays an important role in SMP hierarchical
assembly in 3D, the polymer crosslinking (i.e., chemical/physical crosslinks), and therefore the reversibility and timescale of
any shape switching events. Medical SMPs can be engineered
to respond to various physiological stimuli (e.g., chemical, electromagnetic, temperature etc.) that result in a physicochemical response of the SMP (i.e., changes in chemical structure,
degree of crosslinking and fraction of amorphous/crystalline
domains), which can be tailored to produce application-specific
changes in polymer morphology. Moreover, the material formulation (films, fibers, foams, gels, particulates) also plays an
important role in their task-specific applications. The excitement that these materials have generated has given rise to a
large body of literature (including some systematic studies) of
stimuli-responsive SMP-based materials derived from a variety
of non-biodegradable and biodegradable polymers (most commonly those that respond to temperature), and we direct interested readers towards a series of excellent reviews of the subject
matter.[3]
While a comprehensive review of SMP chemistry (i.e.,
molecular requirements, mechanism of function, synthesis,
their programming, characterization, modeling)[3] is outside
Shape-memory polymers (SMPs) are morphologically responsive materials
with potential for a variety of biomedical applications, particularly as devices
for minimally invasive surgery and the delivery of therapeutics and cells for
tissue engineering. A brief introduction to SMPs is followed by a discussion
of the current progress toward the development of SMP-based biomaterials
for clinically relevant biomedical applications.
1. Introduction
Shape-memory polymer (SMP)-based materials exist in a
“memorized” macroscopic shape, temporarily exist in another
shape and then revert to their original shape upon exposure to
a stimulus. These exciting properties render them attractive for
a variety of applications in both technical industries (e.g., aeronautics, electronics, textiles) and biomedical industries (e.g.,
stents or scaffolds for the delivery of therapeutics and cells).[1]
The application of SMP-based materials for biomedical
applications was pioneered by Lendlein and Langer, who first
described biodegradable temperature-responsive SMP sutures
that tightened and sealed a wound upon the application of heat
(41°C), as demonstrated in a rat model (Figure 1).[2] Their work
and the emerging work of others has inspired this article.
The unique morphologically responsive nature of SMPbased materials has the potential to facilitate their application
Dr. J. G. Hardy
Department of Chemistry
Lancaster University
Lancaster, Lancashire LA1 4YB, UK
E-mail: j.g.hardy@lancaster.ac.uk
Dr. J. G. Hardy
Materials Science Institute
Lancaster University
Lancaster, Lancashire LA1 4YB, UK
Dr. M. Palma
The School of Biological and Chemical Sciences
Queen Mary University of London
Mile End Road, London E1 4NS, UK
Dr. S. J. Wind
Applied Physics and Applied Math
Columbia University
1020 CEPSR, Mail Code: 8903, New York, NY 10027, USA
Dr. M. J. Biggs
Centre for Research in Medical Devices
National University of Ireland Galway
Biosciences Research Building
Newcastle Road, Dangan, Ireland
E-mail: manus.biggs@nuigalway.ie
DOI: 10.1002/adma.201505417
Adv. Mater. 2016, 28, 5717–5724
© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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RESEARCH NEWS
Responsive Biomaterials: Advances in Materials Based on
Shape-Memory Polymers
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Figure 1. Degradable shape-memory suture for wound closure. The photo series from the animal experiment shows (from left to right) the shrinkage
of the fiber with increasing temperature. Reproduced with permission.[3] Copyright 2002, The American Association for the Advancement of Science.
the scope of this article, an overview of the stimuli to which
SMPs respond may serve to spur their further development for
biomedical applications. While the most commonly employed
trigger for shape-memory switching is temperature (directly
or indirectly applied), it is noteworthy that not all SMPs are
body temperature-responsive. In cases where the temperature response of the SMP is above body temperature (e.g.,
MM5520 thermoplastic polyurethane) it is possible to trigger
their shape-memory reversion with photothermal excitation as
demonstrated for SMP-based stents;[4] the photothermal shapememory response has also been demonstrated with SMPs composites containing gold nanorods as SMP-based sutures, where
light-induced heating of the nanorods triggers the SMP-based
sutures to change shape and close a wound.[5] Other triggers
employed in SMP-based materials include: solvent–polymer
interactions (e.g., rehydration), electricity, light (e.g., photoisomerization), magnetism, sound, or indeed chemical stimuli
that utilize redox switches, or reversible/dynamic covalent
bonds (e.g., acylhydrazones, disulfides) and non-covalent bonds
(e.g., supramolecular interactions, hydrogen bonds) engineered
into the polymers.[3] Clearly, the successful translation of SMPbased materials from the laboratory to the clinic relies on their
ability to respond to biocompatible triggering events, and examples of progress in this direction are highlighted below.
2. SMP-Based Medical Devices
2.1. SMP-Based Stents
Stents based on temperature-responsive polyurethanes (and
drugs with undisclosed structures) were some of the earliest examples of SMP-based medical devices studied in vitro,
wherein the shape memory of these materials exhibited at body
temperature could help to fix a device in place in vivo.[6] The
first examples of fully biodegradable body temperature-responsive SMP stents were based on poly(L-lactic acid) (PLLA) and
poly(glycolic acid) (PLGA) bilayers.[7] Stents based on shapememory copolymers (with blocks of polycaprolactone and a
microbial polyester) showed complete self-expansion at body
temperature within 25 seconds.[8] Stents based on poly(t-butyl
acrylate) crosslinked with poly(ethylene glycol) dimethacrylate
were shown to be body temperature responsive; and the time
for full recovery (1–10 minutes) from storage at room temperature could be controlled by tuning the crosslink density
of the polymer and porosity of the stent.[9] SMPs that respond
swiftly to temperature changes have been shown to decrease
surgery times from minutes to seconds for certain minimally
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invasive surgical procedures; as demonstrated using SMPs
(copolymers of t-butyl acrylate and n-butyl acrylate crosslinked
with poly(ethylene glycol) dimethacrylate) that were coated
on poly(ethylene terephthalate) meshes and delivered laparoscopically in vivo in a pig model, reinforcing the importance
of developing such swiftly responding materials.[10] Analogous
SMP-coated meshes implanted in rats were shown to deter the
infiltration/migration of inflammatory cells and fibroblasts relative to uncoated poly(ethylene terephthalate) meshes because
the interstitial space in spaces in the poly(ethylene terephthalate)
meshes was not patent, resulting in the deposition of less collagenous scar tissue deposited around the SMP-coated meshes
than the uncoated poly(ethylene terephthalate) meshes.[11]
Critically, responsive stents that prevent or deter restenosis
(narrowing of blood vessels after surgical interventions) are a
significant focus of SMP technology. Examples of SMP-derived
stents include temperature-responsive devices that elute
sirolimus (a drug with antiproliferative and immune suppressive properties),[12] or paclitaxel (an antiproliferative that limits
the growth of neointima)[13] over a period of weeks. Interestingly, temperature-responsive SMP-based stents that elute curcumin (an antiproliferative and anticoagulant) and mitomycin
C (an inhibitor of smooth muscle cell proliferation and neointima formation) over 14 and 60 days, respectively, were shown
to simultaneously inhibit early thrombosis and long term
smooth muscle cell proliferation, which are promising for the
prevention of restenosis.[14]
A particularly interesting example of a body-temperatureresponsive SMP-based stent is intended for use in patients suffering from esophageal stricture (sometimes induced by cancer
or trauma), based on a copolymer of poly(caprolactone-co-DLlactide). Such SMP-based stents have prospects for the replacement of metal alloy-based stents displaying shape-memory
properties because their mechanical properties are closer to
those of the tissue in which they are implanted, and preclinical
experiments using dogs have successfully demonstrated their
potential advantage over traditional metallic devices.[15]
2.2. SMP-Based Materials with Speculative Application as
Medical Devices
As noted above, the presence of microbes on implant surfaces
can cause life-threatening infections (particularly with the
alarming rise in prevalence of antimicrobial resistant strains).
Consequently, a variety of SMP-based devices have been developed, some of which display antimicrobial activity. Indeed,
SMPs loaded with Fe3O4 nanoparticles (which can trigger
© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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3. SMP-Based Drug Delivery Devices
3.1. SMP-Based Hydrogels as Drug Delivery Devices
Hydrogels are widely used in drug delivery because of their
tunable compositions, crosslinking densities, and the molecular weight distribution of drugs that can be delivered in a
controlled manner. One of the earliest examples of SMP-based
devices designed for drug delivery was reported by Uragami
and co-workers.[22] Non-biodegradable polyacrylamide hydrogels incorporating supramolecular crosslinks formed through
the specific interaction of an antibody and antigen attached to
the backbone of the polyacrylamide chains were observed to
swell upon the addition of competitive antigen to the hydrogel,
enabling the delivery of a high molecular weight model drug
(hemoglobin, 68 kDa) from the hydrogel matrix within a few
hours.[22] Supramolecular polymer-based hydrogels displaying
pH-responsive SMP properties, have also been developed to
allow the passive diffusion of anionic species at low pH (3.2)
and the delivery of cationic species, triggered by an increase in
pH (to 6.2).[23] Alternatively, shape-memory coatings for model
drug-loaded hydrogels have been demonstrated to be effective
for inducing hydrogel-medicated drug delivery resulting from
the stress induced by the shape-memory outer layer following
an increase in temperature.[24]
Hydration-responsive SMP-based materials enable the
delivery of drugs and potentially cells to a precise location
inside the body by minimally invasive surgical procedures. For
example, xerogels based on composites of bacterial nanocellulose with various hydrophilic additives (e.g., glucose, sucrose,
lactose, poly(ethylene glycol), sodium chloride) have been shown
to respond to rehydration by releasing a model low molecular
weight drug azorubine over a period of hours.[25] Furthermore,
macroporous alginate hydrogel scaffolds were introduced into
immunocompromised mice through a small catheter, and were
rehydrated in situ with a suspension of cells (primary bovine
articular chondrocytes) or cell-free medium delivered through
the same catheter. The scaffolds typically recovered their original
shape and size within one hour of implantation, maintained the
Adv. Mater. 2016, 28, 5717–5724
structure of the original scaffold after 2 months and appeared
histologically stable after 6 months in vivo.[26] Analogous alginate-based scaffolds were also shown to allow the adhesion and
growth of stem cells in vitro, and to be capable of controlled
release of insulin-like growth factor-1[27] or macromolecular
model drugs in vivo when implanted subcutaneously in a
mouse model.[28]
3.2. SMP-Based Materials with Speculative Application as Drug
Delivery Devices
RESEARCH NEWS
shape-memory effects through inductive heating)[16] were
shown to display antimicrobial activity towards Staphylococcus
aureus and Klebsiella pneumoniae,[17] and SMPs loaded with
silver nanoparticles were also shown to display antimicrobial
activity towards Pseudomonas aeruginosa and S. aureus.[18]
Therapeutic embolization entails deliberately blocking a
blood vessel (e.g., clipping an aneurysm to prevent internal
bleeding, or reducing/stopping blood flow to tumors), and body
temperature-responsive poly(ether urethane) SMP-based foams
have been shown to be cytocompatible and enable the infiltration of mouse L929 fibroblast cells in vitro which is promising
for potential future applications as aneurysm fillers in vivo.[19]
Different temperature-responsive polyurethane SMPs that
responded to temperature by expanding up to 70 times their
original volume were shown to be relatively non-immunogenic
in vitro[20] and after 90 days of implantation of radio-opaque
analogues in a pig aneurysm model these materials showed low
inflammation and good healing responses.[21]
SMP-based particulate systems are also being widely explored,
for drug delivery applications in vivo. Indeed, temperatureresponsive biodegradable poly(DL-lactic acid)-based particles are capable of delivering the low molecular weight
drug theophylline.[29] More recently, temperature-responsive
particles composed of biodegradable copolymers of poly(ωpentadecalactone) and polycaprolactone have demonstrated the
ability to be switched from oblate spheroid to prolate spheroid
(Figure 2).[30] Analogous temperature-responsive particles composed of polycaprolactone and poly(ethylene glycol) have been
shown to be phagocytosed by macrophages and were subsequently switched from spherical to ellipsoidal. In this study the
authors suggested that it would be possible to either promote
or deter phagocytosis in future studies employing iterations of
these particles.[31]
Temperature-responsive composites-based on polycaprolactone and poly(sebacic anhydride), have been shown to be
capable of delivering paracetamol (5 wt% loading) by passive
diffusion while maintaining their SMP properties,[32] and ultrasound-responsive SMP-based drug delivery devices have been
developed for the delivery of copper sulfate (formerly used as an
emetic and antimalarial),[31] or a high molecular weight model
drug (lysozyme),[33] which may find application in the emerging
area of ultrasound-mediated drug delivery systems.[34]
Lendlein and co-workers have made some interesting
contributions to the literature with temperature-responsive
degradable caprolactone-based polymers for the delivery of
hydrophilic drugs (such as ethacridine lactate) and hydrophobic drugs (e.g., enoxacin).[35] They further developed these
systems to act as implantable devices with body temperature
induced shape change (potentially enabling immobilization in
a fixed location in a patient), enabling the delivery of ethacridine lactate, enoxacin and nitrofurantoin,[36] and these systems
were shown to slowly degrade over the period of weeks when
implanted in rats.[37] Subsequently, other researchers have
manufactured body temperature responsive SMP device that
immobilized a drug delivery device, for the delivery of model
macromolecular drugs to the vagina, as demonstrated in vivo in
a rabbit model.[38]
4. SMP-Based Biomaterials for Tissue Engineering
4.1. Generic SMP-Based Tissue Scaffolds
SMP-based tissue scaffolds potentially enable their implantation via minimally-invasive surgical techniques, and are
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biodegradable temperature-responsive SMPs
that were used as sutures for wounds[2] were
shown to support the adhesion and proliferation of mouse fibroblast NIH 3T3 cells over
a period of one week,[39] and films composed
of temperature-responsive poly(glycerol-cododecanoate) SMPs have been shown to
support the adhesion and proliferation of
human fibroblast cells over a period of three
weeks.[40] Studies involving stem cells and
temperature-responsive SMPs based on polycaprolactone have been shown to support the
adhesion and proliferation of human bone
marrow-derived stem cells over a period
of 3 days.[41] More advanced studies have
focused on the development of biomaterials
with higher technology readiness levels tend
to include in vivo studies in small mammals.
For example, temperature-responsive potato
starch-derived SMP-based fibers implanted in
a rat model exhibited normal tissue integration with a low inflammatory response after
8 days.[42] Interestingly, biodegradable temperature-responsive SMPs based on copolymers of polyhedral oligomeric silsesquioxane
and poly(D,L-lactide) implanted subcutaneously in a rat model elicited a mild foreign
body type immune response, their degradation rates inversely correlated with the length
of the poly(D,L-lactide) chains, and one year
after implantation no pathologic abnormities were detected from the vital/scavenger
organs examined, highlighting their promise
for scaffold-assisted tissue repair.[43]
4.2. Instructive SMP-Based Tissue Scaffolds
Tissue scaffolds that instruct cell behaviour
represent a significant focus of current tissue
engineering strategies.[44] Films composed of
temperature-responsive caprolactone-based
SMPs have been shown to support the adhesion and proliferation of mouse fibroblast
L929 cells over a period of one week.[45]
Subsequent studies on similar temperatureFigure 2. SME of micrometer-sized particles. A) SEM images of particles in their permanent
spherical shape (left) and programmed prolate ellipsoidal shape (right). B) Programming responsive caprolactone-based SMPs have
of spherical particles (permanent shape) embedded in PVA phantoms (l0 = initial length, reported the adhesion and proliferation of
∆lph = length change during stretching; ∆lph·l0−1 = εph) to their temporary shape and microscopy mouse fibroblast L929 cells, rat mesothelial
of temperature-induced shape recovery for isolated particles (εph = 100%). C) Shape recovery to cells, human mesothelial cells and human
non-spherical shape after (i) heating to Tmax > Tm,PPDL, stretching (εph = 50%), and cooling for mesenchymal stem cells on the materials
defining the new permanent prolate spheroidal shape, and (ii) programming in perpendicular
for up to 3 weeks. However, activation of
direction (εph = 50%) at Thigh to temporary oblate spheroidal shape. Reproduced with permisthe shape-memory effect by heating to 54 °C
[
30
]
sion. Copyright 2014, Wiley-VCH.
was shown to affect L929 cell adhesion and
induce apoptosis (although not necrosis).
Control studies showed that these effects was not through celof broad applicability in the body, with examples of both soft
lular exposure to elevated temperature, but were rather related
and hard tissue scaffolds having been reported. The ubiquity
to the shape change process,[46] which may provide mechanof fibroblasts makes them very popular for preliminary in vitro
studies on SMP-based materials. Indeed, Lendlein and Langer’s
ical stimulation to prevent adhesion or promote cell death.
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4.3. SMP-Based Vascular Tissue Scaffolds
Lendlein’s group have further developed SMP-based materials
for vascular tissue regeneration, studying a variety of SMPs,
and exploring processing parameters for the fabrication of
various material formulations. Their studies have employed
block copolymer SMPs based on poly(p-dioxanone)diol and
poly(ε-caprolactone)diol (PDCs), which have been shown to
enable adhesion of endothelial cells,[51] to be hemocompatible
to capillary endothelial cells in the chorioallantois membrane
(CAM) test,[51] and to be angiogenic.[51,52] When compared
to polypropylene (widely used for blood-contacting medical
devices such as blood oxygenators and dialysis tubes), protein
adsorption studies showed higher amounts of blood plasma
proteins adsorbed on PDC.[53] Plasma kallikrein synthesis
was unchanged on PDC and polypropylene, however, platelet
adhesion on PDC materials was markedly lower than on polypropylene, suggesting a reduced thrombogenic potential with
implications for vascular tissue engineering.[53]
RESEARCH NEWS
Body-temperature-responsive SMP-based materials that are
programmed to change surface topography can also be used to
control cell morphology. Indeed, films with micrometer-scale
grooves that act as topographical cues have been explored as
active materials to induce mouse embryonic fibroblasts to alignment. These SMP substrates can be switched from anisotropic
topographies to induce contact guidance to flat featureless surface wherein loss of the topographical cue leads to a decrease
in cell alignment (as evidenced by an increase in angular dispersion while maintaining cell viability);[47] an analogous effect
is observed for human adipose-derived stem cells that align on
aligned electrospun SMP fibers and lose their alignment after
the scaffold is triggered to switch to unaligned fibers.[48] Elegant
experiments showed that SMP-based films with micrometerscale grooves programmed to switch their alignment by 90°
induced mouse fibroblast NIH 3T3 cells to realign with the
grooves over the period of 48 hours.[49] Furthermore, analogous systems with grooves with switchable widths have been
employed to apply mechanical force to regulate the shape and
the cytoskeletal arrangement of rat stem cells, thereby coaxing
lineage-specific differentiation of the stem cell towards myogenic lineages in the absence of any induction factors.[50] Taken
together, this hints that SMP topographies may play important
future roles in smart, tissue engineered implants, or lab-onchip devices.
4.4. SMP-Based Bone Tissue Scaffolds
The development of SMP-based bone-tissue scaffolds has
become a focus of recent research due to the discovery of
responsive bioglass formulations and polymeric nanocomposites with high compression resistance. The benefit of SMP in
orthopedic applications stem from an ability of these materials
to expand into irregular bone defects to promote fixation and
regeneration. Interestingly, hydration-responsive chitosanbioglass composite tissue scaffolds have been shown to rapidly
fill bone defects in vivo,[54] as have body temperature-responsive copolymers of L-lactide/glycolide/trimethylene carbonate
or L-lactide/glycolide/epsilon (Figure 3).[55] Electrospun mats
of temperature-responsive biodegradable SMPs based on
Figure 3. A–D) Photographs presenting the filling process of bone defect with scaffold number 1 in a model bone-tissue defect at few seconds (A),
2 min (B), 11 min (C), and 20 min (D) after application. The test was performed in a water bath maintained at 37 °C. Reproduced with permission.[55]
Copyright 2014, Wiley.
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Figure 4. Schematic overview of the shape-memory process in nanocomposite polymeric materials. Nanoparticulates enhance the polymer relaxation
through localized effects on the polymer netpoints.
poly(D,L-lactide-co-trimethylene carbonate) have also demonstrated to support rat calvarial osteoblast adhesion and proliferation, and functionally promote biomineralization-relevant
alkaline phosphatase expression and mineral deposition in
vitro.[56]
Importantly, temperature-responsive polycaprolactone-based
foams (with an optional bioactive polydopamine coating) are
reported to become malleable when warm and could be pressed
into an irregular model bone defect, and locked within the
defect when cooled. These materials promoted adhesion, proliferation, osteogenic gene expression and extracellular matrix
deposition when cultured with human osteoblasts in vitro.[57]
Furthermore, composite materials incorporating hydroxyapatite are commonplace in bone tissue engineering studies, and
composites of poly(D,L-lactide) and hydroxyapatite have been
reported to display temperature-responsive shape-memory
properties.[58] Studies employing temperature-responsive foams
based on composites of polycaprolactone and hydroxyapatite
showed that they were capable of controlled release of bone
morphogenetic protein-2 and displayed good cytocompatibility
towards rabbit bone marrow-derived stem cells in vitro. Critically, when implanted in a rabbit mandibular bone defect this
material was shown to promote new bone generation after
8 weeks.[59]
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5. Conclusion
SMP-based materials (Figure 4) represent a novel class of biomaterials with potential for biomedical applications including
devices employable via minimally invasive surgery or devices
for the delivery of drugs and cells, as highlighted here.
We see many challenges that first need to be overcome
in terms of the development of polymer chemistry (e.g.,
designing polymers that respond to biocompatible triggers,
potentially even endogenous biological conditions/events);
materials processing (e.g., obtaining materials with biomimetic mechanical properties and topographical properties);
biocompatibility (e.g., biodegradation into safe non-toxic
byproducts), preclinical testing (ideally without the use of animals), and ultimately clinical trials (which requires the technology to offer strategic advantages over others on the market
at an affordable price).
We foresee that these materials have strong prospects for
clinical translation, particularly when attractive multifunctional
properties have been engineered into the polymers (e.g., biodegradable antimicrobial polymers), however, we believe that
such materials have prospects for grand healthcare challenges
such as the provision of affordable healthcare technologies in
both the developed and developing world.
© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Mater. 2016, 28, 5717–5724
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J.G.H. thanks Lancaster University for a 50th Anniversary Lectureship.
M.J.B. thanks Science Foundation Ireland for a Starting Investigator
SIRG COFUND fellowship (grant agreement no. 11/SIRG/B2135), and
the Science Foundation Ireland Centre for Research in Medical Devices
(CÚRAM) for financial support (Grant agreement no. 13/RC/2073). The
authors thank Ms. Ghazal Tadayyon for help with graphic design.
Received: November 3, 2015
Revised: January 26, 2016
Published online: April 27, 2016
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