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com Current Opinion in

ScienceDirect Biomedical Engineering

Engineered stimuli-responsive smart grafts for bone

regeneration
Mohammad Aftab Alam Ansari1,2,3, Madhusmita Dash4,
Gulden Camci-Unal5, Prashant Kumar Jain2,
Syam Nukavarapu6, Seeram Ramakrishna7,
Natashya Falcone8, Mehmet Remzi Dokmeci8,
Alireza Hassani Najafabadi8, Ali Khademhosseini8 and
Himansu Sekhar Nanda1,3,8
4
School of Minerals, Metallurgical, and Materials Engineering, Indian
Abstract
Institute of Technology Bhubaneswar, Argul, Khordha, Odisha 752050,
Complex tissue regeneration through biomaterial-based stra- India
tegies has witnessed a substantial structural transformation to 5
Department of Chemical Engineering, University of Massachusetts
facilitate the attachment and migration of host cells. Smart Lowell, Lowell, MA 01854-2827, USA
6
biomaterials offer exceptional features by rearranging them- Biomedical Engineering, Materials Science & Engineering, University
of Connecticut, 260 Glenbrook Road, Unit 3247 Storrs, CT, 06269,
selves into diverse conformations upon exposure to physical
USA
(e.g., magnetic, temperature, electric field, and light), chemical 7
Centre for Nanotechnology & Sustainability, Department of Mechan-
(e.g., pH and ionic strength), or biological (e.g., enzymes) ical Engineering, Faculty of Engineering, National University of
stimuli. By engineering conventional biomaterials into three- Singapore, Singapore, 117576, Singapore
8
dimensional smart porous constructs (i.e., grafts) with novel Terasaki Institute for Biomedical Innovation (TIBI), 21100 Erwin St
Los Angeles, CA 91367, USA
sensory materials through a range of chemical and physical
processing routes, it is possible to mimic the diverse me- Corresponding authors: Nanda, Himansu Sekhar (himansu@iiitdmj.
chanical, biological, and physiochemical nature of bone tissue. ac.in); Khademhosseini, Ali ([email protected])
The resulting smart grafts can efficiently deliver the appro-
priate signals and guide the stem cells to promote tissue
regeneration. In addition, they regulate the release of various Current Opinion in Biomedical Engineering 2023, 28:100493
bioactive agents in response to external and internal stimuli This review comes from a themed issue on Intelligent Biomaterials
while combatting infections at the wound sites. This review 2023
discusses numerous strategies to engineer synthetic polymers Edited by Seeram Ramakrishna, Ravin Narain, Himansu Sekhar
to yield stimuli-responsive smart grafts suitable for bone tissue Nanda, Masoud Mozafari and Gulden Camci-Unal
engineering. Various additives have also been included, For complete overview of the section, please refer the article collection
ranging from nanoparticles to biologically active agents - Intelligent Biomaterials 2023
responsible for the graft’s smart function. Furthermore, the Received 17 May 2023, revised 11 July 2023, accepted 27 July 2023
review highlights recent trends and developments, contempo- https://doi.org/10.1016/j.cobme.2023.100493
rary challenges, and future perspectives of smart stimuli- 2468-4511/© 2023 Elsevier Inc. All rights reserved.
responsive grafts concerning bone tissue engineering.

Keywords
Addresses Smart biomaterials, Piezoelectric responsive, Smart bone grafts, 3D
1
Biomedical Engineering and Technology Lab, Discipline of Mechan- printing, Shape memory biomaterials, Non-invasive-diagnosis, Stimuli-
ical Engineering, PDPM Indian Institute of Information Technology responsive polymers.
Design and Manufacturing, Jabalpur, Madhya Pradesh 482005, India
2
Fused Filament Fabrication Laboratory, PDPM-Indian Institute of In- Introduction
formation Technology Design and Manufacturing Jabalpur, Madhya
Pradesh 482005, India
Bone tissue injuries constitute one of the most prevalent
3
International Centre for Sustainable and Net Zero Technologies, human body medical conditions, affecting quality life of
PDPM-Indian Institute of Information Technology Design and millions of people worldwide. Genetics, spontaneous
Manufacturing Jabalpur, Madhya Pradesh 482005, India and external factors, leads to bone fractures and abnor-
malities. These include autoimmune diseases, genetic
disorders, degenerative diseases, bone tumors, physical
injuries, or road accidents. Bone loss is an immense
Given his/her role as Guest Editor, Seeram Ramakrishna, Himansu
burden in orthopedic trauma, leading to nearly 2.2
Sekhar Nanda, Gulden Camci-Unal had no involvement in the peer
review of the article and has no access to information regarding its million bone transplant and reconstruction surgeries
peer-review. Full responsibility for the editorial process of this article worldwide, causing billions of dollars in annual health-
was delegated to Ravin Narain. care costs [1]. Followed by the blood transfusion, bone

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2 Intelligent Biomaterials 2023

grafting procedures stand second in the tissue replace- “responsive” refers to transforming the temporality
ment ranking [2]. Even though bones possess the state of the biomaterials to the original state when
intrinsic ability to repair themselves post-fracture, grafts exposed to certain stimuli. By doing so, smart bio-
(autograft, allograft, xenograft) and other substitutes materials can sense and change their properties upon
such as bioceramic (calcium sulfate, hydroxyapatite) exposure to a specific stimulus (physical, chemical, or
with specific stimulation are still considered indis- biological). The broad classification of smart bio-
pensable for the rapid rehabilitation of fractures and materials, their triggering mechanisms, and the types of
bone-related injuries [3,4]. Bone performs various bio- stimuli to activate stimuli-responsive grafts obtained
logical functions, including safeguarding the soft tissues from smart biomaterials are shown in Figure 1.
and critical internal organs, storing minerals, and con-
trolling pH while mechanically supporting locomotion Traditionally, various naturally derived or synthetic bio-
[5]. Therefore, bone diseases, particularly bone de- materials such as metals, ceramics, polymers, and com-
formities, remain a significant challenge and pose clin- posites have been studied for bone reconstruction
ical concerns. applications [6e10]. With the growing demand for novel
biomaterials with smart features to recapitulate the
To bridge this gap in tissue reconstruction, tissue engi- reactivity of native tissues to physical, biological, and
neering (TE) approaches involving smart biomaterial chemical signals, “responsive” biomaterials can percept a
grafts to regenerate the lost bone tissue provides a stimulus and react or respond to it by initiating or
promising solution to achieve efficacious bone tissue executing a specific biofunction, similar to a closed loop
engineering (BTE). In general, smart biomaterials feedback control system [11e13]. For example, PEG
should be able to guide stem cells to enhance tissue diacrylate hydrogels could detect the particular enzyme
regeneration. Adding stimuli-responsive materials to (e.g., protease) released from the neighboring cells and
existing biomaterials is an excellent strategy to improve then release the growth factors (e.g., FGF-1) for tissue
the smartness of existing biomaterials. Here, the term regeneration [14,15]. Smart stimuli-responsive

Figure 1

A schematic showing a broad classification of stimuli responsive smart biomaterials with triggering mechanisms. The schematic also presents the
organization of internal and external types of stimuli that can activate bone grafts [4].

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 Stimuli-responsive smart grafts Alam Ansari et al. 3

biomaterials (SSRBs) can exhibit stimuli-responsive under certain conditions, such as switching ability at
transitions in their structure and volume, enabling room temperature and insufficient shape recovery.
various multidimensional applications. SSRBs can often Therefore, SMPs are typically filled with carbon nano-
respond to minor environmental changes, such as tem- fibers, carbon nanotubes, silicon carbide, ferroferric
perature, pH, ionic strength, chemicals, electrical and oxide, and nickel powder nanoparticles to impart the
magnetic fields, and biological molecules [16e18], and shape-changing effects in response to mechanical, elec-
subsequently change their state (i.e., shape or geometry) trical, and magnetic stimuli [21,22]. For example, gold
from one to another [19]. Due to their shape-changing nanoparticles (AuNPs, 0.5wt %) were incorporated into
characteristics, the SSRBs are commonly termed shape poly (ethylene oxide) (PEO) SMPs to enhance the
memory polymers (SMP). This “time” dependent dy- photothermal effect and also to enable precise defor-
namic behavior of SSRBs, combined with the existing 3D mation control of the SMPs [23]. The AuNPs acted as a
printing technologies, breaks the boundaries of the cur- heat source by absorbing light energy (532 nm, 0.15 W)
rent static 3D printed bone grafts and provides new av- and converting it into heat, thus triggering the shape-
enues in bone defect repairs and regeneration. The smart changing behavior of the polymer. For instance, Zhang
SMPs offer shape-shifting abilities over the conventional et al. [24] developed an enzyme-responsive, Dex phos-
passive grafts, making them self-deployable, self- phate (DexP), loaded hydrogel system containing
expanding, or self-fitting into the tissue defects [20]. pamidronate-grafted hyaluronic acid crosslinked with
Typically, these smart grafts are either thermoresponsive magnesium (Mg) nanoparticles for the localized elution
or hydro responsive, i.e., heat or hydration triggers shape and on-demand release of bioactive ions and small
change, respectively [20]. This novel feature provides molecule drugs. The composite hydrogel system acted as
convenient implantation routes and superior grafte an affirmative feedback circuit governing the activation
tissue interaction to promote tissue healing. Even and release of Dex to enhance bone regeneration. The
though the temperature is a common trigger for SMPs, it activation and release of Dex from the hydrogel through a
has limitations for providing shape-memory switching positive feedback system is illustrated in Figure 2.

Figure 2

Schematic representation of smart hydrogel system constituting affirmative feedback circuit to govern the activation and release of Dex for enhanced
bone regeneration [24].

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4 Intelligent Biomaterials 2023

Till now, there are few commercially available SMPs in networks should be introduced into the polymer chain
the market, namely DYNACORDTM (a self-tightening [32]. Polyurethanes (PUs) are another class of polymer
suture) [25], EclipsetÔ (a soft tissue anchor) [26], and materials that possess long, entangled linear polymer
Morphixs (an orthopedic suture anchor) [27]. These chains and exhibit excellent shape memory effects21.
soft tissue anchors respond positively to the cyclic Various fabrication techniques may be employed to
loading because of their dynamic geometry and stored enhance the effectiveness of SMP grafts. Figure 3
shape memory strain. They are inserted as a low-profile provides an overview of the different methods for
compressed geometry inside the bone. Upon implanta- developing SMP-based biomaterials and the fabrication
tion, the cyclic loads stimulate the anchor to attain its techniques for developing smart, stimuli-responsive
permanent, fully open “zero-strain” state, enabling the grafts.
wings to expand. Various SMP-based smart biomaterials
have been studied to regenerate bone, cartilage, and Physically crosslinked SMPs
cardiovascular tissue for their unique functionality and Physically crosslinked SMPs can be obtained from
breadth of tunable properties. The grafts obtained from copolymerization, nanocomposite formation, and
these biomaterials have enormous potential in TE. blending. Urethanes, lactides, and lactones are most
However, efforts are still needed to create SMP-based commonly used to synthesize physically crosslinked
smart grafts for clinical translation in regenerative en- smart polymers [33]. For example, Poly (D, L-lactide-co-
gineering. This review outlines the recent advances in trimethylene carbonate) (PDLLAeco-TMC or PLMC)
stimuli-responsive smart SMPs as biomaterials for smart and poly(lactide-glycolide)eTMC (PLGAeTMC) co-
bone graft preparation. This knowledge can aid in the polymers were blended through electrospinning to yield
development of versatile biomaterials, innovative grafts, the smart stimuli-responsive grafts for bone and vascular
and novel engineering strategies for bone defect repair TE, respectively [34,35]. TMC was incorporated into
and regeneration. PDLLA through physical crosslinking by chain entan-
glement to modulate the Tg of the grafts to body tem-
Incorporation of smart features into perature (Tbody). The PLMC fibers demonstrated
biomaterials outstanding shape memory characteristics, with shape
The ability of smart grafts obtained from SMPs to recovery ratios of Rr > 94% and shape fixity ratios of Rf
overcome internal stress and recover to their original > 98%, and macroscopically demonstrated a fast shape
intended shape depends on how efficiently they absorb recovery (w10 s at 39
C) in the pre-deformed config-
energy from the surrounding environment. Engineering urations [34].
the material’s responsiveness to internal or external
stimuli could produce grafts with instructive, induc- Blending PLA with PCL is a common strategy to
tive, triggering, or stimulating effects on cells and tis- improve the toughness of PLA, and the blend exhibits a
sues. The tailorable properties and functions of shape memory effect depending on the PLA/PCL
prepared grafts can further encourage tissue repair and weight percent. The shape memory of processed blends
regeneration. Smart stimuli-responsive grafts can be was investigated, and only the blend with 30% PCL
designed using either conventional thermoplastic exhibited shape memory behavior [36]. The phase
polymers such as lactides, trimethyl carbonates separation enables the physically immiscible blends,
(TMCs), glycolides, or polyurethanes. In either case, such as the PLA/PCL structures, to exhibit shape
they usually have two functional design elements: “net memory behavior by allowing PLA to act as the
points,” responsible for shape memory or shape recov- “switching” segment and PCL to act as the “net points”.
ery, and the “switching segments,” responsible for its Pandey et al. [37] investigated the shape memory
temporary programmed shape. Flexible polyethers such response of PLA reinforced with chitosan. The com-
as poly(ethylene glycol) (PEG) or polyesters such as posite filament of PLA with varying chitosan loading up
poly (ℇ-lactone) are mainly employed for soft segments to 2 wt.% was prepared via a twin screw extrusion pro-
[28e31]. For thermoresponsive SMPs, the thermal cess. The entangled chitosan particles in the PLA blend
transition temperature (Ttrans) is associated with the acted as a rigid phase, interrupting the re-ordering of the
SMP switching segment, which could be either a glass PLA chains. This physical crosslinking enabled a shape
transition temperature (Tg) or a melting temperature recovery of 18.8%. The 3D-printed graft further
(Tm). These functional design elements can be pre- demonstrated good wettability and cell proliferation.
pared via various processing routes to achieve variable Furthermore, bioactive fillers such as nano-
network design through chemical and physical cross- hydroxyapatite (nHAP) [38] and alendronate [39] have
linking methods. For example, to include the “switch- been reported in the development of smart stimuli-
ing segment” into polymers, amorphous, crystalline, responsive grafts. For example, Paponi et al. [38].
and liquid crystalline domains should be introduced, investigated the shape memory behavior of the PLA/
whereas for “net points,” chemical crosslinks, crystal- PCL blend with varying the amount of nHAP ranging
line phase, chain entanglements, and interpenetrating from 0.5 to 3 wt%. The results revealed that adding

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 Stimuli-responsive smart grafts Alam Ansari et al. 5

Figure 3

Methods involved in preparing smart stimuli-responsive biomaterials: physical crosslinking, chemical crosslinking, and PU systems (top row), smart
stimuli source (middle row), and the standard fabrication methods employed to develop smart innovative grafts (bottom row).

nHAP could increase the phase separation between PLA Chemically crosslinked SMPs
and PCL, enabling thermally activated shape memory Smart grafts for TE can be obtained through various
response at 55
C. chemically crosslinked SMPs. Chemical crosslinks serve
as “net points” in these systems, while polymer segments
Zhou et al. [39] fabricated shape memory grafts between the crosslinks serve as “switching” segments.
containing HAP and alendronate as a bioactive filler, The shape memory effect in chemically crosslinked
followed by collagen-dexamethasone (Col-Dex) coating. polymers can be activated thermally and via hydration.
The shape memory graft was programmed into a small However, the chemically crosslinked grafts tend to be
temporary size. Upon exposure to a magnetic field, it more robust regarding shape recovery [20]. Acrylate
recovered into a working shape and size capable of filling (Ac)- or methacrylate (MA)-based networks obtained
the bone defect. Apart from the sufficient shape from macromers with these terminal cross-linkable
memory effect, these smart stimuli-responsive grafts groups have been extensively studied for bone and car-
exhibited effective biological activities such as osteo- diovascular tissue engineering applications [20,38,41e
genic effects, demonstrating their potential application 43]. Semicrystalline PCL is commonly used to tune
in BTE. One of the most well-known biodegradable the Ttrans, i.e., the Tm of SMPs. The lower molecular
polyesters, poly(L-lactide) (PLLA), has been exten- weight (Mn) of PCL aids in lowering the Tm(w43e
sively studied for BTE. Grafts made of PLLA can be 60
C). For example, Xie et al. [44] developed a strong
functionalized with shape memory if correctly electroactive SMP network by chemically crosslinking
programmed. Wang et al. [40] modified PLLA with six-armed PLAs with varying chain lengths and an elec-
biodegradable poly(3-hydroxybutyrate-co-3- troactive aniline trimer (AT) segment. The resulting
hydroxyvalerate) (PHBV) to prepare ultrafine compos- SMP exhibited shape memory performance with a short
ite fibers (i.e., PLLA-PHBV) using electrospinning. The recovery time (several seconds), a high recovery ratio
PLLA-PHBV (70:30) exhibited a shape memory effect (over 94%), and a high fixity ratio (almost 100%) under
with a high shape fixing ratio (98%) and shape recovery body temperature, along with robust mechanical prop-
ratio (>96%) while showing enhanced osteogenesis in erties (2.4 GPa). Moreover, these SMP showed a higher
vitro when seeded with mouse bone marrow-derived C2C12 proliferation rate than liner PLA, showing its
stromal cells [40]. promising potential for BTE [44].

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6 Intelligent Biomaterials 2023

Zhang et al. [41] developed a polydopamine-coated tunable Ttrans (Tgw30e40
C), depending on the
SMP graft via photo-crosslinking of PCL diacrylate curing time. The shape-changing graft exhibited a
(DA) with the capacity to “self-fit” into an irregular compact shape before in vivo applications and demon-
defect. Upon exposure to warm saline at T > Ttrans strated tunable recovery into a complex shape due to
(Ttrans = Tm of PCL), the graft became soft and was dynamic response post-implantation [47].
fitted into the irregular model defect, as shown in
Figure 4a. Upon cooling, it locked itself within the Polyurethane-based smart grafts
defect. To further enhance its bioactivity and improve Polyurethanes or PUs are a distinct class of SMPs with
its degradation rate, PCL-DA grafts were modified with long entangled linear polymer chains that exhibit shape
polydimethylsiloxane (PDMS) [45]. After one month in memory effects through physical or chemical cross-
SBF (1X), HAP mineralization was observed on all PCL/ linking. The hard and soft segments in PU-based SMPs
PDMS grafts except for the PCL-DA. are connected through urethane linkage obtained from
the chemical reaction of alcohol and isocyanate moieties
Copolyesters with fumaric acid (FA) segments [20]. PU-based SMPs have many advantages over other
containing cross-linkable double bonds in their back- SMPs, such as ease of processing and manufacturing,
bones have also been used to develop hydro-responsive cost efficiency, a wide and adjustable shape-recovery
grafts [46]. These grafts displayed a water-responsive temperature window, large recovery strain (up to
shape memory effect well-suitable for surgery. The 1000%), excellent chemical properties, and biocompat-
grafts have a fixity and recovery ratio >97% and ibility [21,48,49]. These SMPs generally demonstrate
demonstrated a shape recovery process that lasts for low modulus (less than 150 MPa), inhibiting their
several minutes. More recently, a smart graft for bone application for load-bearing TE applications [50].
TE was prepared from poly (propylene fumarate) (PPF) Therefore, poly(DL-lactide) (PDLLA) and PLLA-based
using 4D printing. Fer et al. [47] developed gyroid grafts macro diols may enrich PU-based SMPs with a high
using photochemical crosslinking of liquid resin with a modulus value of up to 1 GPa [50].

Figure 4

Self-fitting behavior of a PCL SMP scaffold into the irregular defect coated with polydopamine (a) [41], Shape-memory effects of SMPU/GO and SMPU/
iGO: Bending test—(1) original angle (q0 = 0
), (2) temporary angle (qm = 180
), (3) fixed angle (qr), and (4) recovered angle (qr) (b) [62], and Shape
fixity ratios and recovery ratios (c) [54].

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 Stimuli-responsive smart grafts Alam Ansari et al. 7

To further enhance the overall strength of PU-based development. Novel smart stimuli-responsive grafts
SMPs (modulus up to 3.0 GPa), low molecular weight that are autonomous and capable of recapitulating the
diols (or diamines) or chain extenders were used to react piezoelectric nature of native tissue are believed to
with diisocyanates to extend the length of the hard provide promising platforms for electrical and mechan-
segment. This results in the formation of additional ical stimuli to promote tissue regeneration.
hydrogen bonds, which could enhance the chain rigidity
suitable for bone tissue regeneration [51e53]. Yang Li Electromechanical responsive smart grafts
et al. [52] designed a long-chain diisocyanate coupling Applying electrical stimulation in biology has recently
agent to increase the hard segment content of shape been explored for therapies [56,59,60]. Natural bones,
memory polyurethanes (SMPUs). The resulting SMPUs tendons, ligaments, cartilage, and other tissues are
exhibited excellent mechanical properties at room piezoelectric, enabling them to utilize the electrical
temperature, having a satisfactory shape fixity ratio of up signals generated by the native tissues for various
to 99.8% and a recovery ratio of up to 90.2% while having functions such as glandular secretion, neuromuscular
negligible cytotoxicity to cultured osteoblasts. Zhang activities, cell membrane function, tissue repair and
et al. [54] fabricated isocyanate-modified graphene growth [56,58,61]. To enhance tissue regeneration, ef-
oxide (GO) based SMPU composites for achieving me- forts are made to develop smart electrically active bio-
chanical and shape memory effects. The composite materials recapitulating the tissue repair mechanism
exhibited a shape recovery ratio of 98% and a satisfactory through electrical stimulation.
modulus of w339 MPa, providing new insight into the
practical application of SMPs for bone TE. Figure 4 (b- Piezoelectric materials enhance tissue formation
c) shows the bending test performed to evaluate the through an electrically active microenvironment
shape memory behavior of the SMPU composite and its without needing an external power source. These ma-
corresponding shape fixity and recovery ratios. terials act as mechanoelectrical transducers, generating
an electric field in response to a small mechanical vi-
Using additives such as nanomaterials is another strategy bration [63]. The piezoelectric materials lack a center
to improve the properties of PU-based SMPs. 3D printing of symmetry due to the development of opposite
and electrospinning are the most employed methods to charge polarity upon minute deformation [63]. The
produce physically crosslinked PU-based smart grafts grafts incorporating such materials can directly influ-
incorporating HAP nanoparticles (nHAP), iron-based ence the osteoblasts or chondroblasts while improving
nanoparticles, and carbon nanotubes (CNTs). To repair cell adhesion and proliferation, producing an extracel-
bone defects, Yu et al. 61 developed a controlled 3D porous lular matrix (ECM) for repairing damaged tissue sites.
SMPU/nHAP composite smart graft. Adding nHAP par- The mechanotransduction pathway involves mechano-
ticles to the porous composite graft could enhance the receptors such as stretch-activated Ca2þ channels,
compression resistance by 37%, shorten the compression cadherins, a5b1 integrin (mechanoreceptor in chon-
recovery time by 41%, reduce the tensile resistance by drocytes and bone cells) and an autocrine or paracrine
78%, and reach a shape recovery ratio of 99%. Furthermore, interleukin-4 (IL-4) loop [64]. The mechanical stress
cell proliferation was increased by 13% compared to an activates the a5b1 integrin, which translocates the
SMPU graft without nHAP. Shao et al. [55] introduced protein kinase C (PKC) to the cell membrane. As a
CNTs into PLLA and PU blend through a melt result, the integrin-dependent PKC signaling cascades,
compounding process to yield smart grafts. The shape including Ras/Rac dependent MAP Kinase (MAPK)
memory behavior of these grafts was investigated for pathways, are activated [62,63]. The MAPK activity
electrically activated and thermally activated conditions, then plays a crucial role in determining various cellular
and the performances were compared. Incorporating functions, which get communicated to the intracellular
CNTs (5wt.%) could enhance the electrical conductivity environment via mechanoreceptors [62,65]. For
resulting in an accelerated and improved shape recovery example, piezoelectric PHB and PANi-loaded PHB
process at a relatively low recovery temperature. This also grafts promoted human mesenchymal stem cell
inhibited the thermally induced shape recovery process (hMSC) engraftment compared with non-piezoelectric
due to the formation of a percolated network structure. PCL grafts [66]. Figure 5 depicts the mechano-
transduction pathways and other pathway activations in
Smart grafts with enhanced angiogenic response to electrical and mechanical stimulations.
properties and continuous non-invasive Upon exposure to mechanical stimuli, the piezoelectric
monitoring smart grafts generate electric signals, activating the
The piezoelectric properties of osteochondral tissues, voltage-gated Ca2þ channel. An increased intracellular
such as bone and cartilage, have been extensively re- Ca2þ concentration further activates calmodulin (cal-
ported in various studies [56e58]. However, the studies cium-modulated protein), activating the next calci-
involving the native tissue properties for the design of neurin (calcium and calmodulin-dependent serine/
smart porous grafts are in the early stages of their threonine protein phosphatase). The activated

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8 Intelligent Biomaterials 2023

Figure 5

The mechanotransduction pathways involve Ca2+ signal-activated pathways and other miscellaneous pathway activation in response to electrical and
mechanical stimulation [62,63].

calcineurin dephosphorylates the NF-AT, causing it to enhance the biomimetic properties of the piezoelectric
move to the nucleus and act as a transcription factor materials. These grafts exhibited excellent blood
with other associated proteins [62,63]. compatibility. In vitro cell culture using hMSCs and
HUVECs revealed that adding 2 wt.% ZnO promoted
Piezoelectric materials can be broadly classified into angiogenesis. To obtain a realistic expression of the
piezoelectric polymers and piezoelectric ceramics. piezoelectric effects on bone tissue repair, Tang et al.
Polyvinylidene fluoride (PVDF), PHBV, polyamides, [68] developed a dynamic loading device for periodic
PLLA, collagen, cellulose, barium titanate (BaTiO3), loading to piezoelectric materials (HAP/BaTiO3 com-
zinc oxide (ZnO), boron nitride (BN) are some of the posite) cultured with the osteoblast cells. The results
piezoelectric polymers and ceramics used for cartilage revealed that the piezoelectric effect of BaTiO3 pro-
and bone TE. Damaraju et al. [3] evaluated 3D piezo- moted enhanced osteoblast adhesion and proliferation
electric fibrous grafts made of PVDFetrifluoro ethylene more than the pristine HAP grafts. The interaction of
(PVDF-TrFE) to promote stem cell differentiation and intracellular calcium channels could be one of the
in-vitro bone tissue regeneration. The piezoelectric mechanisms of osteogenic differentiation of MSCs
grafts were tested for static mechanical loading and induced by piezoelectric grafts [69,70]. Therefore,
dynamic compression at 1 Hz frequency with 10% piezoelectric materials can significantly enhance cell
deformation. The results revealed that the differentia- function without using additional growth factors or drug
tion of MSCs was dependent on the piezoelectric ac- molecules, making them a promising alternative to
tivity of the grafts, where the lower level of piezoelectric existing biomaterials.
activity promoted chondrogenesis while higher levels of
piezoelectric activity promoted osteogenesis. Augustine Electrochemical-responsive smart grafts
et al. [67] incorporated ZnO nanoparticles into the More often, the premature regeneration of bone may
PVDF-TrFE matrix to enhance the blood vessel forma- cause the formation of cysts on the grafts, necessitating a
tion in grafts for improved cellematerials interaction to second surgery. Furthermore, delayed bone regeneration

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 Stimuli-responsive smart grafts Alam Ansari et al. 9

Figure 6

Schematic showing biomaterials evolution from inert to smart that not only sense and adapt to the surroundings but also respond to the presented cues.

may cause a graft to collapse at an earlier stage [71]. Due crosslinked carboxy methyl chitosan (CMC) hydrogels.
to the variation in proliferation capacity and osteogenic The in vivo results revealed almost no change in elec-
potential of the seeded cells from different donors, the trochemical signal for pure CMS grafts, while CNT/CMS
continuous monitoring of osteogenesis and mineraliza- grafts exhibited a gradual decrease in the peak value of
tion during bone regeneration becomes an essential current, presumably due to bone mineralization.
aspect of TE. The use of electrochemically responsive
materials can be used to target this issue. Electrochem-
ically responsive biomaterials have received tremendous Conclusion and outlook
attention due to their non-invasive detection capabil- Over the past few decades, various biomaterials have
ities, which enable continuous monitoring of celletissue been developed to improve human health. Amongst,
interface interactions [71,72]. In this regard, CNTs have smart biomaterials with chemical, physical, or biological
been investigated and used due to their large surface stimuli have advanced tissue regeneration efforts.
area, hollow geometry, and conductive electrical proper- Bioactive materials that are also bioinert and biocom-
ties. Pure CNTs might have issues and challenges patible, which can replace the injured tissue, are of
regarding their biocompatibility. To address the issue, utmost priority. Smart stimuli-responsive shape memory
carboxylated CNTs are investigated as a particular class biomaterials have witnessed tremendous advances in
of biocompatible nanomaterials containing plenty of research and developments due to their remarkable
oxygen-containing groups. Huang et al. [71] prepared tunable properties in response to external stimuli.
bioactive and electrochemical responsive grafts by inte- However, given the complex microenvironment for bone
grating CNT (8 wt.%) and BMP2 into the chemically defects, the currently available stimuli-responsive

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10 Intelligent Biomaterials 2023

deformation (i.e., the shape-changing ability of grafts) is Author contributions

limited to basic deformations such as folding, assem- All the authors listed have made a substantial, direct,
bling, and spiral twisting. This necessitates the demand and intellectual contribution to the work and approved
for multiple stimuli-responsive hierarchical trans- for its publication.
formations of biomaterials for the complex functionali-
zation of smart grafts. Such biomaterials are sensitive in
Declaration of competing interest
sensing a specific internal or external signal and can
efficiently initiate or execute functional tasks enabling a
The authors declare that they have no known competing
precise response for the targeted TE application. The
financial interests or personal relationships that could
smartness of biomaterials can be further improved by
have appeared to influence the work reported in this
attaining ‘autonomous’ or ‘self-sufficient’ features. Such
paper.
futuristic smart graft systems should be able to detect a
disease at its early stage, communicate, and conse-
quently treat it before any severe damage occurs [73,74]. Data availability
However, biomaterials that possess such intelligence and No data was used for the research described in the
sophistication still need to be developed. The evolution article.
of smart biomaterials over the years has been illustrated
in Figure 6. The degree of “smartness” these grafts References
Papers of particular interest, published within the period of review,
possess depends on several key factors. These include have been highlighted as:
the inherent material properties, types of stimuli, and,
* of special interest
more importantly, the fabrication method. Combining * * of outstanding interest
traditional biomaterials with programmable hydrogels,
nanoparticles, or biomolecules to produce porous tailor- 1. Bai X, et al.: Bioactive hydrogels for bone regeneration. Bioact
made grafts is challenging with conventional Mater 2018, 3:401–417.
manufacturing techniques. The emerging 4D printing 2. Marrella A, et al.: Engineering vascularized and innervated
* bone biomaterials for improved skeletal tissue regeneration.
technology may enable the tailored fabrication of bio- Mater Today 2018, 21:362–376.
materials to yield smart stimuli-responsive grafts. The challenges of integrating and regulating multiple tissue types
Nevertheless, the “smart biomaterials” gave rise to the within artificial materials, results in insuffuicient blood vessels and
nerves formation. This article discusses the structural and osteogenic
addition of the fourth dimension in the existing 3D functions of vascular and nervous system in bone, as well as the
printing technology through its shape memory effect detailed design criteria for engineeirng a vascularised graft for bone
modelling
capabilities leading to structural and functional reconfi-
guration over time. Even though 4D printing has enabled 3. Damaraju SM, et al.: Three-dimensional piezoelectric fibrous
** scaffolds selectively promote mesenchymal stem cell differ-
the fabrication of dynamic and hierarchical stimuli- entiation. Biomaterials 2017, 149:51–62.
responsive orthopedic structures, they are still far from Damaraju et al. demonatrated the fabrication of flexible three dime-
sional piezoelectric scaffolds capable of stimulating human mesen-
ideal programmable materials. Inherent slow fabrication chymal stem cell differentiation as well as its corresponding
speed and unavailability of smart biomaterials are two extracellular matrix formation under physiological condition
significant challenges, and therefore seek urgent inter- 4. Koons GL, Diba M, Mikos AG: Materials design for bone-tissue
vention before they can be successfully commercialized engineering. Nat Rev Mater 2020, 5:584–603.
for clinical transformation. With the continuous evolu- 5. El-Husseiny HM, et al.: Smart/stimuli-responsive hydrogels:
tion of smart biomaterials, smart stimuli-responsive state-of-the-art platforms for bone tissue engineering. Appl
Mater Today 2022:101560. https://doi.org/10.1016/
grafts with multi-responsive characteristics will enable j.apmt.2022.101560.
efficient monitoring and decentralized treatment. 6. Kim HB, Patel DK, Seo YR, Lim KT: 3D-Printed scaffolds with
Recent efforts also focus on developing biomaterials that reinforced poly (lactic acid)/carbon nanotube filaments based
work with the host immune system (immunomodulatory on melt extrusion. J. Biosyst. Eng. 2019, 44:120–127.
biomaterials) for better adaptation and host-tissue 7. Feilden E, et al.: 3D printing bioinspired ceramic composites.
Sci Rep 2017, 7:1–9.
integration. We anticipate that the design of smart
stimuli-responsive grafts with immunomodulatory char- 8. Koons GL, Diba M, Mikos AG: Materials design for bone-tissue
engineering. Nat Rev Mater 2020, 5:584–603.
acteristics will change the way of bone defect repair and
regeneration through advanced tissue engineering and 9. Ansari MAA, et al.: Engineering biomaterials to 3D-print scaf-
folds for bone regeneration: practical and theoretical
regenerative medicine. consideration. Biomater Sci 2022, 10:2789–2816.
10. Ansari MAA, Jain PK, Nanda HS: Preparation of 3D printed
Funding calcium sulfate filled PLA scaffolds with improved mechani-
cal and degradation properties. J Biomater Sci Polym Ed 2023:
This work was supported by the Science Engineering 1–22.
Research Board (SERB, SRG/2019/001504), Depart- 11. Morris E, Chavez M, Tan C: Dynamic biomaterials: toward
ment of Science and Technology, and Ministry of Edu- engineering autonomous feedback. Curr Opin Biotechnol 2016,
cation, Government of India. 39:97–104.

Current Opinion in Biomedical Engineering 2023, 28:100493 www.sciencedirect.com

 Stimuli-responsive smart grafts Alam Ansari et al. 11

12. Montoya C, et al.: On the road to smart biomaterials for bone 32. Pisani S, et al.: Shape-memory polymers hallmarks and their
research: definitions, concepts, advances, and outlook. Bone biomedical applications in the form of nanofibers. Int J Mol Sci
Res 2021, 9. 2022, 23.
13. Tang L: Coupling CRISPR to smart hydrogels. Nat Methods 33. Ramaraju H, Akman RE, Safranski DL, Hollister SJ: Designing
2019, 16. 955–955. biodegradable shape memory polymers for tissue repair. Adv
Funct Mater 2020, 30:2002014.
14. Lu Y, Aimetti AA, Langer R, Gu Z: Bioresponsive materials. Nat
Rev Mater 2016, 2:1–17. 34. Bao M, et al.: Electrospun biomimetic fibrous scaffold from
* * shape memory polymer of PDLLA- co -TMC for bone tissue
15. Ooi HW, Hafeez S, Van Blitterswijk CA, Moroni L, Baker MB: engineering. ACS Appl Mater Interfaces 2014, 6:2611–2621.
Hydrogels that listen to cells: a review of cell-responsive Bao et al. developed multifunctional shape memory fibrous scaffolds,
strategies in biomaterial design for tissue regeneration. Mater mimicking the native tissue architecture. They demonstarted that by
Horiz 2017, 4:1020–1040. varying the monomer ratio in PLMC, the glass transition temperature
can be tuned, which acts as switching segment. The developed PLMC
16. Yang H, Liu H, Kang H, Tan W: Engineering target-responsive
scffolds exhibited excellent shape memory property and supported
hydrogels based on aptamer-target interactions. J Am Chem
osteoblast adhesion.
Soc 2008, 130:6320–6321.
35. Chen M, et al.: Temperature responsive shape-memory scaf-
17. Lu ZR, Kope ek J: Antigen responsive hydro-
ckovci P, Kopec
folds with circumferentially aligned nanofibers for guiding
gels based on polymerizable antibody fab’ fragment. Macro-
smooth muscle cell behavior. Macromol Biosci 2020, 20:
mol Biosci 2003, 3:296–300.
1900312.
18. Ikeda M, Ochi R, Wada A, Hamachi I: Supramolecular hydrogel
36. Navarro-Baena I, et al.: Design of biodegradable blends based
capsule showing prostate specific antigen-responsive func- * * on PLA and PCL: from morphological, thermal and mechan-
tion for sensing and targeting prostate cancer cells. Chem Sci
ical studies to shape memory behavior. Polym Degrad Stabil
2010, 1:491–498.
2016, 132:97–108.
19. Aguilar MR, San Román J: Introduction to smart polymers and Navarro-Baena et al. investigated the shape memory behaviour of low
their applications. Smart Polym. their Appl. 2014:1–11. https:// cost biodegradable PLA and PCL blend at different concentration. The
doi.org/10.1533/9780857097026.1. result revaled that both the polymers are immiscible and the shape
memory effect of the blend was observed only with 30wt% of PCL
20. Pfau MR, Grunlan MA: Smart scaffolds: shape memory poly-
mers (SMPs) in tissue engineering. J Mater Chem B 2021, 9: 37. Pandey A, Singh G, Singh S, Jha K, Prakash C: 3D printed
4287–4297. biodegradable functional temperature-stimuli shape memory
polymer for customized scaffoldings. J Mech Behav Biomed
21. Fu YQ, Huang WM, Luo JK, Lu H: Polyurethane shape-memory Mater 2020, 108:103781.
polymers for biomedical applications. Shape Mem. Polym.
Biomed. Appl. 2015:167–195. https://doi.org/10.1016/B978-0- 38. Peponi L, et al.: Thermally-activated shape memory effect on
85709-698-2.00009-X. * * biodegradable nanocomposites based on PLA/PCL blend
reinforced with hydroxyapatite. Polym Degrad Stabil 2018, 151:
22. Zhao W, Liu L, Zhang F, Leng J, Liu Y: Shape memory polymers 36–51.
and their composites in biomedical applications. Mater Sci Peponi et al. investigated the effect of nanosized hydroxyapatite
Eng C 2019, 97:864–883. (nHAP) on the shape memory behaviour of PLA/PCL blend. The
finding revealed that the addition of nHAP could increase the phase
23. Zhang H, Xia H, Zhao Y: Light-controlled complex deformation separation between PLA & PCL and the nHA did not have any influ-
and motion of shape-memory polymers using a temperature ence on the thermal activation behaviour of the blend.
gradient. ACS Macro Lett 2014, 3:940–943.
39. Zhou W, Dong X, He Y, Zheng W, Leng: J. In-vitro and in-vivo
24. Zhang K, et al.: Adaptable hydrogels mediate cofactor- studies of 4D printed shape memory scaffolds with bioactive
assisted activation of biomarker-responsive drug delivery via fillers and coating for enhanced bone tissue regeneration.
positive feedback for enhanced tissue regeneration. Adv Sci Smart Mater Struct 2022, 31:105002.
2018, 5:1800875.
40. Wang X, et al.: Shape memory and osteogenesis capabilities
25. Metz RM, Kaar SG: Arthroscopic bankart repair with remplis- of the electrospun poly(3-hydroxybutyrate-co-3-
sage: indications and technique. Operat Tech Orthop 2020, 30: hydroxyvalerate) modified poly(l-lactide) fibrous mats. Tissue
100818. Eng Part A 2021, 27:142–152. https://home.liebertpub.com/tea.
26. Christensen J, Fischer B, Nute M, Rizza R: Fixation strength of 41. Zhang D, et al.: A bioactive ‘self-fitting’ shape memory poly-
polyetheretherketone sheath-and-bullet device for soft tissue mer scaffold with potential to treat cranio-maxillo facial bone
repair in the foot and ankle. J Foot Ankle Surg 2018, 57:60–64. defects. Acta Biomater 2014, 10:4597–4605.
27. Berg-Johansen B, Lovald S, Altiok E, Kurtz SM: Applications of 42. Erndt-Marino JD, et al.: Evaluation of the osteoinductive ca-
polyetheretherketone in arthroscopy. PEEK Biomater. Handb. pacity of polydopamine-coated poly(-caprolactone) diacry-
2019:291–300. https://doi.org/10.1016/B978-0-12-812524- late shape memory foams. ACS Biomater Sci Eng 2015, 1:
3.00017-X. 1220–1230.
28. Gorna K, Gogolewski S: Biodegradable polyurethanes for im- 43. Boire TC, et al.: Effect of pore size and spacing on
plants. II. In vitro degradation and calcification of materials * * neovascularization of a biodegradble shape memory polymer
from poly(ε-caprolactone)–poly(ethylene oxide) diols and perivascular wrap. J Biomed Mater Res, Part A 2021, 109:
various chain extenders. J Biomed Mater Res 2002, 60: 272–288.
592–606. Boire et al. investigatd the influence of pore size and its spacing on the
ska-Lipka J, Kalaszczyn
 ska I, Janik H: Devel- implant neovascularization on newly developed thermosresponsive
29. Marzec M, Kucin
shape memory polymer. This study revealed that wider spaced, smaller
opment of polyurethanes for bone repair. Mater Sci Eng C
sized pore design (223 mm and 640 mm respectively) induced the
2017, 80:736–747.
angiogenesis compared to a non-porous and microporous scaffolds.
30. Wozniak P, et al.: Candidate bone-tissue-engineered product
44. Xie M, Wang L, Ge J, Guo B, Ma PX: Strong electroactive
based on human-bone-derived cells and polyurethane scaf-
biodegradable shape memory polymer networks based on
fold. Acta Biomater 2010, 6:2484–2493.
star-shaped polylactide and aniline trimer for bone tissue
31. Liu KL, et al.: Designing poly[(R)-3-hydroxybutyrate]-based engineering. ACS Appl Mater Interfaces 2015, 7:6772–6781.
polyurethane block copolymers for electrospun nanofiber
45. Beltran FO, Houk CJ, Grunlan MA: Bioactive siloxane-
scaffolds with improved mechanical properties and
containing shape-memory polymer (SMP) scaffolds with
enhanced mineralization capability. J Phys Chem B 2010, 114:
tunable degradation rates. ACS Biomater Sci Eng 2021, 7:
7489–7498.
1631–1639.

www.sciencedirect.com Current Opinion in Biomedical Engineering 2023, 28:100493

12 Intelligent Biomaterials 2023

46. Xie Y, et al.: A biocompatible, biodegradable, and functiona- 60. Zhang K, et al.: Advanced smart biomaterials and constructs for
lizable copolyester and its application in water-responsive hard tissue engineering and regeneration. Bone Res 2018, 6.
shape memory scaffold. ACS Biomater Sci Eng 2019, 5:
1668–1676. 61. Ribeiro C, et al.: Enhanced proliferation of pre-osteoblastic
cells by dynamic piezoelectric stimulation. RSC Adv 2012, 2:
47. Le Fer G, Becker ML: 4D printing of resorbable complex 11504–11509.
shape-memory poly(propylene fumarate) star scaffolds. ACS
Appl Mater Interfaces 2020, 12:22444–22452. 62. Kanno T, Takahashi T, Tsujisawa T, Ariyoshi W, Nishihara T:
* * Mechanical stress-mediated Runx2 activation is dependent
48. Liang C, Rogers CA, Malafeew E: Investigation of shape on Ras/ERK1/2 MAPK signaling in osteoblasts. J Cell Biochem
memory polymers and their hybrid composites. J Intell Mater 2007, 101:1266–1277.
Syst Struct 2016, 8:380–386. https://doi.org/10.1177/ Kanno et al. investigated the series of biochemical events that are
1045389X9700800411. responsible for signalling the osteoblast cells when they undergo
mecahnical stress. The study concluded that the activation of Runx2 is
49. Zdrahala RJ, Zdrahala IJ: Biomedical applications of poly- regulated by the mechanical stress, which favours the osteoblast dif-
urethanes: a review of past promises, present realities, and a ferentiation by activating the MAPK signal transduction pathways.
vibrant future. J Biomater Appl 2016, 14:67–90. https://doi.org/
10.1177/088532829901400104. 63. Jacob J, More N, Kalia K, Kapusetti G: Piezoelectric smart
biomaterials for bone and cartilage tissue engineering.
50. Touchet TJ, Cosgriff-Hernandez EM: Hierarchal Inflamm Regen 2018, 38:1–11.
structure–property relationships of segmented poly-
urethanes. Adv Polyurethane Biomater. 2016:3–22. https:// 64. Lee HS, et al.: Activation of Integrin—RACK1/PKCa signalling
doi.org/10.1016/B978-0-08-100614-6.00001-9. in human articular chondrocyte mechanotransduction. Oste-
oarthritis Cartilage 2002, 10:890–897.
51. Lennon AB, Prendergast PJ: Residual stress due to curing can
initiate damage in porous bone cement: experimental and 65. Litzenberger JB, Kim JB, Tummala P, Jacobs CR: b1 Integrins
theoretical evidence. J Biomech 2002, 35:311–321. mediate mechanosensitive signaling pathways in Osteo-
cytes. Calcif Tissue Int 2010, 86:325–332.
52. Yang W, et al.: Synthesis and characterization of biodegrad-
* able linear shape memory polyurethanes with high mechan- 66. Timin AS, et al.: Multifunctional scaffolds with improved anti-
ical performance by incorporating novel long chain microbial properties and osteogenicity based on piezoelectric
diisocyanates. New J Chem 2020, 44:3493–3503. electrospun fibers decorated with bioactive composite mi-
Yang et al. developed high performance polyurethane based shape crocapsules. ACS Appl Mater Interfaces 2018, 10:34849–34868.
memory polymer for bone repair. Inclusion of novel diisocyanates
significanlty improved the mechanical strength while satisfactory shape 67. Augustine R, et al.: Electrospun poly(vinylidene fluoride-
memroy effect was achieved with shape fixity ratio of 99.8%. trifluoroethylene)/zinc oxide nanocomposite tissue engi-
neering scaffolds with enhanced cell adhesion and blood
53. Hou Z, Zhang H, Qu W, Xu Z, Han Z: Biomedical segmented vessel formation. Nano Res 2017, 10:3358–3376.
polyurethanes based on polyethylene glycol, poly(ε-capro-
lactone-co-D,L-lactide), and diurethane diisocyanates with 68. Tang Y, et al.: Fabrication and in vitro biological properties of
uniform hard segment: synthesis and properties. Int. J. piezoelectric bioceramics for bone regeneration. Sci Rep
Polym. Mater. Polym. Biomater. 2016, 65:947–956. 2017, 7:1–12.

54. Zhou W, et al.: Isocyanate modified GO shape-memory poly- 69. Kitsara M, et al.: Permanently hydrophilic, piezoelectric PVDF
urethane composite. Polymers 2020, 12:118. nanofibrous scaffolds promoting unaided electromechanical
stimulation on osteoblasts. Nanoscale 2019, 11:8906–8917.
55. Shao LN, et al.: Thermal and electroactive shape memory
behaviors of poly(L-lactide)/thermoplastic polyurethane 70. Zhang X, et al.: Electroactive electrospun nanofibers for
blend induced by carbon nanotubes. RSC Adv 2015, 5: tissue engineering. Nano Today 2021, 39:101196.
101455–101465.
71. Huang Y, et al.: A non-invasive smart scaffold for bone repair
56. Singh J, Rani S, Rohini, Parida A: Generation of piezoelectricity * and monitoring. Bioact Mater 2023, 19:499–510.
from the human body. In 2014 Annu. Int. Conf. Emerg. Res. Huang et al. developed a non-invasive and intelligent monitoring smart
Areas Magn. Mach. Drives, AICERA/iCMMD 2014 - Proc; 2014. scaffold by incoroporating CNT into the hydrogel. The resulting scaf-
https://doi.org/10.1109/AICERA.2014.6908277. folds was bioactive and demonostrated electrochemical responsive
behavior.
57. Velasco MA, Narváez-Tovar CA, Garzón-Alvarado DA: Design,
materials, and mechanobiology of biodegradable scaffolds 72. Ali E, et al.: Carbon nanotubes: properties, synthesis, purifica-
for bone tissue engineering. BioMed Res Int 2015, 2015. tion, and medical applications. Nanoscale Res Lett 2014, 9:393.

58. Barbosa F, Ferreira FC, Silva JC: Piezoelectric electrospun 73. Tibbitt MW, Langer R: Living biomaterials. Acc Chem Res 2017,
fibrous scaffolds for bone, articular cartilage and osteo- 50:508–513.
chondral tissue engineering. Int J Mol Sci 2022, 23.
74. Ahmed W, Zhai Z, Gao C: Adaptive antibacterial biomaterial
59. Markx GH: The use of electric fields in tissue engineering. surfaces and their applications. Mater. Today Bio 2019, 2:
Organogenesis 2008, 4:11–17. https://doi.org/10.4161/org.5799. 100017.

Current Opinion in Biomedical Engineering 2023, 28:100493 www.sciencedirect.com