Received: 31 May 2023

DOI: 10.1002/bmm2.12046

REVIEW
- Accepted: 9 August 2023

Advanced strategies of scaffolds design for bone

regeneration

Jian Song1 | Longfei Li1 | Lei Fang1 | Enshuo Zhang1 | Yu Zhang1 |

Zhuxuan Zhang1 | Pranav Vangari2 | Yaqin Huang1 | Feng Tian1 | Yu Zhao3 |
Wei Chen2 | Jiajia Xue1
1
Beijing Laboratory of Biomedical Materials, State Key Laboratory of Organic‐Inorganic Composites, Beijing University of Chemical Technology,
Beijing, China
2
Department of Physics, University of Texas at Arlington, Arlington, Texas, USA
3
Department of Orthopaedics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China

Correspondence
Feng Tian, Yu Zhao and Jiajia Xue. Abstract
Email: [email protected], Bone defects are encountered substantially in clinical practice, and bionic
[email protected] and
scaffolds represent a promising solution for repairing bone defects. However, it
[email protected]
is difficult to fabricate scaffolds with bionic structures and reconstruct the
Funding information microenvironment to fulfill the satisfying repair effects. In this review article,
State Key Laboratory of Organic‐Inorganic
we first discuss various strategies for the design and construction of bionic
Composites, Beijing University of
Chemical Technology, Grant/Award scaffolds to promote bone defect repair, especially including the structural
Number: oic‐202201004; National Natural construction of the scaffold and the integration of bioactive substances
Science Foundation of China, Grant/
Award Number: 52221006; Fundamental
together with the application of external stimuli. We then discuss the roles of
Research Funds for the Central artificial intelligence and medical imaging in aiding clinical treatment. Finally,
Universities, Grant/Award Number: we point out the challenges and future outlooks in developing multifunctional
buctrc202312
bone repair scaffolds, aiming to provide insights for improving bone regen-
[Corrections added on 21 September 2023 eration efficacy and accelerating clinical translation.
after first online publication: Author
names have been corrected in footnote of KEYWORDS
page 1] bionic scaffold, bone regeneration, bone repair, external stimuli, medical imaging, tissue
engineering

1 | INTRODUCTION interface usually possess a combination of structural and

compositional gradients and a high degree of homogene-
Bone is a natural nanocomposite consisting mainly of ity. While there is an increasing focus on bone health,
organic proteins, inorganic minerals and multiple cell bone defects caused by injury, degenerative disease and
types.[1,2] The natural bone tissue and the bone tissue bone tumor resection are correspondingly in urgent need

Jian Song and Longfei Li contributed equally to this work.

-
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
© 2023 The Authors. BMEMat published by John Wiley & Sons Australia, Ltd on behalf of Shandong University.

BMEMat. 2023;1:e12046. onlinelibrary.wiley.com/r/bmemat 1 of 21

https://doi.org/10.1002/bmm2.12046
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- SONG ET AL.

of a better clinical outcome.[3] Most minor injuries can regeneration. Exogenous‐stimulus‐responsive scaffolds
recover without surgery due to the regenerative capabil- have “smart” properties that can exert stimulatory or
ities of blood vessels. However, it is difficult for the injured inductive effects on tissues by responding to external
bone to regenerate when the size of the defect surpasses a stimuli.[12] The therapeutic efficacy can be maximized
certain threshold of 2 cm.[2] For these oversized defects, while minimizing the undesirable side effects because the
clinical intervention is required.[4] Bone transplantation is scaffold can rapidly respond to the microenvironment
the primary method for the treatment of bone defects. and can also exert therapeutic effects while preserving
Currently, bone defect repair materials can be generally physiologically healthy cells and tissues.[12,13] To create
divided into autologous, xenogeneic, and artificial bone this, specific components are designed to construct the
repair materials. The autologous bone graft is the gold scaffolds, and some substances with stimuli‐responsive
standard. However, limitations exist, such as operative effects are applied for modification. More importantly,
complications during attaining bone harvest, restricted numerous examinations are needed to reveal the
attainable amount, further surgery, prolonged operation behavior of implants in vivo and assess the outcomes of
time, severe postoperative pain, and scarring at the har- bone healing. To better visualize the healing process,
vest site leading to longer hospital stays.[5] Allogeneic several strategies have been developed to enhance exist-
bone grafts can fill larger bone defects, but their fibrous ing imaging technologies, which will also be briefly dis-
nonunion, inflammation, and microcrack propagation cussed. Overall, the development of novel and innovative
may raise the risk of failure after implantation.[6] There- biomanufacturing techniques for scaffolds will become
fore, there is a contradiction between the high demand for possible and beneficial for bone repair. Although there
bone grafts and the shortage and limitations of autologous have been numerous works on bone regeneration, the
and xenogeneic bone grafts. While developing bone tissue, lack of systematic reviews still exists. Therefore, we
artificial bone repair scaffolds are expected to solve this address effective strategies for scaffold construction for
problem and relieve pain brought on by bone defects. bone regeneration centered around recent advances,
Although bone repair scaffolds have advantages such including bionic fabrication of scaffolds, loading of
as customizable design and objective yield, drawbacks bioactive substances, exogenous stimulation, and the
still exist. For example, most grafts lack bioactivity and possible impact of imaging as well as artificial intelli-
bone conductivity, which is indispensable for an ideal gence. As shown in Figure 1, this review presents an
artificial bone.[7] In general, most scaffolds mainly focus
on recapitulating the physical structures and/or functions
to favor and support the rebuilding of new bone tissue
and restoring its functionality.[2] Producing ideal scaf-
folds remains a challenge to improve the clinical outcome
of bone repair. With an in‐depth understanding of the
bone repair process and the development of innovative
biomanufacturing techniques, scaffolds possessing highly
bionic structures are achievable. Researchers are also
focusing on the functionalization of scaffolds by adding
bioactive substances such as growth factors and natural
substances derived from cells to promote the effects of
immunity‐regulating and vascularized osteogenesis of
scaffolds. When properly designed, the scaffolds can also
successively deliver multiple types of drugs to stimulate
different stages of bone regeneration.
Understanding the pathological microenvironment is
crucial in treating bone defects. For example, excess
reactive oxygen species, specific mild acidity in osteo-
sarcoma,[8,9] as well as reduced pH and enzymes secreted
by bacteria, can hinder new bone growth.[10,11] These
F I G U R E 1 Schematic showing pivotal factors involved in
inspire researchers to create better scaffolds to address bone regeneration, including the bionic design and structural
the specific environmental changes around the defect construction of scaffolds, the advantages of loading bioactive
site. Some exogenous stimuli, such as light, magnetic substances and applying external stimuli, as well as intelligent
field, electricity, ultrasound, and mechanical stimulation, and enhanced imaging systems for the assistance of diagnosis and
can also manipulate cell fate and affect bone treatment.
 27517446, 2023, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/bmm2.12046 by Iraq Hinari NPL, Wiley Online Library on [04/10/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
SONG ET AL.
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overview of current strategies for the fabrication of arti- polycaprolactone (PCL) to form the subchondral bone
ficial bone scaffolds as well as their translation into layer. BMSCs loaded methacrylate hyaluronic acid
functional bioactive and stimuli‐responsive systems. (HAMA) and ketogenic‐loaded PCL were adopted to
Furthermore, the potential of artificial intelligence and form the middle layer to facilitate cartilage regeneration.
medical imaging aids for bone repair is delineated, aim- To regulate inflammation, diclofenac sodium was incor-
ing to explore solutions to facilitate the development of porated into a functionalized HAMA hydrogel as a su-
ideal bone grafts and accelerate clinical research. perficial layer. MEW is a strategy that combines the
advantages of solution electrospinning and 3D printing,
which guarantees the ability to assemble small‐diameter
2 | ADVANCED STRATEGIES FOR fibers precisely.[19] Figure 2b shows the construction of
SCAFFOLDS CONSTRUCTION the tri‐layered scaffold via MEW,[20] and scanning elec-
tron microscope (SEM) images reveal the difference in
Scaffold material selection and structure optimization fiber size and spacing between different layers. Three
affect the quality of bone healing. At different stages, the growth factors were encapsulated in poly(lactic‐co‐gly-
selection of scaffold materials and the optimization of the colic acid) (PLGA) microspheres and dispersed in gelatin
scaffold structure have a significant impact on the repair methacryloyl (GelMA) hydrogel for protection and
outcome.[14–16] Therefore, the rational selection of mate- controlled release. Tri‐layered composite constructs were
rials to promote tissue regeneration and repair, as well as created through a three‐step crosslinking process. The
the optimization and modification of scaffold properties fluorescence photograph confirmed that the growth fac-
in clinical applications are crucial for the treatment effi- tors remained well‐dispersed and retained within their
cacy. Considering the material design from the perspec- respective layers for 8 days.
tive of bionics, structure optimization can be performed
from macroscopic scale to nanoscale based on the hier-
archy of natural bone tissue to simulate the composition 2.2 | Selective laser sintering technology
and structure of bone.
Given the complex structure of natural bone and SLS technology is another additive manufacturing tech-
surrounding tissues, such as the variations in pore size nique that is effective in accurately fabricating complex
between the cortical bone and cancellous bone, it is structures.[21] Typically, researchers generate channels in
difficult for ordinary scaffolds to achieve high‐efficiency sphere‐based scaffolds to obtain better mechanical prop-
and high‐performance repair effects. To mimic the hier- erties and topographic cues for vascularized bone
archical structure of bone tissue, strategies including 3D regeneration.[22–24] In a bone repair scenario, the in-
printing, melt electro‐writing (MEW), and selective laser terspaces between spheres mimic natural porous struc-
sintering (SLS) have been developed to fabricate multi- tures which can be adjusted by the diameter of the
layered or multifunctional scaffolds. spheres. Figure 2c displays the fabrication process and
micromorphology of the microsphere‐based scaffold. By
comparing a bilayer microsphere scaffold with contin-
2.1 | Melt electrospinning writing uous channels and without channels, the inconsecutive‐
technology channel scaffold possessed gradient‐interconnected
porosity to regulate the infiltration of BMSCs and even-
Hydrogel‐filled 3D‐printed scaffolds are also used to treat tually lead to better repair effects.[25] Differences in
osteochondral defects. 3D printing ensures a homoge- structure and composition can also be achieved within
neous spatial distribution of loading substances such as multilayered hydrogels. As shown in Figure 2d, a
matrix, biomolecules, and cells as well as controllable periosteum‐simulating bilayer hydrogel was designed to
structural and mechanical properties, allowing the induce endothelial cell migration and facilitate nerve‐
microstructure of multilayer scaffolds much closer to the related protein expression.[26] Except for multi‐step pro-
geometric structure of natural biological tissues.[17] cedures, the gradient structure can also be generated in
Meanwhile, the combination with hydrogel can further hydrogels through typical strategies. For example,
improve biocompatibility and provide favorable lubrica- photomask and gradient photomask can regulate the
tion in vivo. As shown in Figure 2a, 3D‐bioprinted bone duration of photo‐crosslinking the hydrogel by adjusting
mesenchymal stem cells (BMSCs)‐laden biomimetic the light exposure to endow hydrogel with specific
multiphasic scaffold with three different functional layer properties.[27] Utilizing SLS technology to produce
domains was fabricated to mimic osteochondral struc- microsphere‐based scaffolds along with the development
ture.[18] β‐tricalcium phosphate (β‐TCP) was dispersed in of bilayer hydrogels that simulate the periosteum and
 27517446, 2023, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/bmm2.12046 by Iraq Hinari NPL, Wiley Online Library on [04/10/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
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F I G U R E 2 Advanced strategies for generating bionic structures. (a) Multilayered hybrid scaffolds for osteochondral defects using 3D
printing.[18] Copyright 2021, Elsevier. (b) Integrated tri‐layered melt electro‐written fiber‐reinforced hydrogel to construct the scaffold.[20]
Copyright 2021, Elsevier. (c) Microsphere‐based scaffold fabricated via SLS technology.[25] Copyright 2022, Elsevier. (d) Multilayered
hydrogel for the bionic repair of periosteum. The upper (GelMA‐BP@Mg) hydrogel served as a periosteal repair layer, while the bottom
layer (GelMA‐PEG/β‐TCP) hydrogel served as a bone repair layer.[26] Copyright 2022, Elsevier. (e) 3D‐printed scaffold with different
porosities for the imitation of natural bones. DFO/MnCO@gelatin methacryloyl‐polylactide (DMGP) scaffold comprised DFO@PCL
nanoparticle, MnCO nanosheets, GelMA hydrogel, and PLA/HA matrix.[34] Copyright 2022, Wiley‐VCH. (f) Convert 2D membrane into a
3D scaffold with gradient porosity by foaming.[48] Copyright 2020, Wiley‐VCH. (g) Swelling a HAp‐PCL hybrid film with PCL solution to
obtain scaffolds with gradient HAp.[53] Copyright 2021, Wiley‐VCH. (h) Generating gradient distribution of bioactive components on the
surface of the fibrous mat to facilitate cell migration by masked electrospray.[54] Copyright 2020, Wiley‐VCH.

exhibit tailored characteristics has exhibited encouraging will benefit the regeneration of defected bone. As shown
outcomes in bone regeneration and restoration. Distin- in Figure 2e, a polylactic acid‐hydroxyapatite (PLA‐HAp)‐
guished from the hydrogel scaffolds mentioned above, based scaffold with discrepant porosity was printed, and
injectable hydrogels can be implanted in a minimally hydrogels with functional drugs were injected to induce
invasive manner while matching the irregular geometry vascular formation and regulate inflammation.[34] Elec-
of bone defects at the same time.[28,29] These advantages trospinning represents another prevalent method of
make them particularly prevalent for repairing osteo- fabricating scaffolds; however, the application of electro-
chondral defects caused by osteoarthritis.[30,31] spun fiber membranes is limited to their 2D structure
which can barely fill the defective zones. In this case, the
3D structure can be transformed to match the flawed
2.3 | Technology of fabricating 3D area[35] by post‐processing technologies like foam-
scaffolds and gradient structures ing,[36,37] ultrasonication,[38,39] short‐fiber assembly,[40–42]
and others.[43–47] Gas foaming technology has received
Consisting of collagen and hydroxyapatite nanocrystals, publicity, and the presence of surfactants can influence
bone can be divided into cortical bone and cancellous pore size. Thus, 3D scaffolds with gradient porosity can be
bone by the difference in porosity.[32,33] In this aspect, generated after the foaming process by inducing different
optimizing the scaffold structure from the microscale to concentrations of surfactants into the electrospinning so-
prepare scaffolds with different or even gradient porosity lution.[48] For example, the pore size of the formed 3D
 27517446, 2023, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/bmm2.12046 by Iraq Hinari NPL, Wiley Online Library on [04/10/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
SONG ET AL.
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fiber scaffolds could be successfully regulated by control- customized. It demonstrated that the scaffolds with radi-
ling the content of Pluronic F‐127 (F‐127), a surfactant ally oriented porous structures show great superiority in
that can expand the hydrophilicity and stability of gas guiding bone regeneration. As a typical example, Figure 3c
bubbles.[49,50] SEM images and statistical results demon- exhibits a functional hydrogel combined with a 3D print-
strated that the pore size was greatly enlarged as the ing scaffold for bone repair.[64] In this work, a 3D‐printed
content of F‐127 was increased to 2% (Figure 2f). PCL scaffold was first fabricated to serve as the hard ma-
The biomimetic construction of components is also trix component. Dexamethasone (DEX), a model drug
important.[51,52] Qiu et al.[53] generated a gradient of HAp promoting osteogenic differentiation,[65] was loaded on
density by immersing a PCL‐HAp membrane in the bot- CuS nanoparticles, which were further dispersed in poly-
tom of a PCL solution as the swelling process developed. ethylene glycol (PEG) hydrogel to fill the gaps of the PCL
Afterward, the solvent evaporated to form the scaffold scaffold. Upon exposure to a near‐infrared (NIR) light at
with a transition region. After drilling channels with a 1064 nm, DEX could be released in a controlled manner,
CO2 laser, a porous scaffold with a provable component promoting the osteogenic differentiation of BMSCs. The
gradient was fabricated (Figure 2g). Figure 2h presents a mild heat because of the photothermal effect could further
technology of masked electrospraying to generate a promote the osteogenic differentiation of BMSCs.[64]
directional density gradient of biomacromolecular nano- To further meet the requirements of defects with
particles on the surface of nanofibers.[54] The aligned different shapes, some matrixes with thermoplastic
nanofibers and gradient in concentration promoted the properties have been employed to prepare scaffolds with
migration of BMSCs along the direction of increasing the shape memory. For example, a biodegrading elastomeric
density of nanoparticles. Moreover, some other technol- compound with a hierarchically porous membrane was
ogies such as‐by‐layer self‐assembly,[55–57] diffusion,[51,58] fabricated to address the problems relating to the insuffi-
and altering bio‐ink during the printing process have also cient time of M2 macrophage influx and the recruitment
been developed.[59,60] of BMSCs resulting from the compact structure and rapid
Currently, research is flourishing around these tech- membrane degradation (Figure 3e). The 4D scaffold was
nologies to generate 3D scaffolds. For example, 3D‐ fabricated because of the shape memory of poly (glycerol
printed products can be used as load‐bearing scaffolds sebacate) and PCL under thermal stimulation. The 4D‐
with proper design. As shown in Figure 3a, a series of morphing of tough elastomer was particularly useful in
scaffolds with triply periodic minimum surfaces were the treatment of vertical bone defects around dental im-
created to improve mechanical strength due to their ad- plants in the alveolar bone because of its flexibility in
vantages in bulk moduli and relative density.[61] Revealed maintaining the curving space of the alveolar bone.[66]
by mechanical finite element analysis and compression Optimizing scaffold structures have shown favorable
tests, the stress concentration levels were sharply reduced results in bone regeneration. Using SLS, electrospinning,
compared to common structures. Among these scaffolds, 3D printing, MEW, and hydrogel‐filled 3D printing can
the Split‐P structure possesses equal compressive lead to the ideal fabrication of multilayered and multi-
strength as natural cortical bone. In addition, the surface functional scaffolds, as these methods hold significant
of Split‐P scaffolds allowed for new bone accumulation potential in addressing the limitations of traditional bone
and inward growth through their pores, enhancing repair methods. Another optimistic approach is the design
osteoconductivity and new bone formation. Figure 3b of functional bioactive scaffolds for bone regeneration.
shows one typical method for developing a 2D electro-
spun fiber membrane toward a 3D scaffold with different
pore orientations.[62] When an aligned nanofiber mem- 3 | FUNCTIONAL BIOACTIVE
brane was soaked in NaBH4 aqueous solution, the axis SCAFFOLDS FOR BONE REGENERATION
endowed by thermal treatment would not swell, and the
direction of the pores could be tailored by changing the Bone healing involves complex physiological processes
positional relationship between the axis and the orien- initiated by the early regulation of inflammation. It is
tation of the fiber. When the axis was perpendicular to challenging to meet the whole repair process with a bare
the fiber orientation, a radially porous scaffold was scaffold, as structures must emulate the native micro-
formed, while when the axis was parallel to the fiber environment of bone cells at the same time augment
orientation, the structure of the pores was axial. their proliferation and other differentiation processes.
A similar structure can be fabricated via a modified Adding active substances, such as drugs,[67–69] short
directional freeze‐casting method.[63] By altering the po- peptides,[70–72] growth factors,[73,74] and some cells or
sition of the freezing surface, the temperature gradient genes[75,76] can better promote bone repair and regenera-
and the growth direction and size of the ice crystal can be tion. The reason is that the nutrients required for each
 27517446, 2023, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/bmm2.12046 by Iraq Hinari NPL, Wiley Online Library on [04/10/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
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F I G U R E 3 Bone repair scaffolds with different microstructures. (a) Model and product of 3D‐printed scaffolds with minimal surface
macrostructures for load‐bearing bone regeneration.[61] Copyright 2022, Wiley‐VCH. (b) 3D fibrous scaffold obtained from gas foaming.[62]
Copyright 2021, the American Association for the Advancement of Science. (c) Gross view and SEM images of a 3D‐printed scaffold filled
with multifunctional hydrogel.[64] Copyright 2022, Wiley‐VCH. (d) Radially porous nanocomposite scaffolds obtained by freeze‐drying
technology.[63] Copyright 2022, Wiley‐VCH. (e) PDA‐coated hybrid membrane with 4D structures.[66] Copyright 2021, Elsevier. PDA,
polydopamine; SEM, scanning electron microscope.

stage differ because the early stages of healing focus on delivery strategies show a more satisfactory effect on
anti‐inflammatory, angiogenesis, and cell recruitment,[77] bone regeneration. For example, deferoxamine (DFO) is
while the later ones focus more on osteogenic differenti- an angiogenesis promoter and DEX is a synthetic gluco-
ation. Thus, it is promising to meet the different needs of corticoid that acts as an osteogenic inducer to support the
the bone healing stages by designing functional bioactive differentiation of BMSCs toward osteoblasts at low con-
scaffolds. centrations in vitro. A fiber membrane was prepared
using coaxial electrospinning technology (Figure 4a) to
release DFO and DEX sequentially for assisting angio-
3.1 | Small molecules for bone genesis and bone formation.[78] Figure 4b,c show that
regeneration DFO in the shell was explosively released within the first
12 h, while the release of DEX lasted over 30 days. In
Small molecular drugs have several unique advantages, addition, micro‐CT images demonstrated that the scaffold
including stability, low cost, and easy loading with scaf- loaded with dual drugs significantly promoted skull
folds.[78,79] By loading icariin (ICA), the main active repair (Figure 4d). However, there are limitations to the
ingredient of epimedium, in 3D‐printed PCL/HAP scaf- controllability of drug release through the spontaneous
folds, bone absorption could be inhibited at the early degradation of scaffolds. External stimuli can be used to
stage, while the in situ regeneration was facilitated.[79] achieve triggered drug release, making the release
More importantly, ICA could be released continuously as behavior more controllable. For example, as a typical
the scaffold degrades to promote osteogenic differentia- photothermal agent, polydopamine (PDA) is widely used
tion. Compared to single‐drug delivery, multiple‐drug as a NIR‐responsive carrier to modulate the release of
 27517446, 2023, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/bmm2.12046 by Iraq Hinari NPL, Wiley Online Library on [04/10/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
SONG ET AL.
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F I G U R E 4 Advanced strategies for the delivery of drugs. (a) Schematic diagram of the fabrication of dual‐drug loaded fibrous mat.
Cumulative releasing profile of DFO and DEX for (b) the first 48 h and (c) 30 days. (d) 3D reconstructed micro‐CT images of defected sites
treated with DFO and DEX alone, or together (yellow circle represented the defect region).[78] Copyright 2022, Wiley‐VCH. (e) Schematic
illustration of incorporating NIR‐responsive microsphere into a thermos‐responsive hydrogel for the sequential release of aspirin and BMP‐
2. The cumulative release profile of (f) aspirin in 14 days and (g) BMP‐2 with or without NIR. (h) Micro‐CT reconstruction images of
calvarias after being treated with different hydrogel composites for 8 weeks.[81] Copyright 2022, Elsevier. BMP‐2, bone morphogenetic
protein 2; CT, computed tomography; DEX, dexamethasone; DFO, deferoxamine; NIR, near‐infrared.

drugs.[80] In one study, PDA‐coated magnesium calcium The method for loading growth factors is similar to that
carbonate microspheres were used as NIR‐responsive of drugs but more delicate. Among them, carriers repre-
carriers to regulate the release of bone morphogenetic sented by microspheres[83–85] and exosomes[86,87] are
protein 2 (BMP‐2), while hydroxybutyl chitosan hydro- often presented. Multiple factors usually possess better
gels delivered aspirin, the anti‐inflammatory drug, to regeneration effects for their discrepant contributions to
alleviate adverse inflammatory responses (Figure 4e).[81] different stages, and accordingly, the sequence of their
The loaded aspirin could be released continuously for release also needs to be considered. The commonly used
14 days (Figure 4f), while the cumulative release of BMP‐ growth factors include the BMP family,[69,73,88–92] basic
2 was higher under NIR irradiation (Figure 4g), indi- fibroblast growth factor (bFGF),[28] platelet‐derived
cating a more pronounced effect on promoting bone growth factor,[93] vascular endothelial growth factor
repair (Figure 4h). (VEGF),[74,94] etc. Among them, BMP‐2 plays an impor-
tant role in bone formation due to its high osteoinductive
capacity, and VEGF can promote angiogenesis and drive
3.2 | Growth factors for bone osteoblast maturation as well as cartilage osteogenesis. As
regeneration shown in Figure 5a, a scaffold consisting of an electro-
spun PCL fiber sheath and an alginate saline gel core that
Growth factors also play an important role in the process carried plasmid DNA encoding bone morphogenetic
of bone regeneration and reconstruction, mainly focusing protein 2 (pBMP2) and vascular endothelial growth factor
on enhancing the biological function of bone grafts.[82] (pVEGF), respectively, was fabricated. Figure 5b shows
 27517446, 2023, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/bmm2.12046 by Iraq Hinari NPL, Wiley Online Library on [04/10/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
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F I G U R E 5 Advanced strategies for the delivery of growth factors. (a) Schematic illustration of the core‐sheath structured fiber‐
hydrogel composite scaffold, which can manipulate the spatiotemporal delivery of pVEGF and pBMP2. (b) The release profile of pBMP‐2
and pVEGF, and semi‐quantitative analysis of the α‐SMA expression.[95] Copyright 2022, Wiley‐VCH. (c) Vascular‐derived ECM and BMP‐
2‐loaded hydrogel promoting vascularized osseointegration. (d) Comparison of fluorescence images regarding the tube formation of
different groups.[96] Copyright 2022, Wiley‐VCH. α‐SMA, α‐smooth muscle actin; BMP‐2, bone morphogenetic protein 2; ECM,
extracellular matrix; pBMP2, bone morphogenetic protein 2; pVEGF, vascular endothelial growth factor.

the release profile and fluorescence intensity of α‐smooth 3.3 | RNA molecules and cells for bone
muscle actin (α‐SMA), demonstrating that pBMP2 and regeneration
pVEGF could effectively promote osteoblastic differenti-
ation through spatiotemporal delivery.[95] Vascular‐ Many approaches have been explored to prepare gene
derived extracellular matrix (vECM), which possesses and interfering RNA‐activated scaffolds for bone tissue
great angiogenesis potential and specific affinity for engineering, including activating scaffolds with plasmid
growth factors, was co‐dispersed in GelMA hydrogel to DNA,[76] small interfering RNA,[97–99] and micro-
form a 3D scaffold (Figure 5c).[96] This composite scaffold RNA.[100–102] As a means to overcome the biological bar-
optimized BMP through ECM affinity and promoted rier, bisphosphonate lipid‐like materials with a high
vascularization both in vitro and in vivo. Figure 5d re- affinity for bone minerals could effectively deliver mRNA
veals different angiogenic behavior of human umbilical therapeutics to the bone microenvironment in vivo
vein endothelial cells (HUVECs), and no tube formation (Figure 6a).[103] In the studies regarding the bone‐homing
was observed in the control group, but the capillary ability of BP‐LNPs, an in vivo imaging system was adopted
structure was observed in all other groups. After 6 h, to track their biodistribution. And the functional delivery
more junction points and branches were displayed and was detected in the liver and bones (Figure 6b). Figure 6c
tube formation with a more organized vascular structure reveals that the delivery of BMP‐2 mRNA by BP‐LNPs
was found in the experimental group. In addition, no brings a relatively higher BMP‐2 expression on both the
significant difference was found between GelMA and trabecular and cortical bone surfaces. As shown in
GelMA‐BMP‐2 groups, indicating that BMP‐2 did not Figure 6d, the bisphosphonate lipid‐like nanoparticles
affect the formation of HUVEC tubes, while vECM could enhanced the effect of mRNA delivery and the secretion of
significantly promote the growth of blood vessels in the therapeutic BMP‐2 in the bone microenvironment after
defective area. intravenous administration, promoting bone regeneration.
 27517446, 2023, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/bmm2.12046 by Iraq Hinari NPL, Wiley Online Library on [04/10/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
SONG ET AL.
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F I G U R E 6 Advanced strategies for the delivery of genes and cells. (a) Schematic of injectable lipid nanoparticles containing
bisphosphonate (BP)‐LNPs for mRNA delivery. (b) In vivo imaging system imaging reveals that higher luminescence intensity can be
detected when delivered by 490BP‐C14 LNPs, when IVIS of FLuc mRNA delivery to mice by 490‐C14 and 490BP‐C14 LNPs.
(c) Immunofluorescence images of BMP‐2 expression in the tibia bones of mice treated with (a1–a2) phosphate buffer saline, (b1–b2) 490‐
C14 LNPs, and (c1–c2) 490BP‐C14 LNPs delivering BMP‐2 mRNA, respectively. BMP‐2 expression was shown in green. (d) The influence
on BMP‐2 protein levels on the bone surface (the left) and in the bone marrow (the right) after 490‐C14 LNPs and 490BP‐C14 LNPs
incorporating mRNA encoding for BMP‐2 were delivered by intravenous injection.[103] Copyright 2022, American Chemical Society.
(e) Multichannel honeycomb‐like bioceramic scaffolds seeded with BMSCs (red) and macrophages (green). (f) The osteogenic gene
expression of MSCs in different multicellular patterns on day 3 in vitro. (g) Comparison of 3D reconstruction micro‐CT images of different
groups (red represents newly generated bone and yellow represents scaffolds).[82] Copyright 2022, Wiley‐VCH. BMP‐2, bone morphogenetic
protein 2; BMSCs, bioprinted bone mesenchymal stem cells; LNPs, lipid nanoparticle.

While siRNA plays an important role in regulating gene designed to manipulate cell distribution and improve bone
expression artificially. In a recent study, the researchers formation.[82] By altering the spatial distribution of cells in
adopted siRNA to silence the negative suppressor gene the scaffold, the “crosstalk” between BMSCs and macro-
GNAS in bone MSCs to enhance osteoblast differentiation phages could be effectively regulated to achieve a
and bone formation. The results showed that transfection controlled regulation of the scaffold‐mediated bone im-
of MSCs led to silencing of GNAS and enhanced differ- mune response. As revealed in Figure 6f, compared to
entiation of MSCs into osteoblasts, which demonstrated other groups, the group containing cells with a Tai Chi
the potential of siRNA.[99] spatial distribution in the scaffold (Tai Chi group) behaved
Cell‐based therapy is also effective in treating bone with varying degrees of elevation in alkaline phosphatase
defects, which is mainly used by introducing exogenous (ALP), osteocalcin (OCN) and BMP‐2, etc., displaying a
cells or recruiting endogenous cells to proliferate and more new bone tissue in micro‐CT images (Figure 6g). As
differentiate at defect sites.[104–108] Among them, it is of the understanding of the mechanisms involved in bone
great importance to design the scaffold so that endogenous healing continues to expand, there is an expanded focus on
cells can migrate toward the defect site.[109] In addition to developing functional bioactive scaffolds that can expedite
the growth factors or other active substances in the scaf- this process and enhance clinical translation. Herein,
fold, which are crucial for cell proliferation, growth, and some representative examples of bioactive substances
adhesion, the morphology and structure of the scaffold loading to promote bone repair are listed in Table 1, with
also have a certain impact. For example, artificial scaffolds the expectation that this trend toward academic explora-
with different character patterns (Figure 6e) were tion promises to yield advances in bone regeneration.
 27517446, 2023, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/bmm2.12046 by Iraq Hinari NPL, Wiley Online Library on [04/10/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
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TABLE 1 Representative types of functional bioactive scaffolds for bone regeneration.

Substrate materials Bioactive substrates Load strategies Advantages Ref

PCL DEX/DFO Coaxial electrospinning Sequential release [78]

PCL/HAp Icariin Embed in microspheres Sustained release [79]
Hydroxybutyl chitosan hydrogel Aspirin/BMP‐2 Embed in microspheres Controlled release [81]
PCL/Alginate Plasmid DNA (pBMP2/pVEGF) Core‐sheath structure Gene therapy [95]
GelMA Vascular‐derived extracellular matrix Blend Vascularized bone regeneration [96]
Lipid nanoparticle siRNA Embed in lipid Regulating differentiation [99]
PEG hydrogel Cholesterol‐modified mRNA Blend Controlled release [102]
GelMA hBMSC/HUVEC Load in microspheres Cell delivery [108]

4 | STIMULUS‐RESPONSIVE years.[115–117] The mild heat may promote blood circula-

SCAFFOLDS FOR BONE REGENERATION tion and facilitate tissue regeneration and is expected to
realize precisely controlled drug release by combining
Stimulus‐responsive scaffolds are materials that react to with other components.[118] Among the many thermo‐
external stimuli, triggering a specific biological or responsive materials, phase‐change materials (PCMs)
chemical response. They provide a framework for cell exhibit a solid‐to‐liquid phase transition at a certain
growth and differentiation in tissue engineering and temperature, and then the payloads encapsulated inside
regenerative medicine applications. Stimulus‐responsive will diffuse out with the melted PCMs.[119] PCMs
scaffolds can be designed to respond to environmental composed of natural fatty acids possess both chemical
cues, allowing for precise control of tissue growth, which stability and biocompatibility, which makes them the
solves the problems of poor targeting and controllability most prevalent in tissue engineering.[120,121] In addition,
of non‐responsive systems. Exogenous stimulation ther- thermo‐sensitive liposomes are also fantastic valves in
apies, such as electromagnetic field therapy, low‐intensity controlled release. For example, teriparatide, a bone for-
ultrasound therapy, heat therapy, etc., are currently used mation promoter, was loaded into thermo‐sensitive lipo-
in clinical practice to stimulate bone regeneration and somes and then entrapped in PDA‐coated mesoporous
reduce patient pain with external stimuli, such as heat, bioglass, indicating the potential for controlled drug de-
electric/magnetic field, and ultrasound. In this case, the livery via PTT to promote bone repair.[122]
delivery of drugs and the fate of cells can be further To enhance the efficacy of repairing bone defects, the
precisely regulated to advance the bone repair sequential release of multiple drugs that cater to various
process.[110,111] requirements in different stages should be implemented.
An example demonstrated by a hydrogel created for
controlled delivery of simvastatin and osteogenic pargy-
4.1 | Thermo‐responsive scaffolds for line in response to NIR.[123] Simvastatin was rapidly
bone regeneration released to regulate the migration and recruitment of
endogenous BMSCs initially, and subsequently NIR
For bone repair, heat stimulation can promote osteo- triggered the release of pargyline, promoting osteogenic
genesis and mineralization by significantly enhancing differentiation. Additionally, implants often lead to
osteogenic activity, including the expression of ALP and infection after treatment of bone defects, resulting in
the mineralization ability of BMSCs.[112] Photothermal repair failure or endangerment of patients' health.
therapy (PTT) has been introduced as a glittery part of the Therefore, responsive scaffolds have garnered more in-
treatment of bone defects.[113] In general, photothermal terest as they provide better targeting and controllability
agents, which play a pivotal role in PTT, are defined as a than non‐responsive systems. The increased temperature
kind of substance with the ability to convert NIR light brought by photothermal conversion can also address the
into heat.[114] Most research focuses on light with a bacteria to some degree. Chloroplast is a natural organ-
wavelength ranging from 700 to 1000 nm, namely, the elle in higher plants which can not only harvest light but
NIR‐I biological window, while NIR‐II (1000–1500 nm) also defend against bacterial infection.[124] Inspired by
received popularity for its deeper penetration, less energy this, black phosphorus (BP) nanosheet was adopted to
dissipation, and minimal normal‐tissue toxicity in recent receive NIR light, and fibrous networks made from
 27517446, 2023, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/bmm2.12046 by Iraq Hinari NPL, Wiley Online Library on [04/10/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
SONG ET AL.
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chitosan and PCL mimic the interlinked stroma MoS2,[127,128] gold nanorods,[129] porphyrin,[130]
lamella.[125] These functional components were encom- MXene, [131]
and carbon nanomaterials [29]
have also been
passed in the PDA membrane to fulfill self‐defensive applied in bone repair.
functionality and photothermal stability. To further
enhance the antibacterial properties of the scaffolds, Ag
nanoparticles were loaded in situ (Figure 7a). The 4.2 | Electro‐responsive scaffolds for
chloroplast‐inspired scaffold showed higher anti‐infective bone regeneration
properties as the concentration of Ag nanoparticles
increased. Meanwhile, the scaffold was highly effective in Electrical stimulation has also received increasing atten-
repairing bone defects, and the immunostaining results of tion in bone engineering. Piezoelectricity is one of the
OCN and BMP‐2 revealed that the existence of NIR could inherent properties of natural bone and is mainly derived
greatly promote bone repair (Figure 7b). Similarly, as a from collagen molecules. These features enlighten re-
kind of material with high tunability, layered double searchers to design efficient scaffolds with physiologically
hydroxides (LDH) also possess the property of photo- relevant electrical activity to induce osteogenesis and
thermal transforming.[126] Coating LDH on Mg‐based promote bone regeneration.[132] Piezoelectric materials
implants could provide insight into addressing the prob- mainly include piezoelectric ceramics, piezoelectric poly-
lem of corrosion and low biocompatibility (Figure 7c), mers, and their composites. However, it is difficult for
and Mn2þ was also induced to improve photothermal, piezoelectric materials to maintain a stable electrical po-
antibacterial, and osteo‐promotive properties. The scaf- tential in the dynamic microenvironment among bone
fold demonstrated its ability to possess satisfying tissue.[133] An electreted sandwich membrane was pre-
biocompatibility and suppress bacteria and tumor cells pared to stabilize the charge. As shown in Figure 8a, poly
while facilitating bone regeneration. Figure 7d shows the (dimethylsiloxane) (PDMS) was adopted as the electrical
quantitative evidence proving the upregulating of land- component packaging material, and SiO2 was the elect-
mark factors of osteogenesis, ALP, and OCN in vitro.[125] reted material.[132] Figure 8b reveals that the electreted
Except for the photothermal agents mentioned above, sandwich membrane retained the smallest scratch area,

F I G U R E 7 Advanced strategies for promoting bone regeneration with the stimulation of near‐infrared light. (a) Schematic illustration
of the chloroplast‐inspired scaffold with excellent self‐defensive functionality and photothermal osteogenesis for the treatment of infected
bone defect. (b) Related database favoring the scaffold possesses the considerable ability of bacterial inhibition and upregulating osteogenic
associated protein.[124] Copyright 2022, Wiley‐VCH. (c) Schematic illustration of the multi‐functional scaffolds for osteosarcoma therapy,
bacteria killing, and bone regeneration. (d) Comparison of relative expression of alkaline phosphatase and osteocalcin between different
groups after 3 and 7 days of cultivation.[125] Copyright 2022, Elsevier.
 27517446, 2023, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/bmm2.12046 by Iraq Hinari NPL, Wiley Online Library on [04/10/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
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F I G U R E 8 Advanced strategies for promoting bone regeneration with endogenous and exogenous electrical stimulation. (a)
Schematic illustration of persistent electrical stimulation provided by electreted sandwich‐like SiO2/poly(dimethylsiloxane) composite
membranes to stimulate bone defect repair. (b) Electric stimulation promotes the migration of bioprinted bone mesenchymal stem cells and
the relative expression of osteocalcin.[132] Copyright 2022, American Chemical Society. (c) A scaffold with controlled gene release and Dox‐
regulated gene expression on external electrical stimulation. (d) Repair effects of different groups at 2, 4,8 and 12 weeks with (ESþ) or
without (ES‐) electrical stimulation, scale bar = 1.0 cm.[142] Copyright 2020, Elsevier.

indicating the incomparable ability of the experimental of drugs can be achieved. As shown in Figure 8c, a tri-
group in promoting the migration of BMSCs. Fluorescent block copolymer was combined with PLGA/HAp to
photographs demonstrated the deepest ALP staining and fabricate a composite scaffold for the controlled release of
the most abundant calcium module deposition and OCN gene and DOX, which may regulate the expression of
expression in the group of electreted sandwich mem- human bone morphogenetic protein‐4 (hBMP‐4) under
branes. More importantly, the electreted composite electrical stimulation. In the circumstance without elec-
membrane with 3 wt.% SiO2 nanoparticles exhibited the trical stimulation, the interaction between the conducting
best retention effect of ζ‐potential, falling in the natural polymer and the positively‐charged vector suppressed the
biopotential range for more than 6 weeks. BaTiO3 is also a release rate. While upon the stimulation of electricity, the
common additive in promoting the piezoelectric of scaf- release behavior was significantly accelerated. Moreover,
folds.[134–137] In another work, Ca/Mn co‐doped BaTiO3 the presence of electrical stimulation also promoted the
nanofibers were composited with polarized PLLA, proliferation rates of osteoblasts and eventually exerted
endowing the scaffold with biodegradability, piezoelec- remarkable promotion in rabbit radial bone defects
tricity, and the ability to promote osteogenesis.[138] (Figure 8d).[142]
In recent years, some researchers have shifted toward
wearable fabrications. For instance, triboelectric stimu-
lation generated by wearable pulsed triboelectric nano- 4.3 | Magnetism‐responsive scaffolds for
generators was demonstrated to rejuvenate aged BMSCs bone regeneration
and enhance their biological functions.[139] Piezoelectric
nanogenerators can promote osteogenic differentiation Compared to NIR light, the magnetic field shows a
by integrating with fixation splint.[140] Except for endog- greater ability to penetrate tissue.[146] In response to an
enous electrical stimulation, scaffolds can respond to alternating magnetic field, magnetic particles can
external electrical stimulation by introducing conducting generate heat for magnetic hyperthermia.[147] As shown
components, representatively of which are polyani- in Figure 9a, CoFe2O4@MnFe2O4 core‐shell magnetic‐
line,[141,142] polypyrrole,[143] polyphosphazene[144] and responsive particles with excellent magnetic hyper-
carbon nanotube.[145] Similarly, by altering the on and off thermal efficiency were adopted as the heat gener-
of the electrical stimulation, precisely controlled release ator.[148] The particles were further decorated with Arg‐
 27517446, 2023, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/bmm2.12046 by Iraq Hinari NPL, Wiley Online Library on [04/10/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
SONG ET AL.
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F I G U R E 9 Advanced strategies for promoting bone regeneration with the stimulation of magnetic field and ultrasound. (a) Schematic
diagram of fabrication of magnetic iron oxide nanoparticle‐RGD/Agarose (MRA) hydrogels under mild hyperthermia. (b) New blood and
defective sites on different types of groups were revealed by 3D reconstruction images.[148] Copyright 2022, Elsevier. (c) Schematic design of
endogenous bioprinted bone mesenchymal stem cells repairing bone defect by the ultrasound, and the coordinated irradiation of pulsed
ultrasound (p‐US) and sinusoidal continuous wave ultrasound (s‐US) drives the release of factors, captures recruited endogenous stem cells
and promotes bone regeneration in situ. (d) Representative fluorescence images of rats treated with daily 20‐min p‐US irradiation for
different days, and these circles marked with white‐dotted lines denote the initial site of the scaffold.[149] Copyright 2023, Elsevier.

Gly‐Asp (RGD) to improve the osteoinductivity and then trigger the release of growth factors that recruit endoge-
eventually delivered by agarose hydrogel to repair nous cells for bone regeneration. Afterward, sinusoidal
critical‐sized cranial defects in rats.[148] RGD peptide continuous wave ultrasound was applied, which could
promoted the attachment of BMSCs, while ferric and greatly enhance the adhesive growth of BMSCs and
cobalt ions released during the degradation of agarose reduce the probability of cell escape. Fluorescence images
hydrogel favored neovascularization and improved the indicated that pulsed ultrasound could accelerate the
blood supply at the defect site. Under the effect of mild degradation of hydrogel, which was evidenced by the
magnetic hyperthermia therapy, the expression of heat stronger signals in the early days and the barely existence
shock protein 90 (HSP90) in pre‐osteoblasts and endo- after 10 days (Figure 9d). Scaffolds can also be applied as
thelial cells was upregulated, which activated the PI3K/ ultrasonic transducers, such as Janus scaffolds, which
Akt pathway in pre‐osteoblasts, significantly promoting can convert acoustic signals to mechanical signals and
osteogenesis and biomineralization. HSP90 also pro- then transmit the nano‐vibration to the surrounding cells
moted the expression of HIF‐1α in endothelial cells by to modulate the cellular behavior.[150] Meanwhile, the
stabilizing p‐Akt, which in turn facilitated neo- heat generated by ultrasound may also hinder tumor cells
vascularization. Thus, the hydrogel displayed a fantastic from flourishing and enhance bone regeneration by
ability for vascularized osteogenesis (Figure 9b). accelerating the maturation of new bone and facilitating
Ultrasound is a form of stimulation that can generate cell mineralization.[151]
mechanical signals within tissues. It can regulate cell Stimuli‐responsive scaffolds can react to external
behavior with the targeted release of drugs or growth stimuli and serve as the framework for cell growth and
factors, thus promoting bone repair. As shown in differentiation in bone tissue engineering. Stimuli‐
Figure 9c, an acoustically responsive scaffold was responsive scaffolds encourage the precise control of tis-
embedded in SDF‐1α and BMP‐2 loaded alginate hydro- sue growth in bone repair by responding to external
gel to recruit endogenous BMSCs for promoting bone stimulation. Some representative examples of stimuli‐
repair.[149] Pulsed ultrasound (p‐US) was exerted at the responsive scaffolds for bone regeneration applications
beginning to accelerate the hydrogel degradation and are listed in Table 2. As mentioned above, with the
 27517446, 2023, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/bmm2.12046 by Iraq Hinari NPL, Wiley Online Library on [04/10/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
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TABLE 2 Representative types of stimulus‐responsive scaffolds for bone regeneration.

Substrate materials Stimulus Responsive substances Ref

Gelatin‐based hydrogel Heat BP [113]

Bioglass Heat PDA [122]
PCL Heat MoS2 [127]
PDMS Electro SiO2 electret [132]
PLA Electro BaTiO3 [134]
Agarose hydrogel Magnetism CoFe2O4; MnFe2O4 [148]
Alginate hydrogel Ultrasound PLA [149]
Abbreviations: PCL, polycaprolactone; PDA, polydopamine; PDMS, poly(dimethylsiloxane); PLA, polylactic acid.

presence of gating materials like PCMs and thermo‐ earth elements[156–158] are often used as contrast agents.
sensitive liposomes, responsive scaffolds provide better For example, dopamine‐Fe (III) chelating nanoparticles
targeting and controllability than non‐responsive systems were applied to monitor the state of implanted hydrogels
in bone repair, reducing the risk of infections following and newborn cartilage in a real‐time and non‐invasive
implantation.[122,152] Electrical stimulation can also manner.[159] Furthermore, CT and MRI are employed
induce osteogenesis and promote bone regeneration jointly in the instance where commercial radiolabel
through efficient piezoelectric materials like ceramics, ([99mTc] Tc‐MDP) was utilized to demonstrate metabolic
polymers, and composites.[153] These are effective activity and visualize fresh bone generation with excep-
methods for maintaining the ability to provide a highly tional precision, while superparamagnetic iron oxide
controlled and targeted approach,[130,154] which can nanoparticles administered at a specific dosage were
revolutionize tissue growth and regeneration and over- implemented for echo SPECT/CT and MRI.[160] Figure 10a
come problems of poor targeting due to an uncontrollable shows SPECT/CT obtained up to 5 weeks after surgery,
non‐responsive system. Stimulations do matter even in demonstrating that the metabolic activity climbed to a
some circumstances without scaffolds; for example, many maximum on day 7 and did not show any remarkable
methods like traditional hot compress and electrical changes until day 20. Besides, barium‐containing com-
stimulation have been utilized after surgery to further pounds were also selected to facilitate X‐ray imaging ability
promote bone regeneration. In short, either responsive because of their strong shielding effects.[161]
release of loads or adjunctive means of rehabilitation, the Integrating noninvasiveness, high sensitivity, and high
repairing effects can be improved in varying degrees spatiotemporal resolution, fluorescence imaging is also a
thanks to the presence of the stimulus. highly sensitive imaging technique, making it feasible to
monitor and understand biological and pathological
functions at the cellular level.[162] To overcome the limi-
5 | IMAGING SYSTEMS FOR BONE tations associated with penetration and resolution faced by
REGENERATION short‐emission‐wavelength fluorescent probes, nano-
particles that possess activating wavelengths within the
Medical imaging technologies, primarily non‐invasive in NIR‐II range have been developed.[163–166] The size of the
nature, are crucial tools for replicating the multifaceted nanoparticles may influence their metabolism in different
and diverse structures of tissues and organs. These tech- positions. For instance, the distribution of semiconducting
niques aid in thoroughly capturing the composition and polymer dots shifted from the liver to the bone as their sizes
comprehending the bone construction and cell behaviors decreased from around 25–15 nm, which may provide
involved during bone tissue restoration procedures. In prospective opportunities for the treatment of bone‐related
general, X‐ray computed tomography (CT), nuclear im- diseases.[167] Pei et al.[162] fabricated a bioactive glass
aging, and magnetic resonance imaging (MRI) represent scaffold doped with NIR‐II ratiometric lanthanide‐dye
the most frequently used techniques for bone regeneration. hybrid nanoprobes for in situ monitoring during bone
CT is used in clinical practice for bone mapping; however, repair. The scaffold showed angiogenic and osteogenic
the involvement of ionizing radiation and poor contrast on activities, accurately reflecting early inflammation and
soft tissue structures limits its application. MRI can over- visualizing angiogenesis.
come the disadvantages of the X‐ray‐based technique to In addition, ultrasound imaging, photoacoustic imag-
some extent. For MRI, iron‐based particles[155] and rare ing, and some other technologies have also been adopted to
 27517446, 2023, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/bmm2.12046 by Iraq Hinari NPL, Wiley Online Library on [04/10/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
SONG ET AL.
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F I G U R E 1 0 Advanced strategies for promoting image quality and resolution. (a) CT and SPECT/CT images with and without the
hybrid scaffold filled on days 1, 7, 14, 20, 27, and 33. The 1st row: CT images on the skull of a Swiss Albino mouse model; and the 2nd row:
fused SPECT/CT images at 3 h post‐injection with the bone imaging tracer [99mTc] Tc‐MDP (ca. 2 mCi).[160] Copyright 2021, Royal Society
of Chemistry. (b) Photothermal and (c) photoacoustic imaging of the hydrogel with sericin and different concentrations of GO
contained.[170] Copyright 2021, Elsevier. CT, computed tomography; GO, graphene oxide.

realize real‐time and non‐invasive imaging. Ultrasound Additionally, superb microvascular imaging, which
imaging shows various advantages, including safety, low allows imaging of microvessels in any location, was used
cost, high tissue penetration depth, excellent spatial reso- as a novel method to evaluate the neovascularization of
lution, and real‐time imaging. Gas vesicles, biosynthetic early bone regeneration.[171] In the foreseeable future,
nanobubbles with excellent ultrasound imaging capacity, quantitative imaging technologies are expected to lead
were incubated with MSCs to track the cells real‐time in the way that providing high spatiotemporal resolution of
vivo.[168] Photoacoustic imaging is another novel imaging the 3D tissue microenvironment during bone recon-
technique that combines the most compelling features of struction,[172] which will help to understand the in-
optical and ultrasound imaging to provide both high opti- teractions of host cells, transplanted stem cells, and
cal contrast and high ultrasound resolution at depth in biomaterials, as well as rational improvements of scaffold
living organisms. This approach was adopted to monitor design and clinical applications.
the hemoglobin counts for the study of vascular function
and tissue oxygenation in bone regeneration.[169] More-
over, by combining various functional agents, multi‐modal 6 | CONCLUSIONS AND PERSPECTIVES
imaging can be achieved. For instance, sericin and gra-
phene oxide (GO) possessed considerable synergistic ef- In recent years, advances in the fields of materials science,
fects in bone regeneration and both favored in vivo biomedicine, and biomanufacturing technologies have
imaging.[170] Fluorescent signals were detected when opened great prospects for the treatment of bone defects.
exposed to 430 nm light because of the photoluminescence Researchers are endeavoring to effectively modulate the
of sericin. Figure 10b proves the photothermal effects of cellular behavior in engineered grafts for bone regenera-
GO under 808 nm NIR light, which was utilized to trace the tion by designing the structure and composition of scaf-
location of the hydrogel. The presence of GO also folds and supplementing various biochemical and
strengthened the photoacoustic signals (Figure 10c). physical cues to mimic the microenvironment of native
 27517446, 2023, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/bmm2.12046 by Iraq Hinari NPL, Wiley Online Library on [04/10/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
16 of 21
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bone tissue. Nevertheless, there remain several concerns With the emergence of stimuli‐responsive bio-
that require further investigation and resolution in the materials and a growing understanding of bone regen-
future. These issues include enhancing the bionic level of eration, another promising approach is to develop
scaffolds to a greater extent and optimizing the influence adaptive materials to endow scaffolds with intelligence
of scaffolds on cells, such as recruitment, migration, that allows them to complete programming of the desired
adhesion, proliferation, and differentiation regulation shape and function in response to external stimuli.[178]
mechanisms. Meanwhile, the precise modulation of gene Various types of stimuli can trigger the release of thera-
expression and growth factor release is also crucial as well peutic drugs/growth factors or induce changes in scaffold
as ensuring the safety of clinical applications. properties to manipulate their interaction with cells for
Indeed, the morphological structure and healing pro- enhancing bone regeneration.[179] However, it is chal-
cess of bone provide insight into the design of bone scaf- lenging to precisely determine the optimal parameters of
folds. Typically, the ideal scaffold should have a porous external stimuli and quickly identify the changes in the
structure that allows the migration of cells and circulation internal environment.[180] Biosensors that can monitor
of nutrients as well as excellent biocompatibility which physiological activity provide one chance. Meanwhile,
avoids triggering immune responses after implantation smart medical technologies have given rise to a range of
and during degradation.[14,173] Suitable degradability is products, such as image‐assisted, deep learning, and AI‐
also necessary which promotes the deposition of ECM by assisted diagnostic systems, as well as surgical robots
host cells and the replacement of the scaffold over time. with high‐resolution visualization and real‐time naviga-
Moreover, it should allow the continuous release of rele- tion technologies. They can offer numerous conveniences
vant osteogenic factors that positively regulate scaffold‐cell in bone transplantation and patient rehabilitation.[181]
interactions and fusion with the host tissue. It is also For example, multiple deep learning‐based AI models
desirable for specific applications that the scaffold can be have been applied to musculoskeletal diseases due to
easily customized into different shapes and sizes. Addi- their ability to assist clinical diagnosis and prognosis
tionally, when treating bone defects caused by tumor prediction.[182] In a recent study, deep learning was
resection, the scaffold must meet both bone repair and adopted to classify and predict the mechanical states of
tumor suppression requirements, while for infected bone cortical and trabecular bone tissue, which eventually
defects anti‐infective properties should be considered. achieved over 98% accuracy on the cortical dataset, and
Therefore, the need for repair involving multiple other 99% on the trabecular dataset.[183] Except from deep
tissues, such as blood vessels, nerves, periosteum, and learning, robotic‐assisted arthroplasty has accounted for
cartilage, should also be considered in the future design of an increasing proportion of total knee arthroplasties and
bone scaffolds to achieve structurally and functionally some studies have demonstrated that robotic‐assisted
completed bone regeneration.[174] surgery can offer more precise bony cuts and greater
It seems impossible that any material possesses all the accuracy in implant positioning.[184] The combination of
properties required for bone healing; thus, it is common precision medicine and smart scaffolds can facilitate
to use multiple materials in combination to achieve complex surgery and effective treatment.
multifunction, but cumulative additions may hinder Despite considerable progress in the development of
clinical translation. Furthermore, scaffolds must be scaffolds for bone defects, several challenges and diffi-
developed according to the different needs of patients, for culties still hinder clinical application and commercial
example, scaffolds for the repair of non‐weight‐bearing translation. One of these is the limited knowledge of the
miniature defects are more minimally invasive, while action mechanisms of implanted scaffolds and the
the mechanical properties of grafts for large and load‐ resulting cellular responses; the properties of the
bearing defects are the key factors.[175] However, it is different materials are ambiguous when used individu-
important to note that the dose of bioactive substances ally or in combination. An added difficulty arises from
should be precisely controlled to achieve safe and effec- the diversity of experimental subjects, as the bone defect
tive new bone formation, regardless of the type of bone models primarily consist of vigorous juvenile animals in
defect being repaired.[176] Although gradually optimized these studies; yet, the ultimate implementation in clinical
scaffolds in combination with growth factors can induce settings will involve older humans who may experience
effective bone regeneration, a significant amount of time certain complications during this transition.[185] There-
is still required to achieve complete regeneration of large fore, the age and health status of the patients should also
defects. In this case, exogenous stem cells can compen- be considered in the process of scaffold design to
sate for the lack of endogenous cells, and condensation accommodate individual patient differences rather than a
and pre‐differentiation of stem cells in vitro are expected simple one‐size‐fits‐all strategy. The final concern relates
to shorten the time of in vivo bone regeneration.[177] to commercial translation and product stewardship, in
 27517446, 2023, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/bmm2.12046 by Iraq Hinari NPL, Wiley Online Library on [04/10/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
SONG ET AL.
- 17 of 21

which scaffolds must be mass‐producible, manufacturing 15. C. Xie, J. Ye, R. Liang, X. Yao, X. Wu, Y. Koh, W. Wei, X.
stable, and cost‐effective, meeting production standard Zhang, H. Ouyang, Adv. Healthcare Mater. 2021, 10, 2100408.
grades and clinical needs. Overall, long‐term, interdisci- 16. C. Gao, Y. Deng, P. Feng, Z. Mao, P. Li, B. Yang, J. Deng, Y.
Cao, C. Shuai, S. Peng, Int. J. Mol. Sci. 2014, 15, 4714.
plinary collaborations among researchers in different
17. X. Wang, M. Zhang, J. Ma, M. Xu, J. Chang, M. Gelinsky, C.
fields need to be encouraged to share expertise and
Wu, Engineering 2020, 6, 1276.
improve the clinical efficiency of the scaffolds so that 18. Y. Liu, L. Peng, L. Li, C. Huang, K. Shi, X. Meng, P. Wang, M.
more bone repair grafts can leap from the laboratory to Wu, L. Li, H. Cao, K. Wu, Q. Zeng, H. Pan, W. W. Lu, L. Qin,
the clinical applications, improving the health and qual- C. Ruan, X. Wang, Biomaterials 2021, 279, 121216.
ity of life of patients. 19. Y. Liu, Q. Guo, X. Zhang, Y. Wang, X. Mo, T. Wu, Adv. Fiber
Mater. 2023, 5, 1241.
ACK N O WL ED GM EN T S 20. Z. Qiao, M. Lian, Y. Han, B. Sun, X. Zhang, W. Jiang, H. Li, Y.
Hao, K. Dai, Biomaterials 2021, 266, 120385.
This work is supported by the State Key Laboratory of
21. Y. Du, H. Liu, Q. Yang, S. Wang, J. Wang, J. Ma, I. Noh, A. G.
Organic‐Inorganic Composites, Beijing University of Mikos, S. Zhang, Biomaterials 2017, 137, 37.
Chemical Technology (oic‐202201004), Fundamental 22. H. Liu, Y. Du, G. Yang, X. Hu, L. Wang, B. Liu, J. Wang, S.
Research Funds for the Central Universities (buctrc2- Zhang, Adv. Healthcare Mater. 2020, 9, 2000727.
02312), and the National Natural Science Foundation of 23. W. Tan, C. Gao, P. Feng, Q. Liu, C. Liu, Z. Wang, Y. Deng, C.
China (Grant No. 52221006). Shuai, Mater. Sci. Eng., C 2021, 120, 111592.
24. J. Zhang, B. Song, Q. Wei, D. Bourell, Y. Shi, J. Mater. Sci.
CON F L IC T O F I N T ER EST ST AT EM E N T Technol. 2019, 35, 270.
25. X. Gu, Y. Zha, Y. Li, J. Chen, S. Liu, Y. Du, S. Zhang, J. Wang,
The authors declare no conflicts of interest.
Acta Biomater. 2022, 141, 190.
26. Y. Xu, C. Xu, L. He, J. Zhou, T. Chen, L. Ouyang, X. Guo, Y.
ORC I D Qu, Z. Luo, D. Duan, Bioact. Mater. 2022, 16, 271.
Jiajia Xue https://orcid.org/0000-0002-7209-7935 27. J. M. Lowen, J. K. Leach, Adv. Funct. Mater. 2020, 30,
1909089.
28. B. He, M. Zhang, L. Yin, Z. Quan, Y. Ou, W. Huang, Mater.
REF ER EN C ES Des. 2022, 215, 110469.
1. X. Zhang, S. Koo, J. H. Kim, X. Huang, N. Kong, L. Zhang, J. 29. C. Wei, X. Jin, C. Wu, W. Zhang, J. Mater. Sci. Technol. 2022,
Zhou, J. Xue, M. B. Harris, W. Tao, J. S. Kim, Matter 2021, 4, 118, 64.
2727. 30. W. Yu, B. Hu, K. O. Boakye‐Yiadom, W. Ho, Q. Chen, X. Xu,
2. G. L. Koons, M. Diba, A. G. Mikos, Nat. Rev. Mater. 2020, 5, X. Q. Zhang, Biomater. Sci. 2021, 9, 7603.
584. 31. X. Yan, B. Yang, Y. Chen, Y. Song, J. Ye, Y. Pan, B. Zhou, Y.
3. X. Zhang, Q. Li, L. Li, J. Ouyang, T. Wang, J. Chen, X. Hu, Y. Wang, F. Mao, Y. Dong, D. Liu, J. Yu, Adv. Mater. 2021, 33,
Ao, D. Qin, L. Zhang, J. Xue, J. Cheng, W. Tao, ACS Nano 2104758.
2023, 17, 6466. 32. H. Zhou, J. G. Lawrence, S. B. Bhaduri, Acta Biomater. 2012,
4. E. Roddy, M. R. DeBaun, A. Daoud‐Gray, Y. P. Yang, M. J. 8, 1999.
Gardner, Eur. J. Orthop. Surg. Traumatol. 2018, 28, 351. 33. U. G. Wegst, H. Bai, E. Saiz, A. P. Tomsia, R. O. Ritchie, Nat.
5. L. Yu, S. Cavelier, B. Hannon, M. Wei, Bioact. Mater. 2023, Mater. 2015, 14, 23.
25, 122. 34. J. Zhang, D. Tong, H. Song, R. Ruan, Y. Sun, Y. Lin, J. Wang,
6. M. Qu, C. Wang, X. Zhou, A. Libanori, X. Jiang, W. Xu, S. L. Hou, J. Dai, J. Ding, H. Yang, Adv. Mater. 2022, 34,
Zhu, Q. Chen, W. Sun, A. Khademhosseini, Adv. Healthcare 2202044.
Mater. 2021, 10, 2001986. 35. L. Li, R. Hao, J. Qin, J. Song, X. Chen, F. Rao, J. Zhai, Y.
7. A. Bharadwaz, A. C. Jayasuriya, Mater. Sci. Eng., C 2020, 110, Zhao, L. Zhang, J. Xue, Adv. Fiber Mater. 2022, 4, 1375.
110698. 36. Y. Chen, W. Xu, M. Shafiq, D. Song, X. Xie, Z. Yuan, M. El‐
8. J. Chen, S. Lin, D. Zhao, L. Guan, Y. Hu, Y. Wang, K. Lin, Y. Newehy, H. El‐Hamshary, Y. Morsi, Y. Liu, X. Mo, Mater. Sci.
Zhu, Adv. Funct. Mater. 2020, 31, 2006853. Eng., C 2022, 134, 112643.
9. S. Dong, Y. Chen, L. Yu, K. Lin, X. Wang, Adv. Funct. Mater. 37. Y. Chen, W. Xu, M. Shafiq, J. Tang, J. Hao, X. Xie, Z. Yuan, X.
2019, 30, 1907071. Xiao, Y. Liu, X. Mo, J. Colloid Interface Sci. 2021, 603, 94.
10. Y. Deng, X. Shi, Y. Chen, W. Yang, Y. Ma, X.‐L. Shi, P. Song, 38. A. Rahmani, S. Hashemi‐Najafabadi, M. B. Eslaminejad, F.
M. S. Dargusch, Z.‐G. Chen, Ind. Eng. Chem. Res. 2020, 59, Bagheri, F. A. Sayahpour, J. Biomed. Mater. Res., Part A 2019,
12123. 107, 2040.
11. M. Pourhajibagher, A. R. Rokn, H. R. Barikani, A. Bahador, 39. S. I. Jeong, N. A. Burns, C. A. Bonino, I. K. Kwon, S. A. Khan,
Photodiagn. Photodyn. Ther. 2020, 31, 101834. E. Alsberg, J. Mater. Chem. B 2014, 2, 8116.
12. H. Wei, J. Cui, K. Lin, J. Xie, X. Wang, Bone Res. 2022, 10, 17. 40. M. Mader, V. Jerome, R. Freitag, S. Agarwal, A. Greiner,
13. Y. Zeng, J. Hoque, S. Varghese, Acta Biomater. 2019, 93, 152. Biomacromolecules 2018, 19, 1663.
14. G. Turnbull, J. Clarke, F. Picard, P. Riches, L. Jia, F. Han, B. 41. Y. Li, Y. Liu, X. Xun, W. Zhang, Y. Xu, D. Gu, ACS Appl.
Li, W. Shu, Bioact. Mater. 2018, 3, 278. Mater. Interfaces 2019, 11, 36359.
 27517446, 2023, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/bmm2.12046 by Iraq Hinari NPL, Wiley Online Library on [04/10/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
18 of 21
- SONG ET AL.

42. Y. Shen, Y. Xu, B. Yi, X. Wang, H. Tang, C. Chen, Y. Zhang, 67. R. M. Barros, C. G. Da Silva, K. M. Nicolau Costa, A. A. Da
Biomacromolecules 2021, 22, 2284. Silva‐Junior, C. R. Scardueli, R. A. C. Marcantonio, L. A.
43. Y. Shen, T. Tu, B. Yi, X. Wang, H. Tang, W. Liu, Y. Zhang, Chiavacci, J. A. Oshiro‐Junior, Pharmaceutics 2022, 14.
Acta Biomater. 2019, 97, 200. 68. S. Wu, J. Ma, J. Liu, C. Liu, S. Ni, T. Dai, Y. Wang, Y. Weng,
44. J. V. John, A. McCarthy, H. Wang, Z. Luo, H. Li, Z. Wang, F. H. Zhao, D. Zhou, X. Zhao, ACS Appl. Mater. Interfaces 2022,
Cheng, Y. S. Zhang, J. Xie, Adv. Healthcare Mater. 2021, 10, 14, 15942.
2100238. 69. I. Qayoom, A. K. Teotia, A. Kumar, Biomacromolecules 2020,
45. Y. Han, B. Jia, M. Lian, B. Sun, Q. Wu, B. Sun, Z. Qiao, K. 21, 328.
Dai, Bioact. Mater. 2021, 6, 2173. 70. Y. Ha, X. Ma, S. Li, T. Li, Z. Li, Y. Qian, M. Shafiq, J. Wang,
46. K. Zhang, X. Jiao, L. Zhou, J. Wang, C. Wang, Y. Qin, Y. Wen, X. Zhou, C. He, Adv. Funct. Mater. 2022, 32, 2200011.
Biomaterials 2021, 276, 121040. 71. M. Zhou, X. Wu, J. Luo, G. Yang, Y. Lu, S. Lin, F. Jiang, W.
47. Y. Han, M. Lian, B. Sun, B. Jia, Q. Wu, Z. Qiao, K. Dai, Zhang, X. Jiang, Chem. Eng. J. 2021, 422, 130147.
Theranostics 2020, 10, 10214. 72. C. Wang, J. Lai, K. Li, S. Zhu, B. Lu, J. Liu, Y. Tang, Y. Wei,
48. S. Chen, A. McCarthy, J. V. John, Y. Su, J. Xie, Adv. Mater. Bioact. Mater. 2021, 6, 137.
2020, 32, 2003754. 73. E. Y. Jeon, S. H. Um, J. Park, Y. Jung, C. H. Cheon, H. Jeon,
49. B. Liu, C. Chen, W. Zhang, J. Crittenden, Y. Chen, Desali- J. J. Chung, Small 2022, 18, 2200416.
nation 2012, 307, 26. 74. X. Chen, C. Y. Gao, X. Y. Chu, C. Y. Zheng, Y. Y. Luan, X. He,
50. M. Asama, A. Hall, Y. Qi, B. Moreau, H. Walthier, M. K. Yang, D. L. Zhang, Front. Bioeng. Biotechnol. 2022, 10,
Schaschwary, B. Bristow, Q. Wang, J. Biomed. Mater. Res., 915181.
Part A 2018, 106, 1448. 75. H. J. Kim, S. Lee, J. M. Park, H. B. Cho, J. I. Park, J. S. Park,
51. C. Zhu, J. Qiu, S. Thomopoulos, Y. Xia, Adv. Healthcare K. H. Park, Biomaterials 2021, 277, 121104.
Mater. 2021, 10, 2002269. 76. R. Ding, Y. Liu, D. Cheng, G. Yang, W. Wu, H. Du, X. Jin, Y.
52. B. Zhang, J. Huang, R. J. Narayan, J. Mater. Chem. B 2020, 8, Chen, Y. Wang, B. C. Heng, Q. Yang, J. Xu, Nano Res. 2022,
8149. 15, 6348.
53. J. Qiu, J. Ahn, D. Qin, S. Thomopoulos, Y. Xia, Adv. 77. L. Xiao, Y. Ma, R. Crawford, J. Mendhi, Y. Zhang, H. Lu, Q.
Healthcare Mater. 2021, 11, 2100828. Zhao, J. Cao, C. Wu, X. Wang, Y. Xiao, Mater. Today 2022, 54,
54. J. Xue, T. Wu, J. Qiu, S. Rutledge, M. L. Tanes, Y. Xia, Adv. 202.
Funct. Mater. 2020, 30, 2002031. 78. J. Cui, X. Yu, B. Yu, X. Yang, Z. Fu, J. Wan, M. Zhu, X. Wang,
55. J. Zheng, N. Rahman, L. Li, J. Zhang, H. Tan, Y. Xue, Y. K. Lin, Adv. Healthcare Mater. 2022, 11, 2200571.
Zhao, J. Zhai, N. Zhao, F. Xu, L. Zhang, R. Shi, Y. Lvov, J. 79. L. Zou, L. Hu, P. Pan, S. Tarafder, M. Du, Y. Geng, G. Xu, L.
Xue, Mater. Sci. Eng., C 2021, 128, 112295. Chen, J. Chen, C. H. Lee, Composites, Part B 2022, 232, 109625.
56. D. Li, F. Dai, H. Li, C. Wang, X. Shi, Y. Cheng, H. Deng, 80. L. Wang, S. Liu, C. Ren, S. Xiang, D. Li, X. Hao, S. Ni, Y.
Carbohydr. Polym. 2021, 254, 117438. Chen, K. Zhang, H. Sun, Int. J. Oral Sci. 2021, 13, 27.
57. L. Li, T. Wang, K. Van, X. Zhang, X. Zhang, J. Song, R. Shi, L. 81. Z. Wan, Q. Dong, X. Guo, X. Bai, X. Zhang, P. Zhang, Y. Liu,
Zhang, J. Xue, Mater. Today Adv. 2022, 16, 100301. L. Lv, Y. Zhou, Carbohydr. Polym. 2022, 297, 120027.
58. R. Yang, G. Li, C. Zhuang, P. Yu, T. Ye, Y. Zhang, P. Shang, J. 82. B. Zhang, F. Han, Y. Wang, Y. Sun, M. Zhang, X. Yu, C. Qin,
Huang, M. Cai, L. Wang, W. Cui, L. Deng, Sci. Adv. 2021, 7, H. Zhang, C. Wu, Adv. Sci. 2022, 9, 2200670.
26. 83. Z. Wu, J. Bai, G. Ge, T. Wang, S. Feng, Q. Ma, X. Liang, W. Li,
59. H. Zhang, H. Huang, G. Hao, Y. Zhang, H. Ding, Z. Fan, L. W. Zhang, Y. Xu, K. Guo, W. Cui, G. Zha, D. Geng, Adv.
Sun, Adv. Funct. Mater. 2020, 31, 2006697. Healthcare Mater. 2022, 11, 2200298.
60. D. van der Heide, G. Cidonio, M. J. Stoddart, M. D'Este, 84. W. Zhuang, G. Ye, J. Wu, L. Wang, G. Fang, Z. Ye, G. Lai, X.
Biofabrication 2022, 14, 4. Qiu, H. Sang, Biomater. Adv. 2022, 133, 112619.
61. Q. Zhang, L. Ma, X. Ji, Y. He, Y. Cui, X. Liu, C. Xuan, Z. 85. D. Li, Z. Yang, X. Zhao, Y. Luo, W. Zhou, J. Xu, Z. Hou, P.
Wang, W. Yang, M. Chai, X. Shi, Adv. Funct. Mater. 2022, 32, Kang, M. Tian, Chem. Eng. J. 2022, 435, 134991.
2204182. 86. Y. Gao, Z. Yuan, X. Yuan, Z. Wan, Y. Yu, Q. Zhan, Y. Zhao, J.
62. S. Chen, H. Wang, V. L. Mainardi, G. Talo, A. McCarthy, J. V. Han, J. Huang, C. Xiong, Q. Cai, Bioact. Mater. 2022, 14, 377.
John, M. J. Teusink, L. Hong, J. Xie, Sci. Adv. 2021, 7, 31. 87. Y. Kang, C. Xu, L. Meng, X. Dong, M. Qi, D. Jiang, Bioact.
63. S. J. Jiang, M. H. Wang, Z. Y. Wang, H. L. Gao, S. M. Chen, Mater. 2022, 18, 26.
Y. H. Cong, L. Yang, S. M. Wen, D. D. Cheng, J. C. He, S. H. 88. X. Chen, B. Tan, Z. Bao, S. Wang, R. Tang, Z. Wang, G. Chen,
Yu, Adv. Funct. Mater. 2022, 32, 2110931. S. Chen, W. W. Lu, D. Yang, S. Peng, Biomaterials 2021, 277,
64. X. Xue, H. Zhang, H. Liu, S. Wang, J. Li, Q. Zhou, X. Chen, X. 121117.
Ren, Y. Jing, Y. Deng, Z. Geng, X. Wang, J. Su, Adv. Funct. 89. W. Li, S. Li, J. Zhang, H. Zhong, J. Liang, S. Huang, G. Liao,
Mater. 2022, 32, 2202470. B. Zhang, C. Liu, Int. J. Biol. Macromol. 2022, 210, 350.
65. Y. Chen, K. Lee, N. Kawazoe, Y. Yang, G. Chen, Acta Bio- 90. Y. Wu, X. Li, Y. Sun, X. Tan, C. Wang, Z. Wang, L. Ye, Bioact.
mater. 2020, 114, 158. Mater. 2023, 20, 111.
66. X. Liu, W. Chen, B. Shao, X. Zhang, Y. Wang, S. Zhang, W. 91. K. Dai, S. Deng, Y. Yu, F. Zhu, J. Wang, C. Liu, Bone Res.
Wu, Biomaterials 2021, 276, 120998. 2022, 10, 1.
 27517446, 2023, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/bmm2.12046 by Iraq Hinari NPL, Wiley Online Library on [04/10/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
SONG ET AL.
- 19 of 21

92. P. S. Briquez, H.‐M. Tsai, E. A. Watkins, J. A. Hubbell, Sci. 117. Z. Jiang, C. Zhang, X. Wang, M. Yan, Z. Ling, Y. Chen, Z. Liu,
Adv. 2021, 7, 24. Angew Chem., Int. Ed. Engl. 2021, 60, 22376.
93. J. Lee, S. J. Huh, J. M. Seok, S. Lee, H. Byun, G. N. Jang, E. 118. L. Li, X. Zhang, J. Zhou, L. Zhang, J. Xue, W. Tao, Small
Kim, S. J. Kim, S. A. Park, S. M. Kim, H. Shin, Acta Biomater. 2022, 18, 2107705.
2022, 140, 730. 119. J. Qiu, D. Huo, Y. Xia, Adv. Mater. 2020, 32, 2000660.
94. H. Y. Kim, J. H. Park, M. J. Kim, J. H. Lee, S. H. Oh, J. H. 120. J. J. Ye, L. F. Li, R. N. Hao, M. Gong, T. Wang, J. Song, Q. H.
Byun, Biomater. Sci. 2021, 9, 3675. Meng, N. N. Zhao, F. J. Xu, Y. Lvov, L. Q. Zhang, J. J. Xue,
95. S. He, J. Fang, C. Zhong, M. Wang, F. Ren, Adv. Healthcare Bioact. Mater. 2023, 21, 284.
Mater. 2022, 11, 2201096. 121. C. Zhu, D. Huo, Q. Chen, J. Xue, S. Shen, Y. Xia, Adv. Mater.
96. J. Chen, X. Zhou, W. Sun, Z. Zhang, W. Teng, F. Wang, H. 2017, 29, 1703702.
Sun, W. Zhang, J. Wang, X. Yu, Z. Ye, W. Li, Small 2022, 18, 122. L. Che, Y. Wang, D. Sha, G. Li, Z. Wei, C. Liu, Y. Yuan, D.
2107991. Song, Bioact. Mater. 2023, 19, 75.
97. S. Hinkelmann, A. H. Springwald, S. Schulze, U. Hempel, F. 123. Z. Wan, Q. Dong, Y. Liu, X. Zhang, P. Zhang, L. Lv, Y. Zhou,
Mitrach, C. Wölk, M. C. Hacker, M. Schulz‐Siegmund, Chem. Eng. J. 2022, 438, 135518.
Pharmaceutics 2022, 14, 548. 124. Y. Zhao, X. Peng, D. Wang, H. Zhang, Q. Xin, M. Wu, X. Xu,
98. X. Zhang, Q. Liu, T. Zhang, P. Gao, H. Wang, L. Yao, J. F. Sun, Z. Xing, L. Wang, P. Yu, J. Xie, J. Li, H. Tan, C. Ding,
Huang, S. Jiang, Drug Delivery 2022, 29, 889. J. Li, Adv. Sci. 2022, 9, 2204535.
99. G. Basha, A. G. Cottle, T. Pretheeban, K. Y. Chan, D. Wit- 125. D. Zhang, S. Cheng, J. Tan, J. Xie, Y. Zhang, S. Chen, H. Du,
zigmann, R. N. Young, F. M. Rossi, P. R. Cullis, Mol. Ther. S. Qian, Y. Qiao, F. Peng, X. Liu, Bioact. Mater. 2022, 17, 394.
2022, 30, 3034. 126. M. Q. Zhao, Q. Zhang, J. Q. Huang, F. Wei, Adv. Funct.
100. S. Li, Y. Liu, T. Tian, T. Zhang, S. Lin, M. Zhou, X. Zhang, Y. Mater. 2012, 22, 1102222.
Lin, X. Cai, Small 2021, 17, 2104359. 127. K. Ma, C. Liao, L. Huang, R. Liang, J. Zhao, L. Zheng, W. Su,
101. M. Chen, M. Zhou, Y. Fu, J. Li, Z. Wang, Stem Cell Res. Ther. Small 2021, 17, 2104747.
2021, 12, 85. 128. Y. Zhao, C. Wei, X. Chen, J. Liu, Q. Yu, Y. Liu, J. Liu, ACS
102. M. Gan, Q. Zhou, J. Ge, J. Zhao, Y. Wang, Q. Yan, C. Wu, H. Appl. Mater. Interfaces 2019, 11, 11587.
Yu, Q. Xiao, W. Wang, H. Yang, J. Zou, Acta Biomater. 2021, 129. J. Liao, K. Shi, Y. Jia, Y. Wu, Z. Qian, Bioact. Mater. 2021, 6,
135, 289. 2221.
103. L. Xue, N. Gong, S. J. Shepherd, X. Xiong, X. Liao, X. Han, G. 130. Y. Qu, H. Zhuang, M. Zhang, Y. Wang, D. Zhai, B. Ma, X.
Zhao, C. Song, X. Huang, H. Zhang, M. S. Padilla, J. Qin, Y. Wang, C. Qin, Z. Huan, C. Wu, J. Mater. Chem. B 2021, 9,
Shi, M. G. Alameh, D. J. Pochan, K. Wang, F. Long, D. 4355.
Weissman, M. J. Mitchell, J. Am. Chem. Soc. 2022, 144, 9926. 131. R. Nie, Y. Sun, H. Lv, M. Lu, H. Huangfu, Y. Li, Y. Zhang, D.
104. H. Sun, Q. Guo, C. Shi, R. H. McWilliam, J. Chen, C. Zhu, F. Wang, L. Wang, Y. Zhou, Nanoscale 2022, 14, 8112.
Han, P. Zhou, H. Yang, J. Liu, X. Sun, B. Meng, W. Shu, B. Li, 132. Z. Qiao, M. Lian, X. Liu, X. Zhang, Y. Han, B. Ni, R. Xu, B.
Biomaterials 2022, 280, 121243. Yu, Q. Xu, K. Dai, ACS Appl. Mater. Interfaces 2022, 14,
105. J. Li, Y. Zhang, X. Zhou, S. Wang, R. Hao, J. Han, M. Li, Y. 31655.
Zhao, C. Chen, H. Xu, J. Colloid Interface Sci. 2022, 612, 377. 133. C. Zhang, W. Wang, X. Hao, Y. Peng, Y. Zheng, J. Liu, Y.
106. X. Li, L. Wei, J. Li, J. Shao, B. Yi, C. Zhang, H. Liu, B. Ma, S. Kang, F. Zhao, Z. Luo, J. Guo, B. Xu, L. Shao, G. Li, Adv.
Ge, Appl. Mater. 2021, 22, 100942. Funct. Mater. 2020, 31, 2007487.
107. B. Cai, D. Lin, Y. Li, L. Wang, J. Xie, T. Dai, F. Liu, M. Tang, 134. X. Dai, X. Yao, W. Zhang, H. Cui, Y. Ren, J. Deng, X. Zhang,
L. Tian, Y. Yuan, L. Kong, S. G. F. Shen, Adv. Sci. 2021, 8, Int. J. Nanomed. 2022, 17, 4339.
2100584. 135. T. Zheng, H. Zhao, Y. Huang, C. Gao, X. Zhang, Q. Cai, X.
108. Z. Yuan, X. Yuan, Y. Zhao, Q. Cai, Y. Wang, R. Luo, S. Yu, Y. Yang, Ceram. Int. 2021, 47, 28778.
Wang, J. Han, L. Ge, J. Huang, C. Xiong, Small 2021, 17, 136. C. Shuai, G. Liu, Y. Yang, F. Qi, S. Peng, W. Yang, C. He, G.
2006596. Wang, G. Qian, Nano Energy 2020, 74, 104825.
109. Z. Cao, Y. Wu, L. Yu, L. Zou, L. Yang, S. Lin, J. Wang, Z. 137. J. Lei, C. Wang, X. Feng, L. Ma, X. Liu, Y. Luo, L. Tan, S. Wu,
Yuan, J. Dai, Mol. Med. 2021, 27, 20. C. Yang, Chem. Eng. J. 2022, 435, 134624.
110. M. Filippi, F. Garello, O. Yasa, J. Kasamkattil, A. Scherberich, 138. T. Zheng, Y. Yu, Y. Pang, D. Zhang, Y. Wang, H. Zhao, X.
R. K. Katzschmann, Small 2022, 18, 2104079. Zhang, H. Leng, X. Yang, Q. Cai, Composites, Part B 2022,
111. B. Ozkale, M. S. Sakar, D. J. Mooney, Biomaterials 2021, 267, 234, 109734.
120497. 139. B. Wang, G. Li, Q. Zhu, W. Liu, W. Ke, W. Hua, Y. Zhou, X.
112. S. Sayed, O. Faruq, M. Hossain, S. B. Im, Y. S. Kim, B. T. Lee, Zeng, X. Sun, Z. Wen, C. Yang, Y. Pan, Small 2022, 18,
Mater. Sci. Eng., C 2019, 105, 110027. 2201056.
113. Y. Miao, X. Shi, Q. Li, L. Hao, L. Liu, X. Liu, Y. Chen, Y. 140. Y. Zhang, L. Xu, Z. Liu, X. Cui, Z. Xiang, J. Bai, D. Jiang, J.
Wang, Biomat. Sci. 2019, 7, 4046. Xue, C. Wang, Y. Lin, Z. Li, Y. Shan, Y. Yang, L. Bo, Z. Li, X.
114. D. Zhi, T. Yang, J. O'Hagan, S. Zhang, R. F. Donnelly, J. Zhou, Nano Energy 2021, 85, 106009.
Controlled Release 2020, 325, 52. 141. A. Wibowo, C. Vyas, G. Cooper, F. Qulub, R. Suratman, A. I.
115. X. Yi, Q. Y. Duan, F. G. Wu, Research 2021, 2021, 9816594. Mahyuddin, T. Dirgantara, P. Bartolo, Materials 2020, 13,
116. C. Xu, K. Pu, Chem. Soc. Rev. 2021, 50, 1111. 512.
 27517446, 2023, 4, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/bmm2.12046 by Iraq Hinari NPL, Wiley Online Library on [04/10/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
20 of 21
- SONG ET AL.

142. L. Cui, J. Zhang, J. Zou, X. Yang, H. Guo, H. Tian, P. Zhang, H. Sun, X. Zhang, A. L. Antaris, B. R. Brooks, X. Chen, Sci.
Y. Wang, N. Zhang, X. Zhuang, Z. Li, J. Ding, X. Chen, Adv. 2019, 5, 9.
Biomaterials 2020, 230, 119617. 167. D. Chen, Y. Liu, Z. Zhang, Z. Liu, X. Fang, S. He, C. Wu,
143. Y. Liang, J. C. Goh, Bioelectricity 2020, 2, 101. Nano Lett. 2021, 21, 798.
144. Y. Huang, Z. Du, K. Li, W. Jing, P. Wei, B. Zhao, Y. Yu, Q. 168. Z. Gong, Y. He, M. Zhou, H. Xin, M. Pan, M. Fiaz, H. Liu, F.
Cai, X. Yang, Adv. Fiber Mater. 2022, 4, 894. Yan, Theranostics 2022, 12, 2370.
145. R. Eivazzadeh‐Keihan, A. Maleki, M. de la Guardia, M. S. 169. M. M. Menger, C. Korbel, D. Bauer, M. Bleimehl, A. L. Tobias,
Bani, K. K. Chenab, P. Pashazadeh‐Panahi, B. Baradaran, A. B. J. Braun, S. C. Herath, M. F. Rollmann, M. W. Laschke, M. D.
Mokhtarzadeh, M. R. Hamblin, J. Adv. Res. 2019, 18, 185. Menger, T. Histing, Photoacoustics 2022, 28, 100409.
146. H. Lin, S. Gao, C. Dai, Y. Chen, J. Shi, J. Am. Chem. Soc. 2017, 170. L. B. Jiang, S. L. Ding, W. Ding, D. H. Su, F. X. Zhang, T. W.
139, 16235. Zhang, X. F. Yin, L. Xiao, Y. L. Li, F. L. Yuan, J. Dong, Chem.
147. A. Bigham, A. H. Aghajanian, S. Behzadzadeh, Z. Sokhani, S. Eng. J 2021, 418, 129323.
Shojaei, Y. Kaviani, S. A. Hassanzadeh‐Tabrizi, Mater. Sci. 171. L. Jin, P. Li, Y. C. Wang, L. Feng, R. Xu, D. B. Yang, X. H.
Eng., C 2019, 99, 83. Yao, J. Ultrasound Med. 2019, 38, 2963.
148. L. Wang, P. Hu, H. Jiang, J. Zhao, J. Tang, D. Jiang, J. Wang, 172. A. N. Rindone, W. L. Grayson, ACS Biomater. Sci. Eng. 2022,
J. Shi, W. Jia, Nano Today 2022, 43, 101401. 8, 4610.
149. Y. He, F. Li, P. Jiang, F. Cai, Q. Lin, M. Zhou, H. Liu, F. Yan, 173. Z. Lin, Z. Chen, Y. Chen, N. Yang, J. Shi, Z. Tang, C. Zhang,
Bioact. Mater. 2023, 21, 223. H. Lin, J. Yin, Exploration 2023, 20220149.
150. S. Camarero‐Espinosa, L. Moroni, Nat. Commun. 2021, 12, 174. Y. Y. Du, J. L. Guo, J. L. Wang, A. G. Mikos, S. M. Zhang,
1031. Biomaterials 2019, 218, 119334.
151. T. Levingstone, B. Ali, C. Kearney, N. Dunne, J. Biomed. 175. C. Xie, J. C. Ye, R. J. Liang, X. D. Yao, X. Y. Wu, Y. W. Koh,
Mater. Res., Part B 2021, 109, 1622. W. Wei, X. Z. Zhang, H. W. Ouyang, Adv. Healthcare Mater.
152. J. Qiu, D. Huo, Y. Xia, Adv. Mater. 2020, 32, 00660. 2021, 10, 2100408.
153. M. Li, X. Chu, D. Wang, L. Jian, L. Liu, M. Yao, D. Zhang, Y. 176. A. Ho‐Shui‐Ling, J. Bolander, L. E. Rustom, A. W. Johnson,
Zheng, X. Liu, Y. Zhang, F. Peng, Biomaterials 2022, 282, F. P. Luyten, C. Picart, Biomaterials 2018, 180, 143.
121408. 177. J. Zhou, Z. Zhang, J. Joseph, X. Zhang, B. E. Ferdows, D. N.
154. S. W. Choi, Y. Zhang, Y. Xia, Angew Chem., Int. Ed. Engl. Patel, W. Chen, G. Banfi, R. Molinaro, D. Cosco, N. Kong, N.
2010, 49, 04057. Joshi, O. C. Farokhzad, C. Corbo, W. Tao, Exploration 2021,
155. N. Wang, Y. Xie, Z. Xi, Z. Mi, R. Deng, X. Liu, R. Kang, X. 1, 20210011.
Liu, Front. Bioeng. Biotechnol. 2022, 10, 937803. 178. S. V. Murphy, A. Atala, Nat. Biotechnol. 2014, 32, 773.
156. Y. Huang, X. Zhai, T. Ma, M. Zhang, H. Pan, W. Weijia Lu, X. 179. C. Montoya, Y. Du, A. L. Gianforcaro, S. Orrego, M. B. Yang,
Zhao, T. Sun, Y. Li, J. Shen, C. Yan, Y. Du, Coord. Chem. Rev. P. I. Lelkes, Bone Res. 2021, 9, 12.
2022, 450, 214236. 180. H. P. Wei, J. J. Cui, K. L. Lin, J. Xie, X. D. Wang, Bone Res.
157. J. Gao, L. Feng, B. Chen, B. Fu, M. Zhu, Composites, Part B 2022, 10, 17.
2022, 235, 109758. 181. J. S. Huang, Y. X. Li, L. Huang, J. Robot. Surg. 2020, 14, 11.
158. P. Wang, L. Hao, Z. Wang, Y. Wang, M. Guo, P. Zhang, ACS 182. X. Zhou, H. Wang, C. Feng, R. Xu, Y. He, L. Li, C. Tu, Front.
Appl. Mater. Interfaces 2020, 12, 49464. Oncol. 2022, 12, 908873.
159. H. Zhang, W. Fang, T. Zhao, H. Zhang, L. Gao, J. Li, R. Wang, 183. S. C. Shen, M. Pena Fernandez, G. Tozzi, M. J. Buehler, J.
W. Xu, Front. Bioeng. Biotechnol. 2022, 10, 940735. Mech. Behav. Biomed. Mater. 2021, 123, 104761.
160. E. Campodoni, M. Velez, E. Fragogeorgi, I. Morales, P. de la 184. M. J. DeFrance, M. F. Yayac, P. M. Courtney, M. W. Squire, J.
Presa, D. Stanicki, S. M. Dozio, S. Xanthopoulos, P. Bouziotis, Arthroplasty 2021, 36, 1462.
E. Dermisiadou, M. Rouchota, G. Loudos, P. Marin, S. Lau- 185. X. Xue, Y. Hu, Y. H. Deng, J. C. Su, Adv. Funct. Mater. 2021,
rent, S. Boutry, S. Panseri, M. Montesi, A. Tampieri, M. 31, 2009432.
Sandri, Biomater. Sci. 2021, 9, 7575.
161. X. Liu, Y. Ma, M. Chen, J. Ji, Y. Zhu, Q. Zhu, M. Guo, P.
Zhang, J. Mater. Chem. B 2021, 9, 6691. AUTHOR BIOGRAPHIES
162. P. Pei, H. Hu, Y. Chen, S. Wang, J. Chen, J. Ming, Y. Yang, C.
Sun, S. Zhao, F. Zhang, Nano Lett. 2022, 22, 783.
163. P. Pei, Y. Chen, C. Sun, Y. Fan, Y. Yang, X. Liu, L. Lu, M. Jian Song graduated from Shanghai
Zhao, H. Zhang, D. Zhao, X. Liu, F. Zhang, Nat. Nanotechnol. University of Engineering Science and is
2021, 16, 1011. now a postgraduate student at the
164. H. Yang, H. Huang, X. Ma, Y. Zhang, X. Yang, M. Yu, Z. Sun, School of Materials Science and Engi-
C. Li, F. Wu, Q. Wang, Adv. Mater. 2021, 33, 2103953. neering, Beijing University of Chemical
165. B. Li, M. Zhao, L. Feng, C. Dou, S. Ding, G. Zhou, L. Lu, H. Technology. His research focuses on the
Zhang, F. Chen, X. Li, G. Li, S. Zhao, C. Jiang, Y. Wang, D.
construction of multifunctional scaffolds
Zhao, Y. Cheng, F. Zhang, Nat. Commun. 2020, 11, 3102.
166. R. Tian, Q. Zeng, S. Zhu, J. Lau, S. Chandra, R. Ertsey, K. S.
for osteochondral defects and reconstruction of
Hettie, T. Teraphongphom, Z. Hu, G. Niu, D. O. Kiesewetter, tendon bone interface.
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SONG ET AL.
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more than 20 years. Over the years, he has treated a

Longfei Li graduated from Zhejiang
large number of spinal deformities (scoliosis and
University of Technology and is now a
kyphosis), lumbar/thoracic stenosis, lumbar disc her-
postgraduate student at the School of
niation, cervical spondylosis and other complex clin-
Materials Science and Engineering,
ical cases. His research interests include thoracic
Beijing University of Chemical Tech-
spinal stenosis, spinal deformity, bioactive orthope-
nology. His research focuses on the
dics materials, application of human factors engi-
construction of multifunctional scaf-
neering in orthopedics and robot‐assisted spinal
folds for bone repair and related tissue engineering.
surgery.

Feng Tian received his B.S. degree

Jiajia Xue received her Ph.D. in Ma-
from Zhejiang University in 2013 and
terials Science and Engineering from
his Ph.D. degree from The Hong Kong
Beijing University of Chemical Tech-
Polytechnic University in 2020. He
nology in 2015 under the supervision of
joined the University of California,
Prof. Liqun Zhang. She worked as a
Riverside as a visiting scholar in 2019.
postdoctoral fellow in Prof. Younan
Currently, he is working as an associate
Xia's group at Georgia Institute of
professor in the Center for Advanced Elastomer Ma-
Technology from 2015 to 2019. She is now working as
terials Research (CAEM), School of Materials Science
a professor at the Beijing University of Chemical
and Engineering, Beijing University of Chemical
Technology. Her research interests include the fabri-
Technology (BUCT). His research interests are novel
cation of nanomaterials and scaffolds for tissue engi-
biomaterials for tumor diagnosis and therapy, and
neering and regenerative medicine.
tissue repair.

Yu Zhao, the chief physician and

professor of spine surgery in Depart- How to cite this article: J. Song, L. Li, L. Fang,
ment of Orthopedics, Peking Union E. Zhang, Y. Zhang, Z. Zhang, P. Vangari, Y.
Medical College Hospital, Chinese Huang, F. Tian, Y. Zhao, W. Chen and J. Xue,
Academy of Medical Sciences and BMEMat 2023, 1(4), e12046. https://doi.org/10.
Peking Union Medical College, has 1002/bmm2.12046
been engaged in spine surgery for