REVIEW

published: 24 March 2020

doi: 10.3389/fbioe.2020.00083

Tissue Engineering and Regenerative

Medicine: Achievements, Future, and
Sustainability in Asia
Fengxuan Han 1,2 , Jiayuan Wang 1,2 , Luguang Ding 1,2 , Yuanbin Hu 3 , Wenquan Li 4 ,
Zhangqin Yuan 1,2 , Qianping Guo 1,2 , Caihong Zhu 1,2 , Li Yu 1,2 , Huan Wang 1,2 ,
Zhongliang Zhao 1,2 , Luanluan Jia 1,2 , Jiaying Li 1,2 , Yingkang Yu 1,2 , Weidong Zhang 1,2 ,
Genglei Chu 1 , Song Chen 1,2 and Bin Li 1,2,5*
1
Department of Orthopaedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China, 2 Orthopaedic
Institute, Soochow University, Suzhou, China, 3 Department of Orthopaedics, Zhongda Hospital, Southeast University,
Nanjing, China, 4 Department of Otolaryngology, The Second Affiliated Hospital of Soochow University, Suzhou, China,
5
China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, China

Exploring innovative solutions to improve the healthcare of the aging and diseased
population continues to be a global challenge. Among a number of strategies toward
Edited by: this goal, tissue engineering and regenerative medicine (TERM) has gradually evolved
Ranieri Cancedda, into a promising approach to meet future needs of patients. TERM has recently
Independent Researcher, Genova,
received increasing attention in Asia, as evidenced by the markedly increased number
Italy
of researchers, publications, clinical trials, and translational products. This review
Reviewed by:
Mona Kamal Marei, aims to give a brief overview of TERM development in Asia over the last decade
Alexandria University, Egypt by highlighting some of the important advances in this field and featuring major
Kar Wey Yong,
University of Alberta, Canada achievements of representative research groups. The development of novel biomaterials
*Correspondence: and enabling technologies, identification of new cell sources, and applications of TERM
Bin Li in various tissues are briefly introduced. Finally, the achievement of TERM in Asia,
[email protected]
including important publications, representative discoveries, clinical trials, and examples
Specialty section: of commercial products will be introduced. Discussion on current limitations and future
This article was submitted to directions in this hot topic will also be provided.
Tissue Engineering and Regenerative
Medicine, Keywords: tissue engineering, regenerative medicine, Asia, biomaterials, cell sources, biomechanics
a section of the journal
Frontiers in Bioengineering and
Biotechnology INTRODUCTION
Received: 26 September 2019
Accepted: 29 January 2020 Fully repairing or regenerating damaged tissues or organs and restoring their functions have
Published: 24 March 2020 been a dream of human beings. The advent of tissue engineering and regenerative medicine
Citation: (TERM) appears to make it possible. Tissue engineering combines cells, scaffolds, and growth
Han F, Wang J, Ding L, Hu Y, Li W, factors to regenerate tissues or replace damaged or diseased tissues, while regenerative medicine
Yuan Z, Guo Q, Zhu C, Yu L, Wang H, combines tissue engineering with other strategies, including cell-based therapy, gene therapy,
Zhao Z, Jia L, Li J, Yu Y, Zhang W, and immunomodulation, to induce in vivo tissue/organ regeneration (Lysaght and Crager, 2009;
Chu G, Chen S and Li B (2020)
Lindroos et al., 2011; Salgado et al., 2013; Porada et al., 2016). TERM is a multidisciplinary
Tissue Engineering and Regenerative
Medicine: Achievements, Future,
science and combines basic sciences such as materials science, biomechanics, cell biology, and
and Sustainability in Asia. medical sciences to realize functional tissue/organ repair or reconstruction. With the aging of world
Front. Bioeng. Biotechnol. 8:83. population trend intensifying, there is an increasing demand of organ replacements. TERM holds
doi: 10.3389/fbioe.2020.00083 the potential to meet the future needs of patients (Frey et al., 2016).

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Han et al. Tissue Engineering and Regenerative Medicine in Asia

The aim of TERM is to establish a three-dimensional (3D) formation (Zou et al., 2018). Peng and Wang’s groups used a
cell/biomaterial complex, which has similar function as a living neurotrophic peptide-functionalized, self-assembling nanofiber
tissue/organ and may be used to repair or regenerate injured hydrogel to produce a neurotrophic microenvironment (Lu et al.,
tissue/organ. The basic requirement for the complex is that it can 2018). Dai’s group developed a lot of collagen-based scaffolds
support cell growth, transportation of nutrition and waste, and for nerve regeneration (Chen et al., 2018c; Li X. R. et al., 2018).
gas exchange. TERM usually uses the following three strategies: A collagen scaffold with microchannel and loading paclitaxel
(1) cell/biomaterial complex system, in which cell-seeded liposome-induced neuronal differentiation of neural stem cells
biomaterials are implanted into the body to repair and regenerate (NSCs) through Wnt/β-catenin signaling could be used in spinal
tissues/organs; (2) cell systems, such as stem cell transplantation; cord injury (SCI) repair (Li X. R. et al., 2018). In a recent work,
and (3) biomaterial systems, which will be implanted into body a multichannel poly(propylene fumarate) scaffold modifying
and undergo the process of tissue integration. with collagen-binding neurotrophic factor 3 promoted neural
Tissue engineering and regenerative medicine has been regeneration of SCI (Chen et al., 2018c). They also found that
proposed and developed for more than 30 years. While several controlled release of collagen-binding stromal cell-derived factor-
successful attempts in tissue regeneration have been achieved, 1α (SDF-1α) from the scaffold promoted tendon regeneration
TERM is still in its infancy and there are many fundamental in a rat Achilles tendon defect model (Sun J. et al., 2018).
questions that remain to be answered, including selection Chen’s group also attempted to prepare various porous collagen
of cell sources, development of tissue-specific materials, and gelatin scaffolds for application in TERM (Chen et al.,
development of specialized bioreactors, and construction 2014; Zhang Q. et al., 2014; Chen S. et al., 2015; Chen S. W.
of complex organs. More importantly, the processes and et al., 2017). They found that the pore structure and mechanical
mechanisms of new tissue/organ formed using these tissue- property also regulate cartilage regeneration (Chen S. et al.,
engineered materials in vivo, similarity and difference between 2015). In another work, they also developed collagen porous
these processes with nature tissue/organ development and scaffolds with parallel and concave microgrooves to regulate
healing, and transformation and final destination of these vascular endothelial cells and muscle cells (Chen S. W. et al.,
materials continue to be the critical concerns in this dynamically 2017). Esaki et al.’s (2019) group reported that transplantation
developing field. Addressing these questions is the key to the of olfactory stem cells with biodegradable gelatin sponge could
effectiveness, stability, and security of the clinical application of accelerate facial nerve regeneration after crush injury. They
tissue-engineered materials. also fabricated human ear- and nose-shaped scaffolds used in
The aim of this review is to summarize recent major events gelatin and HA by integrating photocuring 3D printing and
in the broad discipline of TERM in Asia. In constructing this lyophilization techniques (Xia et al., 2018). The natural hydrogel
review, we retrieved a large number of literature and selected such as gelatin methacryloyl (GelMA) could also be electrospun
some representative works that are presented in this review. into 3D fibrous scaffolds (Sun et al., 2017). After GelMA
Indeed, we recognized that we are limited by our own small view fibrous scaffold implantation below the skin flap of rat, more
and specialization, and that this might limit our ability to capture microvascular formation is found. Zhang X. et al.’s (2019) group
the comprehensiveness and diversity of TERM. Therefore, this developed aligned all-cellulose nanofibers coated with bone
review may not be comprehensive, but we will try our best to list morphogenetic protein-2 (BMP-2) via electrospinning. Aligned
some important advances in TERM in Asia. nanofibers instructed cell growth along fiber direction. Gao’s
The population of TERM research community has been group reported that a HA hydrogel modified by laminin-derived
rapidly expanding in Asia. In this review, a brief overview of peptide could promote neurite outgrowth of PC12 cells (Xing
recent development in the broad discipline of TERM in Asia et al., 2017). In another work, they found that cell-responsive
will be summarized. To this end, we retrieved a large number of hydrogel could be used to develop a co-culture system of immune
literature and selected representative achievements to showcase cells and smooth muscle cells (Yu S. et al., 2018). Goh’s group
in this review. Due to the page limit, this review is far from being prepared different silk-based scaffolds for TERM (Shi et al., 2013;
comprehensive; instead, we highlight here only a small fraction of Teh et al., 2013). They prepared aligned fibrous scaffolds using
important advances of TERM in Asia as examples. silk fibroin, and found that it could enhance mechanoresponse
and tenogenesis of mesenchymal stem cells (MSCs). Deng’s
group found enhanced osteogenesis of bone marrow stromal
ACHIEVEMENT OF TERM IN ASIA cells (BMSCs) by a functionalized silk fibroin hydrogel (Yan
et al., 2019). Cho’s group prepared an injectable microgel
Biomaterials composed of arginine–glycine–aspartic acid (RGD)-conjugated
Polymer alginate that encapsulated endothelial cells and growth factors to
Native polymers, such as acellular matrix, collagen, gelatin, enhance vascularization (Kim et al., 2014). Inspired by mussel
hyaluronic acid (HA), silk, alginate, and chitosan, are well- chemistry, Lu’s group developed many polyacrylamide-based
known sources for preparing scaffold in TERM. There are polymers with good tissue adhesiveness that can be used in
many works to explore the interrelationship between the cartilage and skin repair (Han L. et al., 2018; Gan et al.,
composition, structure, and functions of these native polymer- 2019). Wang’s group used a photo-cross-linkable, injectable
based scaffolds. Zeng’s group found that peripheral nerve-derived sericin hydrogel for minimally invasive repairing cartilage (Qi
matrix hydrogel promoted remyelination and inhibited synapse et al., 2018). Gu’s group found that chitosan/silk fibroin scaffold

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Han et al. Tissue Engineering and Regenerative Medicine in Asia

combined with allogeneic bone marrow mononuclear cells could the host and guest could recognize each other immediately to
facilitate nerve regeneration, and the scaffold can improve recombine the damaged area.
macrophage-constructed microenvironments (Yao et al., 2016; Up to now, many strategies were proposed for the fabrication
Zhao Y. H. et al., 2017). of polymer fibers, such as electrospinning, microfluidic spinning,
Although nature polymers usually have good bioactivity, and 3D bioprinting. Mo’s group explores the application of
their mechanical properties are often weak. Compared electrospun fibers in TERM. They reported that modified PCL
with other materials, the properties of synthetic polymer or other polymer electrospun fibers can be used in nerve
could be easily tailored by changing the molecular structure (Yang G. H. et al., 2019), vascular (Liu P. X. et al., 2018),
and processing parameters. Li’s group prepared poly(ether bone (Ye et al., 2019b), and other tissue regeneration in
carbonate urethane)urea scaffolds with tunable elasticity and recent work. Yuan’s group also developed different electrospun
topography, and these properties of scaffolds could regulate fibers for drug delivery and vascular regeneration (Han et al.,
the fate of AF-derived stem cells through a YAP-dependent 2013; Zhang et al., 2013). Recently, they also encapsulated
mechanotransduction mechanism (Liu et al., 2015; Zhu et al., live microorganisms in electrospun fibers (Han J. P. et al.,
2016; Chu et al., 2019). Yeong et al. (2010) presented highly 2018) or prepared antibacterial PCL electrospun membranes
porous polycaprolactone (PCL) scaffold by sintering PCL containing synthetic polypeptides (Liu B. et al., 2018). Many
powder for application in cardiac tissue engineering. The other scholars have also done some interesting work. Yi et al.
mechanical property of this scaffold could be controlled by (2019) prepared aligned electrospun fibers of poly(L-lactide-co-
changing porosity. Kim’s group developed a PCL-based scaffold caprolactone)/poly(L-lactic acid) (PLCL/PLLA) shell–core fibers
with uniaxially aligned surface topography by stretching a via coaxial electrospinning and found that the stiffness of aligned
3D-printed scaffold (Yang G. H. et al., 2019). To modify the fibers could regulate the phenotypic expression of vascular
bioactivity of polymer, polydopamine (PDA)-assisted surface smooth muscle cells (VSMCs) (Yi et al., 2019). In another
modification is an easy approach (Jia et al., 2019a). Poly(ether study, via a novel stable jet electrospinning, highly aligned
ether ketone) (PEEK) has good mechanical property and has hyaluronan/PLLA nanofibers with core–shell structure were
been used as orthopedic implants. Many researchers aim to also prepared for vessel regeneration (Yuan H. et al., 2016).
improve the biofunction of this material by endowing its Combining the aligned nanofibers and hydrogel, Guo’s group
antibacterial property and osseointegration property. Gao C. developed a 3D hybrid scaffold based on an aligned conductive
et al. (2017) developed a biocompatible and antibacterial coating nanofiber yarn network composed of silk fibroin, PCL, and
for PEEK using PDA-based surface modification technology and carbon nanotubes within a hydrogel to mimic the structure of
subsequent deposition of silver nanoparticles, which permits its native cardiac tissue (Figure 1A; Wu et al., 2017). Microfluidic
potential use as an orthopedic material. There are also many technology is also used to prepare fibrous scaffold for TERM.
studies to design hydrogels with tunable mechanical property to Matsunaga’s group prepared a gel fiber using a microfluidic
mimic natural tissues. Some groups tried to prepare hydrogel device system to manufacture a phase separation polymer
with high mechanical strength. In a study, the hydrophobic, π–π blend solution containing hydroxypropyl cellulose and sodium
interactions and chemical bonds between the polymer binders alginate (Tachizawa et al., 2017). This fiber could be used as a
and substrate surfaces could improve mechanical performance scaffold for in vitro neuronal induction. Ying’s group developed
(Shin et al., 2012). What’s more, the structure of protein could hydrodynamic spinning of gelatin-hydroxyphenylpropionic acid,
affect the strength of protein hydrogel (Fang et al., 2013). Liu alginate, poly(N-isopropylacrylamide), and polysulfone hydrogel
group developed a lot of high-strength hydrogels (Dai et al., fibers (Hu et al., 2010). Takeuchi’s group also described a long
2015; Xu et al., 2017; Gao F. et al., 2018). Among them, a high- and finely handleable cell alginate fiber, by using a microfluidic
strength poly(N-acryloyl glycinamide) hydrogel with additional device (Figure 1B; Onoe et al., 2013). This cell fiber could
function of reverse transfection and cell detachment (Dai et al., encapsulate extracellular matrix (ECM) proteins and somatic
2015). Recently, they also reported a 3D-printing high-strength stem cells or differentiated cells and could mimic muscle
gradient hydrogel synthesized by N-acryloyl glycinamide fibers, nerve networks, or blood vessels in vivo. Gu and Zhao’s
and N-(tris(hydroxymethyl)methyl) acrylamide for efficient groups explored cell-laden alginate microfibers with the tunable
repair of osteochondral defects (Gao F. et al., 2018). Guo’s structures through microfluidic technology (Cheng et al., 2016).
group developed various tough hydrogels using non-covalent Further, they demonstrated that these cell-laden fibers could
interaction (Guo et al., 2014; Zhao T. et al., 2014; Cui et al., 2015). be further constructed into microfiber-like tissues by stacking
A multi-responsive supramolecular hydrogel, which could be the microfibers. Fan’s group also co-developed a simple and
induced by temperature, light, and redox, was prepared by the reliable way to create cell-laden alginate fibers with hierarchical
formation of host–guest complexes between the polyethylene architecture through a microfluidic-based strategy (Wei et al.,
ethanol-polyhedral oligomeric silsesquioxane-(CD)7 polymer 2017). Jiang’s group constructed an artificial blood vessel
and azo-SS-azo dimer (Wang X. et al., 2017). In another study, with simulating autologous vascular structures from PCL and
Chen et al. (2018a) also prepared supramolecular hydrogels poly(lactide-co-glycolide) (PLGA), combining electrospinning
based on host–guest interaction; this hydrogel could protect and microfluidic technology (Cheng et al., 2017).
myoblasts from deleterious mechanical stimulus. Recently, Wang In situ forming hydrogels from polymers have also been widely
Z. et al. (2018) fabricated robust and biocompatible hydrogels used for TERM because of the ease of encapsulating proteins,
via host–guest interaction. When the hydrogels were damaged, drugs, genes, and cells (Yang et al., 2014; Park and Park, 2018).

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Han et al. Tissue Engineering and Regenerative Medicine in Asia

FIGURE 1 | (A) An interwoven aligned conductive nanofiber yarn/hydrogel hybrid scaffolds for mimicking the native cardiac tissue structure (reproduced with
permission from Wu et al., 2017). (B) A thin, long, and finely handleable cell fiber fabricated by using a microfluidic device (reproduced with permission from
Onoe et al., 2013).

Various cross-linking strategies, including physical interactions quickly be formed by mixing β-CD modified poly(acrylic acid)
(ionotropic interaction, thermo-sensitivity, and host–guest (pAA) with ferrocene modified pAA (Nakahata et al., 2011).
interaction) and chemical cross-linking reactions (enzyme- Photo-cross-linking hydrogels are also widely investigated. Park’s
mediated or light-controlled cross-linking and click chemistry), group prepared a variety of in situ forming hydrogels (Le Thi
have been utilized to create in situ forming hydrogels (Park et al., 2017; Lee et al., 2017). An in situ forming gelatin hydrogel
and Park, 2018). For example, Harada’s group developed by horseradish peroxidase–tyrosinase cross-linking resulted in
redox-responsive self-healing supramolecular hydrogel formed strong tissue adhesion (Le Thi et al., 2017). In another work, they
from host–guest polymers. A supermolecular hydrogel could fabricated in situ forming H2 O2 -releasing gelatin-hydroxyphenyl

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Han et al. Tissue Engineering and Regenerative Medicine in Asia

propionic acid hydrogels, which could be used in treatment of release of Li and Si ions, suggesting the bi-lineage bioactivities
drug-resistant bacterial infections (Lee et al., 2017). Recently, of these scaffold for osteochondral defect regeneration (Deng
they reported an injectable gelatin-based hydrogels that could et al., 2018a). The effect of nanotopography surface on
release nitric oxide and show good antibacterial property due bone regeneration was investigated by Yang C. et al. They
to the in situ formation of peroxynitrite (Hoang Thi et al., demonstrated that the needle-like structure can better enhance
2018). Hwang’s group fabricated tissue adhesive hydrogels from the bone regeneration in vitro and in vivo in comparison with
tyramine conjugated HA and gelatin for meniscus repair (Kim pure tricalcium silicate scaffolds (Yang C. et al., 2017). Chang and
S. H. et al., 2018). This tissue adhesive hydrogel was obtained by Wu’s groups prepared porous akermanite (AKT, Ca2 MgSi2 O7 )
tyrosinase-mediated cross-linking. scaffold with lotus root-like structures via a modified 3D-
printing strategy, and these scaffolds promote bone regeneration
Ceramics (Feng et al., 2017).
Being one of the important components in bone and teeth, Silicon dioxide (SiO2 ) was also widely applied in TERM.
calcium phosphate-based materials have attracted substantial For example, Bian’s group coated a photocleavable linker and
attention in TERM (Wu et al., 2011). Porous calcium phosphate- Arg–Gly–Asp (RGD) peptide-bearing molecular cap on the
based scaffolds with various compositions and controlled pore surface of mesoporous silica by host–guest complexation. Remote
size and porosity are designed to achieve the desired biological control of calcium release and cell fate could be realized using
functions. Zhao N. et al. (2017) have studied hydroxyapatite these particles (Kang et al., 2018a,b). Bioactive glass, with a
(HAp)/β-tricalcium phosphate (β-TCP) scaffolds with different typical composition of 46.1% SiO2 , 26.9% CaO, 24.4% Na2 O,
weight ratios and macropore percentages, showing that scaffolds and 2.6% P2 O5 , is the first biomaterial that is able to bond
with 40% HAp and 50% macropores are optimum for cell to bone (Hench, 2006). The ions such as Si, Ca, and P
proliferation, while 60% HAp and 30% macropores are the best released from the bioactive glass have the effect of stimulating
for osteogenic differentiation. Another study conducted by Chen osteogenesis and bone metabolism (Maeno et al., 2005). By
Y. et al. (2015) have revealed that porous calcium phosphate doping with elements such as copper (Cu) (Zhao et al., 2015a),
ceramics could promote angiogenic induction ability, and a strontium (Sr) (Pan et al., 2010), zinc (Zn) (Wang H. et al.,
higher amount of β-TCP is favorable for neovascularization of 2015), and boron (B) (Li X. et al., 2016), the promotion and
the ceramics. However, the mechanical insufficiency of calcium stimulation effects on osteoblast activity and angiogenesis are
phosphate biomaterials limits their further applications in greatly enhanced. More recently, mesoporous bioactive glass with
tissue regeneration. High-temperature sintering could strengthen ordered porosity and pore structures has been demonstrated,
their mechanical performance, but the crystallinity increases promising biomaterials for bone regeneration (Zhou et al.,
during the sintering process, which significantly reduces the 2017). Zhao et al. (2015b) fabricated Sr-containing mesoporous
degradability of the scaffold. An alternative way is to use polymers bioactive glass scaffolds with high porosity and interconnected
to strengthen the calcium phosphate matrix. Kang et al. (2017) pores through 3D-printing technique. The mesoporous scaffolds
applied Ca2+ as “ion glue” to improve the bonding between have exhibited good ability to stimulate the proliferation and
calcium phosphate minerals and organic polymers. Ma Y. et al. differentiation of MC3T3-E1 cells, excellent osteoinductive
(2016) used PEGylated poly(glycerol sebacate) to enhance the activity to enhance bone formation, and ability to promote new
calcium phosphate matrix, resulting in scaffold with enhanced blood vessel formation (Zhao et al., 2015b). Xie et al. dispersed
mechanical behavior and osteogenic differentiation of BMSCs. the mesoporous bioactive glass nanorods in bioactive glass sol to
Calcium phosphate nanoparticles with various sizes and shapes form scaffolds with hierarchical pore structures. The scaffolds are
are also synthesized and applied in the area of tissue engineering able to promote the biomineralization process and to stimulate
(Lin K. et al., 2014). Cai et al. have demonstrated that the the proliferation of rat BMSCs (Xie et al., 2019).
dimension of HAp nanoparticles has great influence on the
biological activities of bone-related cells. In comparison with Metal
particles in diameters of 40 and 80 nm, 20-nm-sized HAp Metal, with high compressive strength, can satisfy the demand
has shown the best stimulating effect to bone marrow MSCs of load bearing in orthopedics such as replacement of hip.
(Cai et al., 2007). However, metallic scaffolds lack bioactivity and have problems
Calcium silicate materials, particularly tricalcium silicate such as degradability and possible release of toxic metallic
(Ca3 SiO5 , C3 S), have shown great potential in bone regeneration ions. Non-biodegradable titanium (Ti) alloys, specifically Ti-
area (Zhao et al., 2005; Lin Q. et al., 2014). Deng et al. (2018b) 6Al-4V, are widely used in orthopedics; they have superior
prepared 3D-printed bioactive ceramic scaffolds composed of biocompatibility and mechanical property to stainless steel,
Sr5 (PO4 )2 SiO4 and showed that Sr and Si ions can stimulate Co-based alloys, and pure Ti (Alvarez and Nakajima, 2009;
cartilage regeneration by activating the hypoxia-inducible factor Li Y. et al., 2009). However, Ti-6Al-4V contains vanadium,
pathway. These ceramics are efficient to reconstruct the cartilage– which is cytotoxic. Some researchers tried to develop new Ti
bone interface, making them promising materials for the alloys containing nontoxic elements such as niobium (Nb) and
regeneration of osteochondral defect (Deng et al., 2018b). tantalum (Ta) (Alvarez and Nakajima, 2009). Due to the fact
Another study has shown that Li2 Ca2 Si2 O7 bioactive scaffold that the porous metallic scaffolds are more suitable for tissue
can promote the maturation of chondrocytes and stimulate ingrowth, a porous Ti-6Ta-4Sn alloy scaffold was fabricated with
the osteogenic differentiation of rabbit MSCs by continuous a space holder sintering method by Li Y. et al. which showed

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excellent biomechanical properties as an orthopedic implant Ti or using Mg alloys as an alternative. Hiromoto’s group
(Li Y. et al., 2009). Surface modification is used to further used octacalcium phosphate and HAp coatings to control
improve the bioactivity of Ti alloys. Jang’s group fabricated an the degradation speed and to improve the biocompatibility
antibacterial Ag nanostructure on a Ti surface by a two-step of biodegradable Mg alloys (Hiromoto and Yamazaki, 2017).
process involving target-ion-induced plasma sputtering and Ag Yeung’s group prepared a Ti dioxide (TiO2 ) nano-layer on
sputtering (Kim S. et al., 2018). Yamamoto’s group prepared the surface of ZK60 Mg substrate through Ti and O dual
carbon layer coating Ti and carbon-coated oxygen-diffused plasma ion immersion implantation technique (Lin Z. et al.,
Ti for TERM (Yamamoto et al., 2011a,b). Liu’s group used 2019). They also constructed a TiO2 /Mg2 TiO4 nano-layer on
graphene oxide films loaded with minocycline hydrochloride to the surface of WE43 Mg implant. With these methods, the
modify the surface of Ti, to enhance osteogenic activity in the modified Mg or Ma alloy implants showed enhanced corrosion
presence of bacteria (Qiu et al., 2019). They also found that resistance, osteoconductivity, and antimicrobial activity (Lin Z.
the topography and elastic modulus could affect cell adhesion et al., 2019). Park and Kim’s groups coated a Zn oxide/polylactic
and spread on Ti surface (Chen L. et al., 2019). Kim and acid (PLA) nanocomposite layer on Mg alloys; this method
Cha’s groups assembled silica nanoparticle nanostructures on the could not only control the degradation rate but also control the
surface of Ti to enhance in vitro osteogenesis and in vivo bone surface topography of Mg alloys substrate (Mousa et al., 2018).
formation (Jo et al., 2017). Bioactive molecules are also used to Moreover, this coated layer also exerted antibacterial properties.
modify the Ti and Ti alloys. Cai’s group fabricated a functional In a study, Mg was also incorporated into PLGA/TCP porous
molybdenum disulfide/PDA–RGD coating on Ti implant to scaffold by 3D printing to promote osteogenic and angiogenic
inhibit bacterial infection and improve osseointegration (Yuan properties of the scaffold (Lai et al., 2019). Iron (Fe) exhibits
et al., 2019a). Recently, a synergistic photothermal/photodynamic high mechanical strength and slow corrosion rate, which has the
therapy (PTT/PDT) strategy aiming for remotely controlling the potential as higher load-bearing implants. Zhang and Zheng’s
eradication of biofilm was developed (Yuan et al., 2019b). Huh’s groups reported that the Fe-based scaffold showed good long-
group immobilized recombinant human platelet-derived growth term biocompatibility in both rabbit and porcine model. Its
factor-BB plus recombinant human BMP-2 on heparinized-Ti corrosion products were biosafe and could be cleared away by
implants, and the results showed more new bone formation the macrophages. Pandey’s group found that the corrosion rate
around implants (Lee S. H. et al., 2018). Nishimura’s group of Fe scaffold could be affected by the property of interconnected
revealed that neuronal PAS domain 2 modified on the rough micropores (Lin et al., 2017). Sun and Wang’s groups generated
surface of Ti implant could facilitate osseointegration through engineered human ventricular heart tissue based on Fe oxide
neuroskeletal regulatory pathways (Morinaga et al., 2019). Like scaffolds (Yang H. et al., 2019).
Ti, Ta possesses a low modulus similar with natural subchondral
and cancellous bone that could facilitate load transfer and Composite Materials
reduce stress shielding. In addition, Ta could still show unique The composite materials that can keep the advantages from
mechanical properties even at high porosity (>80%), which polymer, inorganic material, and metal are developed for TERM.
allows rapid bone ingrowth (Alvarez and Nakajima, 2009). In Collagen and HAp are the most common organic and inorganic
a comparison study by Wang H. et al. (2019), porous Ta compounds in bone. Ma X. et al. (2016) prepared biomimetic
showed an equivalent biological performance with porous Ti in composite hydrogel for bone repair composed of collagen
repairing bone. Zhang and Lei’s groups reported that Ta-coated and HAp; alendronate (ALN), an anti-osteoporosis drug, was
porous Ti-6A1-4V scaffolds loading rabbit BMSCs exhibited also incorporated into this composite hydrogel. Chen et al.’s
better fusion efficacy than Ti-coated Ti-6A1-4V scaffolds in the (2018d) group prepared biphasic calcium phosphate/collagen
lumbar vertebral defects of rabbits (Wang F. Q. et al., 2018). porous composite scaffolds and incorporated dexamethasone
In another study by Kim’s group, the introduction of Ta on in this composite scaffold for bone tissue engineering. Han
the silicone surface could reduce fibrous capsule formation F. et al. (2019) prepared silk fibroin/octacalcium phosphate
(Park C. et al., 2019). composite scaffold for bone tissue engineering; the addition of
Biodegradable metals such as magnesium (Mg) and its alloys silk fibroin could improve the weak mechanical property and
have been attracting great attention in TERM due to their poor processability of octacalcium phosphate. Tanaka’s group
satisfactory mechanical property, biodegradation property, and found that the proliferation and alkaline phosphatase (ALP)
bioactive effect. Okuzu et al.’s (2017) group investigated the activity of MC3T3-E1 cells was enhanced when 10 wt% Zn
effect of Mg ions released from Mg–Ti alloy on MC3T3-E1 calcium phosphate was added to calcium phosphate cement
cell proliferation and osteogenic differentiation, and the results (Horiuchi et al., 2014). The combination of organic and inorganic
showed that Mg–Ti could promote early bone healing. In materials can enhance the mechanical properties. Kinsuk’s
another study, the Mg2+ and Si4+ ions released from Mg- group dispersed nHA particles into an electrospun solution
smectite can also promote skin regeneration (Sasaki et al., containing polyurethane/polydimethylsiloxane to prepare a
2017). However, Mg implant has too fast degradation rate to series of composite nanofibers with different mechanical
support completely healing the tissue before its degradation. properties (Drupitha et al., 2018). Ao et al. (2017) obtained
In addition, the H2 produced during the corrosion is also electrospun cellulose/nano-HAp nanofibers, whose Young’s
a problem. Therefore, many studies began to find ways to modulus and tensile strength were higher than commonly used
delay its degradation, including coating ceramic coating and polymer fibers such as PLA. In other work, calcium silicate and

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Han et al. Tissue Engineering and Regenerative Medicine in Asia

Mg silicate were also doped into electrospun fibers and enhanced et al. (2013) also showed potential application in TERM. The
the mechanical properties of these fibers (Wu Z. et al., 2016; urinary stem cells possess robust proliferative potential and
Su et al., 2017). The combination of organic and inorganic multi-potent differentiation potential (Zhang D. et al., 2014).
materials can also improve the bioactivity. Ruszymah’s group Recently, they reported the potential use of urinary stem cells
incorporated Zn oxide nanoparticles into chitosan–collagen in urinary tract reconstruction (Chen L. et al., 2017). Lee and
porous scaffolds, and the results showed that the incorporation Kwon groups reported that the neuronal differentiation of human
of Zn oxide nanoparticles could both enhance the mechanical urine-derived stem cells could be promoted by the presence
property and biocompatibility of porous scaffold (Ullah et al., of laminin and platelet-derived growth factor-BB (Kim J. Y.
2017). Prabhakaran and Ramakrishna’s groups also found that the et al., 2018). Wang and Wu’s groups found that the exosomes
incorporation of inorganic nanoparticles into polymer fiber could secreted by urine-derived stem cells could repair pubococcygeus
improve the bioactivity such as protein absorption (Esfahani muscle injury and improve stress urinary incontinence in rats
et al., 2015; Zhang S. et al., 2017). Nguyen Thi’s group coated (Wu R. et al., 2019).
electrospun PCL membrane with gelatin–silver nanoparticles; Takahashi and Yamanaka’s (2006) groups reported an induced
this composite membrane showed good antibacterial ability (Tra pluripotent stem (iPS) cell, which could express the marker
Thanh et al., 2018). Sun’s group also incorporated Ag nanowires genes of embryonic stem cells and exhibit properties similar to
into polyvinyl alcohol nanofibers for their antibacterial properties embryonic stem cells (Okita et al., 2007; Hamanaka et al., 2011).
(Zhang Z. J. et al., 2017). Jiang’s group coated gold nanoparticles With this method, Zeng and Zhou’s labs first generated several
with 6-aminopenicillanic acid, and then these particles were iPS cell lines that could meet the most stringent criteria for
added into electrospun fibers of PCL/gelatin fibers against pluripotent stem cells and maintained a pluripotent potential
bacteria (Yang X. L. et al., 2017). Tang’s group prepared nano- close to embryonic stem cells (Zhao et al., 2009). In another
TiO2 /collagen–chitosan porous scaffold, with the addition of study, when the somatic cells were exposed to transcription
TiO2 , and the mechanical properties, resistance to degradation, factors (Oct3/4, Sox2, Klf4, and c-Myc), iPS cells were formed
and antibacterial ability were all improved (Fan et al., 2016). with pluripotency (Takahashi and Yamanaka, 2006). However,
Jayakumar’s group fabricated chitosan hydrogel/nano-ZnO reactivation of the c-Myc retrovirus with this method can
composites; these nanocomposite bandages enhanced wound increase tumorigenicity and hinder its clinical applications.
healing by promoting faster re-epithelialization and collagen In their further study, they developed a modified approach
deposition (Sudheesh Kumar et al., 2012). for the generation of iPS cells that avoid the use of Myc
retrovirus (Nakagawa et al., 2007). Other strategies to induce
Cell Sources reprogramming with quicker action or reducing risk of tumor
Cell sources are one of three important factors in TERM. Until formation are also developed. Subsequently, iPSCs have been
now, identifying and acquiring sufficient numbers of cells for successfully obtained from different species, including humans,
application in therapeutics remain a challenge (Mao and Mooney, rats, and rhesus monkeys (Okita et al., 2007; Liu et al., 2008; Kang
2015). Various stem cells, progenitor cells, and adult tissue- et al., 2009; Hamanaka et al., 2011).
derived cells are widely being investigated in TERM, among In addition, compared with in vitro reprogramming, direct
them adult tissue-derived cells are the dominant cell type used in vivo reprogramming by retroviral injection has greater
in clinic because of their ready availability and perceived safety efficiency, due to avoiding the steps of in vitro culture and
(Fisher and Mauck, 2013). transplantation (Sadahiro et al., 2015). In vivo, the induced
Stem cells are still the frontline in TERM, because they efficiency is different with in vitro, because transcription factors,
have indefinite cell division potential and multiple differentiation epigenetic factors, microRNAs, secreted molecules, and cellular
potential (Mahla, 2016). MSCs isolated from various tissues microenvironment are all important for cell fate specification.
including bone marrow, adipose tissue, blood, and amniotic fluid A work done by Deng and Ding’s labs reported that appropriate
have potential uses in TERM (Fontaine et al., 2016; Schäfer chemical cocktails were needed to add into the medium of
et al., 2016; Bertheuil et al., 2019). The summary of stem cell pluripotent rat cells to maintain their characteristics (Li W. et al.,
used in TERM is shown in Table 1. Except for the above stem 2009). This work also underscores the combined importance
cells, several new stem cells also show potential application of the fibroblast growth factor (FGF), WNT, and transforming
in TERM. Menstrual blood-derived stem cells (MenSCs) were growth factor-β (TGF-β) pathways in regulating pluripotency
discovered by Meng et al. (2007) and Cui et al. (2007) a decade in different species. To improve direct reprogramming, the
ago. Since its discovery, more studies have been focused on strategies that combine reprogramming with morphogens could
MenSCs. The representative advantages of MenSCs compared potentially be adapted for inducing cells into target cells.
with other six sources of MSCs are the higher proliferation rates, A variety of cells, including cardiomyocytes, vascular cells,
painless procedures, and almost no ethical issues (Khoury et al., hepatocytes, neural cells, and pancreatic cells, have been obtained
2014; Zhao et al., 2018). Moreover, Xiang’s group proved that from both direct reprogramming and iPS cell differentiation
MenSC-derived exosomes could inhibit hepatocyte apoptosis in methods (Table 2).
D -galactosamine and lipopolysaccharide-induced FHF in mice
(Chen L. et al., 2017). They also found that MenSC can treat Enabling Technologies for TERM
Alzheimer’s disease and acute lung injury (Xiang et al., 2017; The rapid development of TERM is inseparable from
Zhao et al., 2018). Urinary stem cells discovered by Bharadwaj research and development of new technologies. As tissue

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Han et al. Tissue Engineering and Regenerative Medicine in Asia

TABLE 1 | Examples of MSC used in tissue engineering and regenerative medicine in Asia.

Cells Disease Mode of stem cell application References

Bone marrow Bone injury 1. BMSC and endothelial progenitor cell mixture for large segment of bone defect Peng et al., 2019
stem cell 2. Calcitonin-related gene-modified rat BMSCs for skull defect Yu et al., 2019
(BMSC) 3. Repair of oligo(poly(ethylene glycol)fumarate) hydrogels seeded with BMSCs for Lim et al., 2013
repairing osteochondral defects
Cartilage injury 1. Reconstruction of human-ear-shaped cartilage by co-culturing chondrocytes Zhang L. et al., 2014
with BMSCs
2. In vitro engineered cartilage based on autologous BMSC He et al., 2017
Spinal cord injury 1. BMSC-derived extracellular vesicles to repair spinal cord injury Lu Y. et al., 2019
2. Exosomes derived from BMSCs repair traumatic spinal cord injury Liu W. et al., 2019
Lung injury 1. Mice BMSCs were injected into mice via the tail vein to treat acute lung Feng et al., 2019
2. BMSC transplantation to treat smoke inhalation injury Liang et al., 2019
Liver cirrhosis Autologous BMSCs transplantation in human Rajaram et al., 2017
Severe Asherman GFP-labeled BMSCs was injected systemically through the tail vein in rat Gao L. et al., 2018
syndrome
Intrauterine adhesion BMSC-loaded elastic poly(glycerol sebacate) scaffold Xiao et al., 2019
Hearing loss BMSC transplantation recovery functional restoration of mouse cochleae Kada et al., 2019
Peripheral nerve injury BMSC-derived acellular matrix-coated chitosan/silk scaffold Xue et al., 2017
Type 2 diabetes Autologous BMSCs transplantation in human Wang et al., 2011; Bhansali
et al., 2014
Adipose Osteoarthritis ADSCs with hyaluronic acid were intra-articularly injected into the knee Kuroda et al., 2015
mesenchymal Cartilage injury 1. ADSC/hyaluronic acid (HA)-modified thermoresponsive Wang C. Z. et al., 2018
stromal cell poly(N-isopropylacrylamide) hydrogel
(ADSC) 2. Controlled chondrogenesis from ADSC by recombinant transforming growth Zheng et al., 2015
factor-beta 3 fusion protein in peptide scaffolds
Bone injury MiR-135-modified ADSC Xie et al., 2016
Intervertebral disc injury ADSC-derived tissue-engineered construct Ishiguro et al., 2019
Stricture after extended ADSC-sheet transplantation Perrod et al., 2017
esophageal endoscopic
submucosal dissection
Urethral defect Polylactid acid fibrous membrane seeded with ADSC Wang D. J. et al., 2015
Atrophied muscle Autologous ADSCs transplantation Park and Kwon, 2017
Type 2 diabetes Autologous ADSCs transplantation Qi et al., 2019

TABLE 2 | Summary of direct reprogramming by lineage-specific transcription factors.

Original cells Reprogramming factors Induced cells

Oct4/Sox2/Klf4/c-Myc (mouse and human) Pluripotent stem cell

1. Brn2/Ascl1/Myt1l (BAM) (mouse) Excitatory neuron
2. BAM/NeuroD1 (human)
BAM/Lhx3/Hb9/lsl1/Ngn2 (mouse) Motor neuron
Ascl1/Nurr1/Lmx1a (mouse and human) Dopaminergic neuron
Fibroblast Sox2 (mouse and human) Neural stem cell
1. Hnf4a/Foxa1 (mouse) Hepatocyte
2. Hnf1a/Hnf4a/Hnf6/Atf5/Prox1/Cebpa (human)
Erg/Gata2/Lmo2/Runx1c/Scl (mouse) Hematopoietic progenitor cell
Foxo1/Er71/Klf2/Tal/Lmo2 (mouse) Endothelial cell
Gata4/Mef2c/Tbx5 (mouse) Cardiomyocyte
MyoD Skeletal myocyte
Exocrine cell 1. Neurogenin3/Pdx1/Mafa (mouse) Pancreatic β-cell
2. Epidermal growth factor/ciliary neurotrophic factor (mouse)
Myeloid cell Run1t1/Jlf/Lmo2/Prdm5/Pbx1/Zfp37 Hematopoietic stem cell

BAM indicates Brn2, Ascl1, and Myt1l.

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Han et al. Tissue Engineering and Regenerative Medicine in Asia

engineering advances, new technologies, such as 3D printing Functional vascular with perfusion performance could also
and microfluidics, have attracted a lot of attention for preparing be prepared using bioprinting cells and biological matrices
materials or scaffolds. To obtain suitable cells for TERM, (Lee et al., 2014b). This perfusable vascular can support the
cell sheet and genome engineering have also been widely viability of tissue up to 5 mm in distance. Du et al. (2015)
explored. To construct mature tissues/organs for in vivo prepared BMSC-laden microfibers immobilized with BMP-2 by
implantation, a variety of bioreactors have been developed. In bioprinting. These prepared CBD-BMP-2-collagen microfibers
addition, microfluidics and organ-on-a-chip were also effective induced osteogenic differentiation of BMSCs within 14 days more
technologies for TERM. efficiently than the osteogenic medium. Jia et al. (2016) directly
printed perfusable vascular constructs using a mixed bioink,
3D Printing composed of GelMA, sodium alginate, and 4-arm poly(ethylene
One of the developments for preparing tissue-engineered glycol)-tetra-acrylate. These constructs could support the growth
constructs is bioprinting. Bioprinting is an effective method to of encapsulated endothelial and stem cells. Finally, highly
fabricate tissue-mimicking constructs through patterning cells, organized and perfusable vessels could be obtained. Jang
biomaterials, and biomolecules (Arslan-Yildiz et al., 2016; Tasnim et al. (2017) prepared a stem cell patch with pre-vascularized
et al., 2018; Matai et al., 2020). The 3D bioprinting of cells, growth and functional multi-material structures by 3D printing using
factors, and hydrogels is mainly based on laser (Ali et al., 2014), bioink consisting of cell-laden decellularized ECM (dECM),
droplet (Cui et al., 2014), and extrusion (Iwami et al., 2010) which promoted rapid vascularization after transplantation and
bioprinting. Bioprinting greatly promoted the development of enhanced the therapeutic efficacy for cardiac repair. This method
skin tissue engineering. Fu’s group prepared 3D-ECM through was applied in many tissues including adipose, cartilage, and
3D bioprinting (Huang et al., 2016). The created 3D-ECM heart. The use of tissue-specific dECM in this process promised
could direct cell differentiation and promote functional skin high cell viability and functionality (Pati et al., 2014).
regeneration (Huang et al., 2016). They also developed different Chang et al. (2010) fabricated a 3D liver micro-organ by the
bioinks to regulate the property of stem cell (Li Z. et al., combining direct cell writing bioprinting process with micro-
2018; Wang R. et al., 2019). Recently, Park’s group prepared patterning techniques; this liver model could act as an in vitro
a hybrid bioink composed of bioactive peptide-immobilized model for drug metabolism. Scientists from Japan fabricated a
acrylated HA and tyramine-conjugated HAs (Lee J. et al., 2018). liver model using the system “PLUTO.” The 3D-printed liver
Results demonstrated that MSCs in these hybrid bioinks had assisted the minor hepatectomy following liver partition (Igami
high angiogenic and osteogenic activity. Bioprinting technology et al., 2018). In hepatectomy for a small tumor that is invisible
is also used to prepare a skin model in vitro. Kim et al. (2017) to intraoperative ultrasonography, the application of 3D-printed
printed a 3D human skin model with a functional transwell liver makes the procedure easy and feasible (Igami et al., 2014).
system. Maturation of the skin model could be achieved with Besides, 3D printing can also be used in fabricating other tissues.
the support of printed PCL constructs (Kim et al., 2017). Kim’s Scientists from South Korea and India printed a kidney, heart,
group and Cho’s group also used skin-derived ECM as a bioink and tooth, which presented the applications of 3D printing in
to fabricate a full thickness 3D skin, and the matured bioprinted regenerating heterogeneous organs and tissues to treat specific
skin tissue was significantly contracted during in vitro culture defects or injuries (Jung et al., 2016; Mishra, 2016).
(Kim B. S. et al., 2018).
With this new method, a series of studies in which different Cell Sheet Technology
materials (alginate, fibrin, gelatin, etc.) were performed to Cell sheet technology is a scaffold-free approach that has
construct various tissues/organs (liver, adipose tissue, nerve, and great potential in TERM (Kobayashi et al., 2019; Li M. et al.,
so on) (Yang et al., 2013; Jung et al., 2016; Mishra, 2016; Igami 2019). Compared with traditional cell therapies (cell suspension
et al., 2018; Liu F. et al., 2018). Other researchers also fabricated injection or cells/scaffold construct), cell sheet technology
many kinds of cell/material complexes. Patterning of Sf-9 cell enables transplanted cells to stay completely in the target sites
tissue was achieved using a mixture of cells and thermoreversible and fully maintain their viability. Since Okano’s group first
hydrogel (Iwami et al., 2010). Engineered human cartilage was devised a scaffold-free method of constructing cell sheets using
prepared using an inkjet printer by printing poly(ethylene glycol) thermoresponsive poly(N-isopropylacrylamide)-grafted surfaces,
diacrylate (PEGDA) containing human chondrocytes (Cui et al., this technology has been applied to the regeneration of a
2014). Gao G. et al. (2017) developed a 3D cartilage using variety of tissues (Takezawa et al., 1990; Sekine et al., 2013). In
bioprinting and simultaneous photopolymerization. This printed addition, it has also been used in cell micropatterning, cell co-
cartilage showed excellent production of glycosaminoglycan and culture, and drug discovery (Hannachi et al., 2009; Takahashi and
collagen type II. In the ear reconstruction field, bioprinting is also Okano, 2019). Compared to other tissue engineering techniques,
widely used. For example, a tissue-engineered ear was prepared one of the major advantages of cell sheet is the absence of
by printing PCL, cell-laden hydrogel, and sacrificial polyethylene potential material degradation-associated cytotoxicity. Different
glycol (PEG) layer (Lee et al., 2014a). The chondrocytes and methods have been developed to prepare cell sheets, including
adipocytes differentiated from ADSCs were encapsulated in thermo-responsive systems, electro-responsive systems, photo-
hydrogel and distributed to the regions of cartilage or fat, responsive systems, pH responsive systems, magnetic responsive
respectively. The hydrogel could promote both chondrogenesis systems, and so on (Inaba et al., 2009; Chen et al., 2012; Hong
and adipogenesis of encapsulated ADSCs. et al., 2013; Pan et al., 2013; Zhang W. et al., 2017; Koo et al., 2018;

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Han et al. Tissue Engineering and Regenerative Medicine in Asia

Li M. et al., 2019). Li’s group reported several new methods for The safety of technology is the primary issue to be
cell sheet preparation (Pan et al., 2013; Guo B. et al., 2015). considered (Pineda et al., 2019). One of the safety concerns
Compared with physical absorption and covalent immobilization for CRISPR technology is unforeseen genetic, which may
approaches, the method through thermo-responsive specific bring unpredictable physiological changes or even death to
binding RGD in the imprinted hydrogel not only promoted patients. The off-target genomic and cellular events are also
cell adhesion during cell culture but also facilitated cell scientists’ concerns. In addition, mutations in vital genes
detachment during cell sheet harvest (Pan et al., 2013). In the could cause cancer or the damage of organs. Hence, the
electricity-induced method and magnetic method, electricity- safety evaluation for CRISPR technology needs to advance
responsive thiol layers and pH-responsive layers have been in parallel with CRISPR technologies. To improve the safety
designed to harvest cell sheets, respectively (Hong et al., 2013; and efficiency of CRISPR/Cas9 gene-editing elements, Leong’s
Koo et al., 2018). groupreported an efficient CRISPR/Cas9 delivery system
Cell sheet technology has been applied to treat damaged comprising PEGylated nanoparticles based on poly (γ-4-((2-
tissues including bone, articular cartilage, corneas, periodontal (piperidin-1-yl)ethyl)aminomethyl)benzyl-L-glutamate) for
ligaments, blood vessels, and the myocardium (Takezawa et al., delivering Cas9 expression plasmid and sgRNA (Wang H. X.
1990; Sekine et al., 2013). Yang et al. (2007a) focused on et al., 2018). This CRISPR/Cas9 delivery system could reach
using temperature-responsive surfaces to harvest cell sheets, 47.3% gene editing efficiency in single or multiplex gene editing
and their applications in corneal dysfunction, tracheal resection, in vitro, achieve 35% gene deletion in HeLa tumor tissue,
esophageal cancer, and cardiac failure. They have also created suppress the tumor growth by >71%, and prolong the animal
thick vascularized organ-like systems for the heart and liver survival rate to 60% within 60 days. Peng’s group analyzed the
based on cell sheet. To construct 3D tissues, some studies function and structure of two archaeal anti-CRISPR proteins
tried to prepare multilayered cell sheets. Most multilayered cell (Acrs) from the lytic rudiviruses, SIRV2 and SIRV3 (He et al.,
sheets were fabricated by layer-by-layer stacking individual cell 2018). Tan’s group developed a Cas9 variant whose activity can
sheet using a gelatin gel plunger or forceps (Haraguchi et al., be switched on or off in cells by 4-hydroxytamoxifen; this Cas9
2012; Ren et al., 2014). Furthermore, 3D tissues can also be variant showed high gene editing efficiency and could reduce 437
constructed via this protocol. At present, the cell sheet technique off-target cleavage (Liu et al., 2016). Dong et al. (2017) revealed
has already been applied to human clinical trials for regenerating the mechanism of SpyCas9 inhibition by AcrIIA4, which make
heart, cornea, blood vessels, periodontal membrane, esophagus, it possible to develop “off-switch” SpyCas9 systems to avoid
cartilage, functional tendons, and middle ear (Egami et al., 2014; unwanted genome edits within cells and tissues.
Yamamoto et al., 2017). For example, Yamamoto et al. (2017)
developed a novel treatment method to regenerate the middle Microfluidics
ear mucosa by tympanoplasty and autologous nasal mucosal In the past two decades, various cell microencapsulation
epithelial cell sheet transplantation. All patients showed good technologies have been developed (Alkayyali et al., 2019).
regeneration result with no adverse complications and adverse Cells encapsulated in microbeads or microfibers could be
effect on the patients’ hearing ability. Cell sheets composed of prepared by changing microfluidic devices or materials. The
corneal epithelial cells or autologous oral mucosal cells could flexibility of microfluidic technology allows the preparation
also repair severe corneal injury in patients (Nishida et al., 2004). of multi-structured fibers such as hollow, multilayer, grooves,
In another study, transplantation of multilayered cell sheets etc. Yu et al. (2017) prepared alginate helical microfiber
composed of patients’ periodontal ligament derived MSCs was with complex structures such as Janus, triplex, core–shell,
proved to promote regeneration of the periodontal and bone and even double-helix based on rapid ion cross-linking
(Iwata et al., 2015). through microfluidic devices. In recent years, the application
of microfluidics in cell-laden droplet production and single-
Genome Editing cell encapsulation has been reviewed (Zhu and Yang, 2017;
Recent advances in genomic technology and genome Alam et al., 2018; Alkayyali et al., 2019; Shen et al., 2019).
engineering make it possible to modify the genome in Zhao’s group prepared uniform microfibers by simple injection
cells. A great progress of genome editing technologies, the capillary microfluidics, core–shell or spindle-knot structured
CRISPR/Cas system (Komor et al., 2017; Kim, 2018), can microfibers by hierarchical injection capillary microfluidics,
directly modify the genome. Therefore, this technology and microfibers with multiple components by multi-barrel
can be used to systematically dissect the functional effect injection capillary microfluidics (Wang J. et al., 2017; Yu
of genetic variants. Recently, there is much work done by et al., 2017; Yu Y. et al., 2018). A cell microcarrier with
Asian researchers (Duan et al., 2014; Liang et al., 2015; Kang controllable macropores and heterogeneous microstructures
et al., 2016; Xue et al., 2016). Gao et al. (2016) determined could also be fabricated by a capillary array microfluidic
the mechanism of CRISPR-Cpf1 system, by analyzing the technology (Wang J. et al., 2017). These microcarriers with
structure of Acidaminococcus sp. Cpf1 in complex with spatially heterogeneous cell encapsulations may be used for
crRNA and target DNA. Recently, Zhou et al. (2018) mimicking physiological structures of nature tissues or organs.
improved the Cas9 system to be much precise and could Lee’s group encapsulated Escherichia coli (E. coli) in PEGDA
simultaneous activate multiple genes and long noncoding RNAs microdroplets using a microfluidic device (Lee K. G. et al., 2010).
in the nervous system. This encapsulated E. coli may be used in biotransformation,

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Han et al. Tissue Engineering and Regenerative Medicine in Asia

bioremediation, biosensing, and artificial cells. Jia et al. (2019b) Bone

prepared biomimetic cell-laden helical hydrogel microfibers Mechanical stimulus is one of the most important physical
as blood-vessel-on-chip using alginate based on microfluidics stimuli for bone, which is known to regulate the osteogenic
methodology. This hollow microfiber had decent perfusability differentiation of MSCs and other osteogenic precursor cells.
and could generate swirling blood flow to provide a platform for However, the various modes of stimuli showed different effects
mimicking nature swirling blood flow. Except cell encapsulation, on osteogenesis. For example, cyclic mechanical tension inhibited
the applications of microfluidics in single molecule/cell culture Runx2 expression in MSCs through the RhoA-ERK1/2 pathway
and analysis (Zhu and Yang, 2017), cell sorting (Shen et al., 2019), (Shi et al., 2011). In a study, 1 Hz cyclic mechanical stretch for
continuous cell separation (Yan et al., 2017), and orthopedics 30 min (twice a day) could enhance osteogenic differentiation of
(Wang L. et al., 2019) were also reported in some reviews. BMSCs and restrain osteoclastogenesis of RAW264.7 cells in vitro
(Guo Y. et al., 2015). In another study, 2 h of cyclic stretch of 2.5%
elongation at 1 Hz on 3 days significantly decreased osteogenesis
Organ-on-a-Chip of adult MSCs by the increased reactive oxygen species (Tan
Bridging the gap between findings in 2D cell culture in vitro et al., 2015). The mechanical stretch could also affect antioxidant
and 3D tissue culture condition in vivo has been a challenge. 3D responses and osteogenic differentiation in human MSCs
printing and microfluidic devices also offer great development through activation of the adenosine 50 -monophosphate-activated
of an in vitro model in TERM, organ-on-a-chip (Kim et al., protein kinase–Silent mating type information regulation 2
2013; Bang et al., 2017; Lee and Jun, 2019; Mobini et al., 2019; homolog-1 (AMPK-SIRT1) signaling pathway (Chen et al.,
Ranjith Kumar et al., 2019; Sun W. et al., 2019). Jeon’s group 2018b). Additionally, exercise can strengthen bones (Niinimaki,
reported several work in this field (Kim et al., 2013; Bang et al., 2012). Exercise was proved to inhibit bone loss in ovariectomized
2017). They constructed a low-permeability blood–brain barrier rats (Bu et al., 2012). The expression of Runx2 was reported to
platform by microfluidics (Bang et al., 2017). Using this platform, gradually increase under strain stimulation (Li C. J. et al., 2015; Li
co-culturing human umbilical vein endothelial cells and neural R. et al., 2015). The same result was also found in another study
cells with independent culture medium could be easily realized. in rats (Notomi et al., 2014). In conclusion, suitable exercise may
In another work, they modeled natural cellular programs through promote osteogenic differentiation of MSCs by upregulating the
a microfluidic-based platform, and using this platform, they expression of key molecules in Wnt signaling pathway.
could spatially control co-culture of endothelial cells with stromal
fibroblasts, pericytes, or cancer cells (Kim et al., 2013). The lab- Tendon and Ligaments
on-a-chip devices were also used to construct ex vivo models Mechanical stimuli play an important role in regenerating or
for neural tissue engineering (Mobini et al., 2019). The group repairing tendons and ligaments. Mechanical stimuli can enhance
of He fabricated 3D hydrogel-based vascular structures with cell proliferation and tenogenic differentiation of tendon-derived
macrochannels (Gao Q. et al., 2017). These 3D hydrogel-based stem cells (TDSCs). In a study, the TDSCs-poly(LLA-CL)/Col
vascular structures could be further integrated into organ-on- scaffolds were stretched at 4% elongation, 0.5 Hz, and 2 h
chip devices to better simulate the microenvironment of blood per day for 14 days, the mechanical stimuli could promote
vessels. In addition, the organ-on-a-chip also has great potential formation of tendon tissues after the implantation of TDSCs-
in preclinical testing of drugs (Ranjith Kumar et al., 2019). poly(LLA-CL)/Col scaffolds in nude mice (Xu et al., 2014). This
result showed that dynamic mechanical stimulus was helpful for
the maturation of tissue-engineered tendon in vivo. In another
study, the mechanical stretch (10% elongation for 48 h, 10
Mechano-Regulation in TERM cycles/min, each cycle containing 2 s of stretch, and 2 s of
The organism in a complex mechanical system consists of relaxation) accelerated the healing of tendon–bone by promoting
external and internal forces. Cells, tissues, and even organs are proliferation and matrix production of MSCs and tendon cells
stimulated by mechanical stimuli of different intensity, frequency, (Song et al., 2017). However, there was also a report that the cyclic
and direction. Mechanical stimuli regulate cell function by stretch could induce apoptosis of human periodontal ligament
affecting gene expression and protein synthesis in cells and cells via a caspase-dependent pathway (Chen J. et al., 2016; Wu
then regulate cell differentiation, growth, and development of Y. et al., 2016; Zhao D. et al., 2017). In another study, the cyclic
organisms. Therefore, mechanical stimuli also play an important tensile promoted BMP-9 synthesis and in vitro mineralization in
role in TERM. This unique form of mechanical force is regulated human periodontal ligament cells (Tantilertanant et al., 2019).
in real time by a variety of factors, such as exogenous force, motor The study of mechanical stimuli on tendon/ligament repair has
proteins, osmotic pressure, mechanosensitive ion channels, been extensively studied with variable degrees of efficacy. In
intracellular mechanosensors, and actin assembly. Traditional the future, synergistic therapies for tendon/ligament repair and
approaches in cellular mechanobiology include loading tissues regeneration may be created by combining mechanical loading
or organ culture in vivo, or loading cells in monolayer with biochemical cues.
and scaffolds in vitro at various modes, magnitudes, and
frequencies of mechanical stimuli. In the past decades, the field Cartilage
of mechanoregulation of tissue engineering and regeneration Due to its avascular nature and limited proliferative potential
medicine has witnessed tremendous progress in Asia. of mature chondrocytes, cartilage only has limited intrinsic

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Han et al. Tissue Engineering and Regenerative Medicine in Asia

regeneration ability. Mechanical stimuli have been shown to pulposus (NP) cell, but increased TUNEL-positive cells and
affect the gradient of nutrient and ion, pH, cell deformation, apoptosis index (Kuo et al., 2014). Moreover, this effect is in
bioactivity, and synthesis of ECM components or growth a dose-dependent manner. It was thought that the intrinsic
factor (Bleuel et al., 2015). Different levels of shear stress (mitochondrial) apoptotic pathway played an important role
could affect the expression of inflammatory stimuli-induced in compression-induced NP cells apoptosis. Further research
genes in chondrocytes through macrophage-induced c-Jun showed that the dynamic compressive load reduced the density
N-terminal kinase and Akt phosphorylation, nuclear factor and viability of NP cells. The localization and mRNA expression
κ-B activation, and urokinase plasminogen activator expression of integrin α5β1 were increased in both NP and annulus fibrosus
(Yeh et al., 2013). The compressive stress may promote (AF) under dynamic mechanical stimuli. Dynamic compression
chondrogenic differentiation by increasing the activity of load (1.3 MPa, 1.0 Hz) also showed a catabolic effect, and the
TGF-β1 and regulating the downstream targets of TGF-β expression of matrix metalloproteinase-3 and metalloproteinase-
signaling. It was reported that Smad pathways would be 13 in NP and AF cells would be regulated by dynamic mechanical
involved in the conversion of mechanical stimuli into biological stimuli (Kurakawa et al., 2015).
responses (Li J. et al., 2012). While the physiological level of
mechanical stimuli helps the maintenance of healthy tissues, Blood Vessels
excess mechanical stimuli result in damage of tissues. Koike The mechanical stimuli also play an important role in blood
et al. (2015) demonstrated that excess mechanical stimuli vessels. The suitable cyclic stretch also induced vascular
promoted mitochondrial superoxide generation and caused remodeling by promoting VSMC proliferation. In a study,
imbalance of superoxide dismutase 2 in chondrocytes, which the physiological cyclic stretch promoted the contractile
would result in cartilage degeneration. Recently, Iran researchers differentiation of VSMCs via the SIRT1/FOXO pathways and
constructed a new microdevice used to study chondrogenesis thus maintained vascular homeostasis (Huang et al., 2015).
under unidirectional compressive stimulus of cells in a 3D cell Mechanical stretch-induced endoplasmic reticulum stress could
culture condition (Kowsari-Esfahan et al., 2018). The results also promote the apoptosis, inflammation, and degeneration of
showed that the dynamic mechanical compression enhanced cell VSMCs (Jia et al., 2015).
viability and upregulated the expression of Sox-9, collagen II, and
aggrecan in the absence of exogenous growth factors. Moreover,
10% strain was considered as optimal mechanical stimulus for APPLICATIONS OF TERM IN DIFFERENT
chondrogenic differentiation of ADSCs. TISSUES
Cardiac Tissue Cartilage
Regenerating the beating heart is still a formidable The repair and regeneration of cartilage, such as ear and
bioengineering challenge. The pumping action of the heart joint, are still associated with various limitations and degrees
requires mechanical forces to compress a blood-filled chamber of success (Bauer, 2009; Lee T. S. et al., 2010; Tang et al.,
with a defined in- and outlet. It is widely accepted that mechanical 2017). TERM provides us a new way to construct engineered
loads are important in the development and morphogenesis cartilage substitutes, which could match both the function
of cardiac tissue. In a study, it was demonstrated that fluid and appearance of native ears (Peer, 1954; Watson, 2009).
shear stress would affect cardiomyogenic differentiation of By combining suitable cell source with scaffolds, engineered
rat BMSCs (Huang Y. et al., 2010). Zhang W. et al. (2017) cartilage constructs could replace injured tissues. Since 1997,
prepared cardiac muscle strips by encapsulating cardiomyocytes Cao and colleagues have used engineered cartilage to treat
derived from human embryonic stem cells in collagen-based cartilage diseases. They found that both component and
biomaterials. The results demonstrated that the mechanical structure of the scaffolds would affect cartilage regeneration.
stretch could promote the maturation of human embryonic Cao and Zhou’s groups successfully regenerated ear-shaped
stem cell-derived cardiomyocytes. Cyclic biaxial tensile strain cartilage combining electrospun gelatin/PCL membranes and
promoted the differentiation of BMSCs into cardiomyocyte-like cells (Zheng R. et al., 2014). Further, they successfully regenerated
cells by miRNA-27a (Cao et al., 2018). subcutaneous cartilage using BMSCs directed by chondrocyte
sheet (Li et al., 2017). Liu and Zhou’s groups created a human-
Intervertebral Disc ear-shaped cartilage tissue by seeding the microtia chondrocytes
Intervertebral disc (IVD) not only absorbs the mechanical and BMSCs into the ear-shaped biodegradable scaffold and
load but also maintains multi-axial flexibility of the spine. subcutaneously implanting them into nude mouse, which
The mechanical disorder of IVD will ultimately cause tissue provides a promising strategy to construct stable ectopic cartilage
dehydration, fibrosus, nerve, and vessel ingrowth, and disc (Zhang L. et al., 2014). He and Fu’s groups fabricated the
degeneration (Chu et al., 2018; Li and Chen, 2019). For instance, ear tissue using a method named scanning printing polishing
the increasing frequency and amplitude of dynamic compress casting. They designed a mold according to the 3D scanner
would contribute to higher cell density, because dynamic of ear and generated ear tissue by casting medical grade
compression facilitated the diffusion of nutrients around IVD silicone to the mold. This strategy provided a method that
cells (Zhu et al., 2012). But another study showed that static has a lower cost than the current soft prostheses fabrication
compression significantly decreased the density of nucleus methods (He et al., 2014). Cho’s group generated an artificial

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Han et al. Tissue Engineering and Regenerative Medicine in Asia

ear containing auricular cartilage and fat tissue using 3D favorable results (Park Y. B. et al., 2019). In a clinical trial,
printing technology. In this process, ADSCs were differentiated they successfully regenerated articular cartilage in the defects
to chondrocytes and adipocytes, and then encapsulated in of osteoarthritis patients, using a composite of allogeneic
hydrogel, respectively. The ear tissue was printed with PCL umbilical cord blood-derived MSCs and hyaluronate hydrogel
and cell-laden hydrogel to ear-shaped structures (Lee et al., (Park Y. B. et al., 2017).
2014a). Hwang et al. (2014) spray-coated a mixture of
chondrocytes and fibrin hydrogel on a human ear-shaped Skin
implant and implanted it into the dorsal subcutaneous space The development of artificial skin has attracted a lot of Asian
of athymic mice. The formation of neocartilage covered the researchers. Various skin wounds will be caused by burn,
implants after 12 weeks. freezing, surgical procedures, radiation, and chronic skin ulcers.
Successful regeneration of critical-sized cartilage defects The skin substitutes prepared by tissue engineering could be
in weight-bearing region remains a major challenge in clinic. used to promote acute and chronic skin wound healing (Tang
In the past decades, biomaterials aiming to repair cartilage et al., 2017). Several Asian research groups have made great
have been rapidly developed (Zhang Y. B. et al., 2019). efforts in skin tissue engineering. Jin’s group developed several
Zhang’s group developed injectable carboxymethylated multilayered skin substitutes (Zhu et al., 2008; Wang et al.,
pullulan/chondroitin sulfate hydrogel and collagen I/II 2009; Huang S. et al., 2010). For instance, they prepared a
composite hydrogel for cartilage tissue engineering (Chen tricopolymer scaffold consisting of collagen, chondroitin sulfate,
F. et al., 2016; Yuan L. et al., 2016). Yu’s group created and HA to mimic ECM of the skin (Wang et al., 2009).
chitosan microspheres to carry cells, and this system could Further, they also attempted different cell sources for skin
be used for cartilage tissue engineering (Zhou et al., 2016). repair, including BMSCs, melanocytes, keratinocytes, dermal
The chitosan microspheres showed an ECM-mimicking fibroblasts, human amniotic epithelial cells, human amniotic
nanofibrous structure and tunable size could be constructed mesenchymal cells, and adipose tissue-derived stem cells (Liu
into 3D-shaped cartilage-like composite in vitro. Collagen et al., 2007, 2014; Li H. et al., 2012; Lu et al., 2012; An et al.,
is a widely used material in cartilage tissue engineering. To 2015). Based on these works, Jin’s group first developed tissue-
improve the unmatched stiffness and rapid degradation rate engineered artificial skin in China. Fu’s group has constructed
of collagen, Lu Z. et al. (2019) conjugated biocompatible different skin substitutes by tissue engineering. A collagen-
carbon dot nanoparticles onto collagen to prepare an injectable based and cell-seed skin construct was prepared by culturing
hydrogel. This injectable composite hydrogel combined with sweat gland cells on gelatin microspheres and then combining
PDT enhanced chondrogenesis. To encapsulate chondrocytes them with collagen (Huang S. et al., 2010). This artificial skin
in scaffolds to promote cartilage regeneration, Wang C. Y. construct promoted skin repair and wound healing. Further,
et al. (2019) prepared an injectable cholesterol-enhanced they designed a skin scaffold with modifying spatial inductive
stereocomplex polylactide thermogel; the modification of cues by bioprinting, which could promote differentiation of
cholesterol on the 4-arm PEG-PLA could not only promote epidermal lineages into sweat glands (Huang et al., 2016). In
the preservation of morphology and biomechanical property addition, they also tried various cells for skin tissue engineering
but also promote cartilaginous gene expressions. Ding’s group (Li H.-H. et al., 2008, 2009). Ruszymah’s group did some
found that nanoscale spatial arrangement of RGD peptides studies on skin tissue engineering (Chowdhury et al., 2015;
could affect the dedifferentiation of chondrocytes (Li S. Y. et al., Law et al., 2016, 2017; Fauzi et al., 2019). They found that
2015). To realize the controlled chondrogenic differentiation, skin cells, keratinocytes, and fibroblasts showed different cellular
Wu’s group successfully regulated the anti-apoptotic gene and activities within collagen and fibrin constructs (Law et al.,
chondrogenic regulator using a double duration inducible 2016). Co-culturing keratinocytes with fibroblasts in the collagen
gene expression system (Ma Y. et al., 2016). Ouyang’s group scaffold could reduce the proliferation of fibroblast and collagen
successfully used chondrocyte-derived progenitor cells to contraction. In another study, they demonstrated that dermal
repair large knee cartilage defects of patients (Jiang et al., fibroblast conditioned medium promoted skin wound healing
2016). In another work by Ouyang’s group and Wu’s group, (Chowdhury et al., 2015). In addition, they found that plasma-
they used a silicate-based bioceramic scaffold with the ability derived fibrin could promote wound healing (Law et al., 2017).
to regulate cartilage and bone dual-lineage regeneration and Recently, they reported rapid repair of full-thickness skin injury
repaired the osteochondral defect (Bunpetch et al., 2019). using ovine tendon collagen I scaffold combining with skin cells
Recently, Fan and Wang’s groups constructed an acellular (Fauzi et al., 2019).
matrix microsphere as a scaffold for engineering cartilage (Liu Until now, different types of scaffolds, including the
J. et al., 2019). Park’s group and Min’s group used decellularized nanofibers (Xu et al., 2019; Yao et al., 2019; Zhang K. X.
porcine cartilage-derived ECM to fabricate scaffolds (Oh et al., 2019), hydrogels (Hsu et al., 2019; Muthuramalingam
et al., 2018). This ECM-derived scaffold could provide suitable et al., 2019; Patel et al., 2019), porous scaffolds (Wang et al.,
environments for chondrocyte growth. In another work, 2009), particles (Shi M. et al., 2019), decellularized bioscaffolds
they repaired human partial thickness cartilage defects using (Cui et al., 2019), and bioadhesives (Deng et al., 2019; Park
a cartilage ECM membrane that can deliver chondrocytes E. et al., 2019) have all been applied in skin repair. The
(Park et al., 2016). Ha’s group used human umbilical cord antibacterial conductive hydrogels fabricated by supramolecular
blood-derived MSCs to repair cartilage of rats and obtain assembly of PDA-modified silver nanoparticles, polyaniline, and

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Han et al. Tissue Engineering and Regenerative Medicine in Asia

polyvinyl alcohol could be used for epidermal sensors and and tailorable gradient capability. Lin’s group used a HAp–
diabetic foot wound dressings (Zhao Y. et al., 2019). A β-glucan- calcium sulfate–HA composite carrying collagenase to repair
based hydrogel significantly not only accelerated wound healing alveolar bone (Subramaniam et al., 2016). Dewi et al. (2015, 2017)
but also promoted the regeneration of skin appendages added calcium carbonate into plaster of Paris to improve the
(Muthuramalingam et al., 2019). To eliminate the undesired mechanical and degradable property of the bone substitutes. In
immune responses in practical use of chitosan–catechol in the addition, Wu’s group also prepared lithium-containing bioactive
clinic, a catechol-conjugated glycol chitosan adhesive hydrogel glass ceramic, which promoted angiogenesis for bone tissue
was proposed as an alternative and exhibited negligible immune engineering (Liu L. et al., 2019), and an injectable sodium
responses (Park E. et al., 2019). Another bioinspired adhesive alginate/bioglass composite hydrogel containing BMSCs for
derived from skin secretion of Andrias davidianus showed subchondral bone regeneration (Zhu et al., 2019). Kim and Yoo’s
stronger tissue adhesion strength than fibrin glue, which may groups first reported that immobilizing BMP-2 into hydrogel
be used for wound healing. Moreover, the elasticity and promoted osteogenic differentiation of human periodontal
biocompatibility of this adhesive were better than those of ligament stem cells (Park S. H. et al., 2017). Liu’s group promoted
cyanoacrylate glue (Deng et al., 2019). The addition of bioactive rapid bone regeneration by spatiotemporal delivery of BMP-2 or
substances, such as the grape-seed extracts containing rich interleukin-8 from scaffolds (Chai et al., 2017; Lin D. et al., 2019).
flavonoids with oligomeric proanthocyanidins, could promote Qin’s group designed a targeted delivery system that could release
wound healing (Ma et al., 2019). The multifunctional Zn- osteogenic phytomolecule icaritin to prevent osteoporosis in a
doped hollow mesoporous silica/PCL electrospun membranes bone-targeting manner (Huang et al., 2018). Wang’s group used
with good antibacterial activity were shown to enhance hair allogeneic mesenchymal stromal cell with low immunogenicity
follicle regeneration and wound healing (Zhang Y. et al., 2019). to construct bone substitutes and to repair bone defects in pigs
The electrospun poly(gamma-glutamic acid) fibrous scaffolds (Chen Q. et al., 2010; Ren et al., 2012). In addition, they also found
decorated with ginsenoside Rg3 could accelerate fibroblasts to the function of modulating immunity and inducing immune
sprout and grow, promote scar-free wound healing in vivo, tolerance of allogeneic mesenchymal stromal cells (Peng et al.,
and prevent hypertrophic scars (Xu et al., 2019). In a recent 2012). Likewise, growth factors such as BMP-2 and TGF-β1 and
study, researchers combined 3D printing of poly (L-lactide- vascular endothelial growth factor (VEGF) are also introduced to
co-caprolactone) scaffold with bioactive peptide hydrogel and scaffolds to enhance bone repair (Qu et al., 2015; Yan et al., 2016).
showed a good treatment modality in treating skin defects (Im Yang’s group developed PLGA/PCL scaffold modified by silver
et al., 2018). In a recent study, Koo et al. (2019) transplanted a impregnation, collagen coating, and electrospinning; this scaffold
three-layered cell sheet stacked by ROS-induced method which showed osteogenic and antimicrobial properties for orofacial
took only a short time. The results showed that the stacked cell tissue regeneration (Qian et al., 2019). Chua et al.’s (2004) group
sheet promoted angiogenesis and skin regeneration. prepared polyvinyl alcohol/HAp biocomposite by selective laser
sintering; this material showed good potential for craniofacial
Bone repair. Due to their cortical bone-like mechanical properties,
The aim of bone tissue engineering is to develop ideal bone biometals may become potent options for bone scaffolds. Among
substitutes (Shrivats et al., 2014). Generally, these substitutes them, Mg has attracted a lot of attention of researchers (Zhang
contain cells and should support cellular behaviors and guide et al., 2009; Lai et al., 2019). Dai’s group and Chang’s group
bone regeneration. Yanaga et al. (2006) made an attempt to use have prepared calcium Mg silicate bioceramic scaffolds and found
a composite of autologous human auricular chondrocytes with that the scaffolds enhanced angiogenesis in bone regeneration
autologous serum for craniofacial augmentation in a pilot clinical (Huang Y. et al., 2009; Zhai et al., 2012). Yang’s group evaluated
study. Otsu’s group revealed that neural crest-like cells from the in vivo degradation of Mg alloy implant and showed more
iPS cells could differentiate into osteoblasts and contribute to new bone tissues around the implant after 10 and 26 weeks
craniofacial bone regeneration without tumor formation in vivo post-implantation, while only causing little change to blood
(Kikuchi et al., 2018). This method could resolve the limitation composition (Zhang et al., 2009). They also developed various
of insufficient source of reconstructive material. Cui’s group metal implants for bone tissue engineering (Li Y. et al., 2016;
developed various scaffolds to mimic the natural bone ECM Zhang X. Z. et al., 2017). Qin’s group investigated the osteogenic
niche. They developed a nano-HAp/collagen/PLA composite capacity of Mg and found that PLGA/TCP porous scaffold
(Liao et al., 2004) or constructed a porous bone scaffold (Li incorporated Mg by 3D printing and had better repair result in
X. et al., 2006). They also added the mineralized collagen challenging bone defect (a 12-mm segment of ulna in rabbit)
into poly(methyl methacrylate) (PMMA) bone cement (Li T. (Lai et al., 2019).
et al., 2015). Now, they have developed a variety of artificial
bone repair materials, which acquired the product registration Cornea
certificate from the Chinese government. Cho’s group and Lee’s The development of corneal repair and regeneration is a
group prepared a synthetic scaffold with patient-customized pressing issue in TERM. Zhao X. et al. (2019) introduced gold
structure and mechanical properties for bone repair (Lee et al., nanoparticle-loaded microRNA-133b into collagen membrane.
2019). Aiming to repair bone defects with irregular shapes, These collagen membranes could rapidly repair corneas and
Wang L. H. et al. (2019) recently developed 3D super-elastic effectively inhibit scar formation. Hashimoto et al. (2019) realized
scaffolds based on electrospun SiO2 nanofibers with self-fitting the re-epithelialization and remodeling of rabbit decellularized

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Han et al. Tissue Engineering and Regenerative Medicine in Asia

corneal matrix, suggesting that this material may be a useful graft tissue-engineered corneal stroma. A cell-laden and orthogonal-
for corneal tissue regeneration. Developing a synthetic scaffold multilayer tissue-engineered corneal stroma facilitated the
with similar properties to native cornea remains a challenge. In construction of physiological feature tissue-engineered corneal
a study, the researchers developed elastomeric and biodegradable stroma and helped to reverse fibrosis pathologies in general
poly(glycerol sebacate)-PCL nanofibrous scaffolds and they show (Cui et al., 2018).
similar optical and mechanical properties with cornea (Salehi
et al., 2017). Choi et al. (2018) also used biofunctionalized
lysophosphatidic acid/silk fibroin film for corneal regeneration; Nerve
this film showed higher specific gene and protein expression The regeneration of traumatic and degenerative central or
of cornea endothelial cells. Lee H. J. et al. (2018) used an peripheral nervous system (CNS or PNS) injuries is still a
in situ forming corneal stromal substitute based on collagen big challenge. The CNS of adult mammalian is difficult to
type I, after encapsulating keratocytes; this substitute exhibited regenerate by itself, while the PNS only has limited axonal
surface epithelialization with multilayered morphology when regeneration ability (Gu et al., 2011). Tissue-engineered neural
implanted to rabbit corneas in an organ culture model after scaffold may help to repair SCI or brain injury. Li’s group
keratectomy. The researcher also tried to use short collagen- developed a neurotrophin-3 (NT-3)-containing chitosan-based
like peptides (CLPs) to replace collagen in corneal tissue scaffold, which could promote axon regeneration and functional
engineering. They found that CLP-modified implants promoted recovery of SCI or brain injury (Li et al., 2009; Mo et al., 2010).
stable regeneration of corneal and nerve tissues in a mini-pig In another work, NT-3-containing chitosan-based scaffold could
model (Jangamreddy et al., 2018). Cells were used to promote elicit activation of endogenous NSCs, enhance neurogenesis
corneal regeneration. For example, Yamashita et al. (2018) found and vascularization, and reduce inflammatory responses, thus
that MSCs derived from human umbilical cord transplanted improving the recovery of sensory and motor behavior (Duan
into a rabbit could maintain the thickness and transparency et al., 2015; Yang Z. et al., 2015). Recently, they have obtained
of cornea. Cell sheets are also used to repair cornea. Okano’s good repair results using the NT-3-containing chitosan scaffold
group successfully regenerated cornea in rabbit by transplanting in monkeys after SCI (Rao et al., 2018). Dai’s group developed
corneal epithelial cell sheets prepared with automated cell culture collagen-based neural scaffold to promote axonal and spinal
system (Kobayashi et al., 2013). Later, they reported a novel cord regeneration in canine and rodent models (Duan et al.,
cell culture device for preparation of corneal epithelial cell 2015; Li X. et al., 2015). They also combined scaffold with
sheets (Nakajima et al., 2015). Fujita’s group transplanted an BMSCs to construct a collagen/BMSCs construct, which showed
autologous corneal epithelial cell sheet in corneal injury of good repair result for severe uterine injury in rats (Ding et al.,
canine and demonstrated that the cell sheet may restore corneal 2014). In a recent study, Dai’s group implanted linear-ordered
transparency and prevent irreversible opacity caused by severe collagen scaffold (LOCS) and LOCS combined with collagen
injury (Nam et al., 2018). binding NT-3 (CBD-NT-3) into an acute thoracic complete
Corneal stroma provides the principal functions of the transaction model in rhesus monkeys, which is closer to humans
cornea. Tissue-engineered corneal stroma will be a promising (Han S. et al., 2019). Ten months after surgery, both the LOCS
strategy to overcome donor shortage in cornea replacement. and LOCS + CBD-NT-3 groups facilitated the ingrowth of
Jin’s group attempted to implant a corneal stroma by seeding axonal fibers at the lesion site. Moreover, the LOCS + CBD-
rabbit stromal keratocytes onto decellularized porcine cornea NT-3 displayed a significant locomotor and electrophysiological
(DPC) into a model of corneal ulcer (Zhang et al., 2007). recovery effect compared to other groups. Zeng’s group also
Recently, they used an artificial cornea composed of amniotic loaded NT-3 in gelatin sponge scaffold, which facilitated the
epithelial cells and acellular porcine cornea to treat corneal regeneration of spinal cord in dogs or rats (Li G. et al., 2016). In
alkali burn (Luo et al., 2013). Cao’s group demonstrated that other studies, they attempted to combine BMSCs with scaffolds
a polyglycolic acid (PGA) scaffold loading corneal stromal (Zeng et al., 2011, 2016). For instance, they found that the BMSC-
cells successfully repaired cornea (Hu et al., 2005). Moreover, seeded gelatin scaffold could attenuate inflammation, promote
they also reported a composite corneal scaffold containing vascularization, and reduce the formation of cavity in the injured
acellular corneal stroma sheets and keratocytes (Ma et al., spinal cord of rat (Zeng et al., 2011). In another study, BMSCs
2015). Wang’s group fabricated engineered lamellar cornea by and Schwann cells combined with gelatin scaffold could induce
seeding genetically modified embryonic stem cells and corneal neurite elongation and promote the regeneration of nerve fiber
epithelial cells on decellular porcine corneal stroma and amniotic in SCI (Zeng et al., 2016). Cui’s group and Xu’s group have made
membrane (Zhou Q. et al., 2014). The results showed that an attempt to use HA-based scaffolds for repair or regeneration
this substitute promoted wound healing and showed epithelial of CNS. They found that the HA-poly-L-lysine/nogo-66 receptor
barrier functions. Recently, Xie and Shi’s groups developed a antibody composite scaffold could enhance axonal regrowth (Wei
new method to prepare DPC grafts, which could efficiently et al., 2010). Further, they demonstrated that the modification of
remove the major xenoantigen but preserve corneal original laminin or Ile–Lys–Val–Ala–Val peptide in HA hydrogel could
structural and transparency (Shi W. Y. et al., 2019). These DPC promote the regeneration of nerve (Hou et al., 2005; Wei et al.,
grafts showed similar epithelial regeneration rate, transparency 2007). In addition, the scaffolds with different structures were
restoration, and visual acuity improvement when using human also prepared for SCI repair. In a work, multi-channel PLLA
donor cornea grafts. Cells were also introduced into developing conduits with nano-fibrous channel walls promoted directional

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Han et al. Tissue Engineering and Regenerative Medicine in Asia

growth of nerve fiber within the channels compared to multi- repairing a sciatic nerve defect (10 mm) in rats (Wang J.
channel PLLA conduits with ladder-like porous channel wall et al., 2019). A drug-loaded PEG–PCL nanoparticle in GelMA
(Sun X. et al., 2019). Other composite hydrogels consisting of hydrogels prepared by 3D printing showed effective nerve repair
polyacrylamide, graphene oxide, gelatin, and sodium alginate (Tao et al., 2019). Other acellular nerve grafts were also prepared.
were also developed for repairing SCI (Chen S. et al., 2019). The A joint research by Lu and Wang’s groups reported novel 3D
photoimmobilization of protein on the inner surface of poly(2- helix-flexible nerve guide conduits used for nerve repair (Quan
hydroxyethyl methacrylate) hydrogel could further improve the et al., 2019). This style of helix-flexible nerve guide conduits could
adhesion and survival of NSCs in the conduit, and exhibited the be used to repair peripheral nerve in a cross-joint region due
sustainable release of basic FGF (bFGF) (Cai et al., 2019). This to the lower tension during operation and easy rehabilitation
hydrogel created favorable biologic niches to promote SCI repair. after operation. Lu and Peng’s groups developed acellular nerve
A variety of fibrous scaffolds were also used in neural tissue grafts transfected with hepatocyte growth factor to repair rat
engineering (Li Y. et al., 2019; Ye et al., 2019a). Chew’s group used sciatic nerves (Li Z. et al., 2008). Recently, they combined
poly(ε-caprolactone-co-ethyl ethylene phosphate) electrospun acellular cauda equina allograft with chitin to repair long-distance
nanofibers–collagen hybrid scaffold to repair SCI (Nguyen et al., sciatic nerve defect in rats (Zhao Y. H. et al., 2017). They also
2017). They reported that the aligned nanofibers could enhance combined different cells, including BMSCs (Zhao et al., 2011),
axonal regeneration in SCI (Chew et al., 2015). Further, they used BMSC-containing fibrin glue (Zhao Z. et al., 2014), and Schwann
a hybrid scaffold composed of aligned nanofibers and hydrogel, cell-like cells derived from ADSCs or BMSCs (Wang Y. et al.,
which could deliver drug or gene to direct axon regeneration in 2012), with acellular nerve grafts to repair nerve injury. Other
SCI (Nguyen et al., 2017). In addition, Kwon’s group introduced researchers also focused on the application of cells in repairing
PLA nanorods to improve the mechanical property of agarose peripheral nerve. In an interesting work, researchers found that
hydrogel-based integrated neuro-electrodes, making it a useful gingiva-derived MSC-extracellular vesicles could activate the
material in neural tissue engineering (Heo et al., 2017). Okano’s repair phenotype of Schwann cells and thereby promote nerve
group has done some clinical trials in human for treating SCI regeneration (Mao et al., 2018). In another work, conduits with
using iPSC-derived neural precursor cells (iPSC-NPCs) (Isoda spatially neurotrophic factors improved peripheral nerve repair
et al., 2016; Nagoshi and Okano, 2018; Tsuji et al., 2019). They (Sun A. X. et al., 2019). Liu’s group found that the acellular
have successfully generated NPCs from iPSCs and proved their nerve allografts loaded with etifoxine or platelet-rich plasma can
function and safety (Isoda et al., 2016; Nagoshi and Okano, 2018). achieve a similar effect with autografts for nerve regeneration and
At present, 2 × 106 iPSC-NPCs was transplanted into the SCI functional recovery (Zheng C. et al., 2014; Zhou X. et al., 2014).
patients at 14–28 days after injury and followed-up for 1 year. Furthermore, Liu’s group also attempted to use these nerve grafts
There are also many efforts to promote the repair of peripheral in clinic. The results of clinical trial from 72 patients showed that
nerve and clinical translation of tissue-engineered products (Gu, the human acellular nerve grafts could repair digital nerve injury
2015). Gus’s group has long contributed to use biomaterials in human (1–5 cm length) (He et al., 2015). They also used this
for peripheral nerve regeneration (Gu X. et al., 2014). For human acellular nerve allograft to repair the injured nerves in the
example, they reported work using silk fibroin and chitosan hand and upper extremity of patients (Zhu et al., 2017).
for peripheral neural tissue engineering (Wu et al., 2005; Yang
et al., 2007b). They further engineered chitosan- and silk fibroin- Tendon/Ligaments
based neural scaffolds by seeding BMSCs and implanted them Tissue engineering strategy is also being used to treat
in rats (Yang et al., 2011), dogs (Xue et al., 2011), and rhesus tendon/ligament injury. Ouyang’s group has prepared nano-
monkeys (Hu et al., 2013). Successful nerve repair and functional microfibrous PLGA or collagen/silk scaffold (Ouyang et al.,
recovery indicated the therapeutic effect of combining scaffolds 2003; Chen et al., 2008; Chen J. L. et al., 2010), or supplemented
and BMSCs. In addition, they identified a bioactive molecule different cells, including MSCs (Ouyang et al., 2005), human
(achyranthes bidentata polypeptides) from a traditional Chinese embryonic stem cells (Chen et al., 2009), and human embryonic
medicine (Cheng et al., 2014). This molecule could promote stem cell-derived MSCs (Chen J. L. et al., 2010) for tendon
repair of peripheral nerve like as growth factors. In recent studies, healing. Later, they found that the combination of histone
Gu Y. et al.’s (2014) group proposed that it was important to deacetylase with well-aligned PLLA nanofibers may be more
improve and proved to be regenerative within a neural scaffold. efficient to promote tenogenic differentiation of stem cells
For example, the degradation products from chitosan scaffold (Zhang et al., 2018a). Recently, they also attempted to use
may facilitate the regeneration of peripheral nerve by improving histone deacetylase inhibitor-treated tendon stem/progenitor
macrophage-constructed microenvironments (Zhao Y. H. et al., cell-derived cell sheet to promote tendon repair (Zhang et al.,
2017). Gu’s group also promoted the clinical translation of 2018b). In another report, they modified the tendon ECM into
neural scaffolds in China (Hvistendahl, 2012). In a report, they a random-aligned-random composite, and the results showed
repaired two patients by chitosan-based scaffolds, and the 3- that the biomimetic tendon ECM composite enhanced the
year follow-up displayed good functional recovery of injured bone and fibrocartilage formation in the interface (Liu H. H.
nerves (Fan et al., 2008; Gu et al., 2012). Many other nerve et al., 2017). It was also reported that modifying the PLGA
grafts were also developed (Tao et al., 2019; Wang J. et al., 2019). scaffold with fibronectin and type I collagen can promote the
Mo’s group fabricated a composite nanomaterial by coating adhesion of human embryonic tenocytes (Qin et al., 2005). Xie’s
bioactive graphene oxide on nanofibrous scaffold for successfully group demonstrated that tissue-engineered tendons combined

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Han et al. Tissue Engineering and Regenerative Medicine in Asia

with cells and scaffolds could enhance the repair result (Yang biomimetic vasculature for tissue regeneration. For instance,
et al., 2000). Cao and Liu’s groups used PGA unwoven fibrous Lei et al. (2019) developed perfusable and hierarchical networks
scaffold seeded autologous dermal fibroblasts and tenocytes to with microchannels (PHMs) via the combination of 3D-printed
repair Achilles tendon defect in a rabbit model (Deng et al., sacrificial caramel templates, polymer coating, and phase
2014). Later, they found that aligned nanofibers could facilitate separation. The PHMs could support the metabolic functions of
in vitro tenogenic differentiation and in vivo tendon regeneration heart cells in vitro and efficiently treat myocardial infarction.
(Wang et al., 2016). They also found that tendon-like tissue Current heart transplantation therapy is still limited by
was generated in a parthenogenetic stem cell-derived tenocytes- lacking donors, suffering from chronic immunosuppressant
PLGA scaffold after in vivo heterotopic implantation (Liu therapy, and taking risks of subsequent development of graft
W. et al., 2017). Recently, Lin’s group developed an oxidized vasculopathy (Stehlik et al., 2011). TERM provides several
HA/adipic acid dihydrazide hydrogel, the regimen of which could potential strategies for heart regeneration. The mammalian
be used as a drug carrier and a mitigating agent of symptoms myocardium of human only has a limited regenerative capability.
(Hsiao et al., 2019). This study provided a platform for exploring In situ tissue regeneration through mobilizing endogenous cell
new therapeutics against tendinopathy. has been widely investigated. In a study, the phosphorylated
form of 7A was loaded in collagen hydrogel to promote
Cardiovascular Tissues regeneration of infarcted myocardium and improve heart
Cardiac disease remains one of the leading causes of death function in a rodent model (Zhang Y. et al., 2019). Decellularized
worldwide (Investigators et al., 1991). The goal of cardiovascular matrix is also used for heart regeneration. Dai et al. (2019)
tissue engineering is to construct arteries, heart valves, and fabricated a composite scaffold by combining a porous matrix
myocardium substitutes (Rabkin and Schoen, 2002). Similar metalloproteinase degradable PEG hydrogel with SDF-1α. The
to other fields of TERM, cardiovascular tissue engineering also findings suggested that the SDF-1α-loaded hydrogel was efficient
consists of scaffolds, cells, and soluble mediators. Wang’s group to develop functional decellularized heart valve. MicroRNA was
constructed cardiac tissue, which could beat synchronously and also used to promote cardiac regeneration. For example, Chen’s
similarly to native cardiac muscle by mixing embryonic stem group proved that miR-19a/19b had a therapeutic effect in cardiac
cell-derived cardiomyocytes with collagen I (Guo et al., regeneration and protection (Gao et al., 2019). In addition,
2006). They also tried to use an electrically conductive Sun’s group and Wang’s group successfully generated human
double-network hydrogel consisting of poly(thiophene-3- ventricular-specific heart tissue (EhVHT) based on 3D Fe oxide
acetic acid) and methacrylated aminated gelatin for cardiac scaffolds (Yang H. et al., 2019). This EhVHT could not only
tissue engineering (Yang et al., 2016). The injectable HA meet the specific requirements for ventricular damages in most
hydrogel, fullerenol/alginate hydrogel, and oligo(poly(ethylene myocardial infarction but also be used to screen drugs targeting
glycol)fumarate) hydrogel, which could deliver stem cells or some ventricular myocardium. Another way of TERM is to induce
therapeutic drugs, helped the treatment of myocardial infarction differentiation of cardiac progenitor cells into cardiomyocytes
and were also developed (Lü et al., 2009; Wang H. et al., 2012; in damaged hearts (Garbern and Lee, 2013; Senyo et al., 2013).
Hao et al., 2017). Ge’s group explored bioabsorbable sirolimus- Exogenous sources, such as embryonic stem cells and iPSCs,
loaded PLLA stents (Xinsorb) for coronary angioplasty. The are also used to repair the heart (Shiba et al., 2012). In a
preclinical and clinical outcomes of Xinsorb were further study, mouse cardiac fibroblasts (CFs) were reprogrammed into
studied (Shen et al., 2017; Lv et al., 2018; Wu Y. Z. et al., 2019). induced cardiomyocyte-like cells (iCMs) in the presence of
Recently, they reported 5 years of serial intravascular imaging Mef2c, Gata4, and Tbx5 (Ieda et al., 2010). Human fibroblasts
outcomes of Xinsorb scaffold (Wu Y. Z. et al., 2019). Other were also reported to be induced into cardiomyocyte-like cells
biomimetic vascular substitutes were also developed. Kong and (Fu et al., 2013; Wada et al., 2013). To improve the survival
Zhao’s groups developed many small-diameter vascular grafts of transplanted cells and reprogramming efficiency of iPSCs in
based on PCL electrospun fibers (Wang Z. H. et al., 2015, 2017; the injured heart, in vivo reprogramming could generate more
Wang K. et al., 2017; Gong et al., 2016; Dong et al., 2018), for mature iCMs. Therefore, directly injecting the reprogramming
example, grafted fusion protein VEGF-HGFI on PCL to enhance factors into the damaged heart may convert the endogenous CF
vascular regeneration (Wang K. et al., 2017). A bilayered vascular population into new functional iCMs. Compared with in vitro
graft aiming to improve hemocompatibility and endothelial reprogramming method, this in vivo reprogramming approach,
cell monolayer formation was also constructed using smooth which is simple, has lower risk of tumor formation, and avoids
PCL surface as internal layer and PCL microfibers as external cell transplantation, may be a future cardiac regenerative therapy
layer (Dong et al., 2018). In a recent work, they found that (Figure 2; Sadahiro et al., 2015). With this method, the diseased
MSC-derived small extracellular vesicles functionalized PCL myocardial tissue covered by fibrous tissue consisting of CFs
electrospun grafts could enhance patency and inhibit calcification and ECM can be converted into cardiomyocytes by defined
by immunomodulation in a rat model of hyperlipidemia (Wei factors in situ by direct cardiac reprogramming approach using
et al., 2019). Han’s group reported that a dual functionalized defined factors.
vascular stent prepared by spatio-temporal coating of HA
conjugated with dopamine showed improved neointimal area Dental Tissues
and inflammation score in a porcine restenosis model (Kim A vast array of metals including gold, silver, Cu, palladium,
et al., 2016). 3D printing is also a promising method to construct platinum, nickel, and Ti have been widely used for dental

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Han et al. Tissue Engineering and Regenerative Medicine in Asia

FIGURE 2 | Future cardiac regenerative therapy by cell transplantation-based approach using iPS cell-derived cardiomyocytes (Upper) and direct cardiac
reprogramming approach (Lower) (reproduced with permission from Sadahiro et al., 2015).

restorations. However, the oral environment will cause corrosion fabricated Ag HAp/functionalized multiwall carbon nanotube
of metallic restorations and generation of metal ions. Ti (Ag-HA/f-MWCNT) T coating on passivated 316L stainless steel
is a common material used in dentistry. In particular, the as a novel alternative to dental implant. The results showed that
modulus of Ti alloys could be regulated similarly to human 3 wt% Ag-substituted HA/f-MWCN coating is nonhemolytic and
cortical bone by Yang’s group to reduce the stress-shielding most suited (Sivaraj and Vijayalakshmi, 2019). Cho and Kim’s
effect after implantation (Hao et al., 2007a,b). However, the groups found that 3D-printed cobalt–chrome (Co–Cr) alloys
surface of Ti alloys is basically bioinert, which means it is were more biocompatible than nickel–chrome (Ni–Cr) alloys
not conducive to osseointegration. Huang’s group attempted (Ganbold et al., 2019).
to use nano/submicron-scale TiO2 network (Yang et al., In addition, other materials and their functions were
2009), oxygen plasma immersion ion implantation treatment also determined. Tsuji group reported a fully functional
(Yang C. H. et al., 2015), and genipin (Sun Y. S. et al., tooth replacement in mouse through the transplantation of
2018) for improving cell response on Ti surface. Recently, bioengineered tooth germ into the alveolar bone (Ikeda
they developed a multiform nano-network of TiO2 on Ti et al., 2009). For the purpose of better esthetics, zirconia
surface. This multiform nanostructure was shown to enhance ceramics may be an alternative to Ti (Miyazaki et al., 2013).
proliferation and differentiation of human BMSCs and regulate The zirconia ceramics could be fabricated into fixed dental
the formation of focal adhesion complex (Yang and Huang, prostheses, by computer-aided/computer-aided manufacturing
2019). Hwang’s group found that UV treatment of large grit system. Nakamura et al.’s (2019) group evaluated the mechanical
sand-blasting and acid-etching implants followed by wet storage properties of some zirconia-based materials (Itakura et al.,
could enhance bioactivity (Choi et al., 2019). Different from 2019). Lee group proved that zirconia implants with acid-etched
other methods using bone matrix components to promote cell showed comparable osseointegration with Ti implants (Kuo
adhesion on the surface of implant, Wang’s group developed a et al., 2017). Triethylene glycol dimethacrylate (TEGDMA) and
polysaccharide coating that could improve osseointegration by mineral trioxide aggregate (MTA) are also common materials
regulating macrophages into a pro-regenerative phenotype and used in dentistry. Peng’s group found that the autophagy was
producing abundant osteogenic/angiogenic cytokines to enhance activated by TEGDMA via the AMPK/mTOR pathway, but this
osteogenesis locally (Shi et al., 2018). Vijayalakshmi’s group effect could be abrogated by N-acetyl cysteine pretreatment

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Han et al. Tissue Engineering and Regenerative Medicine in Asia

FIGURE 3 | The number of publications in different Asian countries (A), and different fields in China (B), Japan (C), and South Korea (D) from 2009 to 2019.

(Zhu et al., 2015). Shie group evaluated the feasibility of MTA Sr2+ or Ce3+ ions doped fluorapatites into chitosan scaffold,
powder coated with PDA and MTA/PCL scaffold by 3D printing the results displayed that Sr2+ presented high osteoconductivity
in dental tissue regeneration, and found that these materials while Ce3+ could retain the good antibacterial property and
showed potential application in dental tissue engineering (Chiu osteoconductivity (Anastasiou et al., 2019). Lee group used
et al., 2017; Tu et al., 2018). Lim group found that modified chlorhexidine has been incorporated into the composition
MTA with propolis could promote odontogenic differentiation of PMMA dental restorations to enhance their antimicrobial
and mineralization of human dentalpulp stem cells (DPSCs) performance (Mai et al., 2019). Bindal et al.’s (2019) group
through ERK pathway (Kim J. H. et al., 2019). However, Lee’s determined that 20% human platelet lysate could be optimum for
group thought that it should be careful consideration of the maintaining the in vitro proliferative and angiogenic potential of
concentration of MTA extracts, especially when applying MTA inflamed dental pulp stem cells. Venkatasubbu group developed
to the elderly patients to maintain the viability of human MSC polyvinyl alcohol/alginate/HAp films loaded with amoxicillin,
(Kim S. Y. et al., 2019). Shie group prepared mesoporous calcium and the loading amoxicillin helped in healing the infection
silicate nanoparticles as endodontic materials, which could while HAP nanoparticles helps in periodontal regeneration
have osteogenic, drug delivery, and antibacterial characteristics (Prakash et al., 2019).
(Huang et al., 2017). iRoot BP Plus, a promising MTA alternative,
were proved to promote in vitro recruitment of DPSCs and
facilitate dentin bridge formation in a pulp repair model in vivo CONCLUDING REMARKS
(Zhu et al., 2014). Honda group prepared protamine-loaded
dicalcium phosphate anhydride (DCPA), which showed excellent We used the Wed Web of Science database to search for original
antimicrobial activity against Streptococcus mutans (Fujiki et al., articles on the topics of “Bone,” “cartilage,” “tendon/ligament,”
2019). Lee and Kim’s groups developed a Sr ion-releasing “cardiovascular,” “nerve,” “skin,” “intervertebral disc,” “urethra,”
nanobiocement (Sr-NBC) based on sol–gel method. This Sr- “bladder,” “cornea,” and “regeneration” published between 2009
NBC showed excellent biocompatibility and high odontogenic and August 2019 inclusively. In Asia, China is one of the
potential in vitro and more new dentin formation in vivo leading countries in regenerative medicine research, as shown
(Mandakhbayar et al., 2019). Anastasiou group incorporated in Figure 3. Based on the quantity of publications, China,

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Han et al. Tissue Engineering and Regenerative Medicine in Asia

TABLE 3 | Examples of clinical trials on MSC cell therapy.

NCT Disease MSC source Objectives Country Status

NCT01302015 Buerger’s Autologous ADSCs Treat patient with Buerger’s disease South Korea Completed Estimated study
disease Completion Date: June 2019
NCT01309061 Romberg’s Human ADSCs Treat patient with progressive hemifacial atrophy South Korea Completed Estimated study
disease Completion Date: June 2019
NCT00979758 Myocardial Bone marrow Improve the outcome of patients with impaired China Completed Estimated study
infarction mononuclear cells left ventricle function after myocardial infarction Completion Date: January 2018
NCT02948023 Corneal injuries Ex vivo cultivated limbal Treat different superficial corneal pathologies in India Recruiting Estimated study
stem cells human Completion Date: March 2018
NCT02260713 Acute spinal Autologous bone Treat acute complete spinal cord injury India Completed Estimated study
cord injury marrow cells Completion Date: March 2018
NCT02669199 Large area skin Allogeneic umbilical Treat large area skin lesions of the subjects China Recruiting Estimated study
wound injury cord derived MSCs Completion Date: February 2016
NCT00981006 Ischemic Autologous human Treat severe refractory heart failure patients with Japan Completed Estimated study
cardiomyopathy cardiac-derived stem chronic ischemic cardiomyopathy concordance Completion Date: April 2015
cell with reduced left ventricular dysfunction
NCT02338271 Intervertebral Autologous ADSCs Treat chronic low back pain patients with South Korea Completed Estimated study
disc lumbar intervertebral disc degeneration Completion Date: January 2015
degeneration

TABLE 4 | Examples of 3D bioprinting companies and products in Asia.

Company Project/products Founding year Country Website

Next 21 Custom-made artificial bone implants 2000 Japan http://next21.info

Osteopore International Osteoplug; Osteomesh 2003 Singapore http://osteopore.com.sg
Cyfuse Biomedical Bone, cartilage, blood vessel, neural tissue, liver 2010 Japan http://cyfusebio.com
Regenovo Biotechnology Bone, blood vessel, cartilage 2013 China http://regenovo.com
SUNP BIOTECH Custom-made products, bioink, bioprinter 2014 China http://sunpbiotech.com
Rokit Skin, bioink, bioprinter South Korea https://onsbio.com/bioprinting
Pandorum Technologies Liver, cornea 2011 India http://www.pandorumtechnologies.com

Japan, South Korea, India, and Singapore have paid more the development in chemistry and materials also promotes the
attention on TERM. rapid development of biomaterials-based scaffold. Through the
First of all, we must admit that this review of recent advances chemistry modification, we could improve the properties of the
in TERM in Asia is far from comprehensive and a large number existing materials. A variety of new materials are also created and
of excellent research teams and their work might be missed due used in TERM. Furthermore, the materials could be processed
to limited space. To date, great progress in TERM has been into hydrogels, porous scaffolds, and fibers, to meet the different
made by Asian researchers, not only by their publications, but needs of TERM. In the future, researchers will continue to
also by their active efforts to promote the clinical transformation develop numerous functional biomaterials to engineer tissue-
of their research results. We believe that TERM will experience specific scaffolds.
a rapid development, because Asian governments and society The extension of cell sources also promotes the development
are increasingly concerned with TERM. For example, in China, of TERM. To date, the seed cells are no longer confined
regenerative medicine is regarded as one of the five biotechnology to autologous adult cells. Various multipotent cells, including
fields in the National Medium to Long-term Plan for Scientific embryonic stem cells, bone marrow stem cells, tissue-specific
and Technological Development (2006–2020). There are also progenitor stem cells, umbilical cord stem cells, and iPS cells,
many foundations to support the basic research and clinical are proved to be effective in TERM. In particular, the iPSC
transformation of TERM. cell is a novel discovery by Asian scholars. Furthermore, the
Biomaterials, various cell sources, and bioactive factors generation of iPS cell lines by Asian scholars, which could
are essential to TERM. Asian scholars have studied polymer, generate fertile progeny by tetraploid complementation, is also
ceramic, and metal for TERM with the aim of having different a breakthrough. In addition, the direct in vivo reprogramming
applications. There are various preparation methods to construct approach, which is reported simple, has a lower risk of tumor
biomaterials-based scaffold. Among them, 3D bioprinting and formation and avoids cell transplantation as proposed by Asian
microfluidics technology excel due to their precision and scholars. The future direction of stem cells is how to induce
controllability in preparing personalized materials and complex stem cell into specific cells showing similar functions with
tissues/organs. In particular, cell sheet is a novel technique first adult cells (Tabar and Studer, 2014). It is predictable that the
proposed by Asian scholars. Except for the preparation method, future of TERM may be updated with stem cell technologies

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Han et al. Tissue Engineering and Regenerative Medicine in Asia

(Tang et al., 2017). Here, we provide some of the recent cartilage, functional tendons, and middle ear (Nishida et al.,
preclinical and clinical studies using stem cell therapy. In the 2004; Egami et al., 2014; Iwata et al., 2015; Yamamoto et al.,
clinic, allogeneic MSCs from bone marrow or umbilical cord 2017). Okano’s group has done some clinical trials in humans
have been evaluated in cartilage defect, SCI, corneal injuries, for treating SCI using iPSC-NPCs (Isoda et al., 2016; Nagoshi
cardiomyopathy, IVD degeneration, and bone defect with an and Okano, 2018; Tsuji et al., 2019). In the past decades, part
excellent safety profile. The available clinical studies in cell of the tissue-engineered products has been applied to the clinic
transplantation indicate that some autologous and allogeneic (Tang et al., 2017). However, they make up only a very small
stem cell therapy from different sources is safe (Table 3). percentage. Although the therapeutic effect of cell–materials
In order to promote the development of TERM, it composite is better than materials, most successful products are
is also important to better understand and replicate the still biomaterial-based scaffolds. The clinical application of stem
microenvironment around tissue/organ. The improvement of cells is mostly involved in hematological diseases. In the future,
microenvironment may be realized by applying bioactive factors, we still have a long way to go in combining TERM with the clinic.
including growth factors, chemokines, cytokines, or other signals,
such as electric, mechanical, and magnetic stimulation.
The ultimate goal of TERM is to translate the findings AUTHOR CONTRIBUTIONS
of basic research into the clinic. The mineralized collagen,
which mimics the natural bone ECM, has acquired the product BL and FH conceived and designed the review. FH wrote the
registration certificate from China government. Some nerve manuscript. JW, LD, YH, ZY, QG, CZ, LY, HW, ZZ, LJ, JL, YY,
scaffolds, including human acellular nerve grafts and chitosan- WZ, and GC all participated in the data search and analysis. WL
based grafts, have been promoted the clinical translation in and SC assisted with the revision of this manuscript.
China (Fan et al., 2008; Gu et al., 2012; Hvistendahl, 2012; He
et al., 2015; Zhu et al., 2017). Using a composite of allogeneic
umbilical cord blood-derived MSCs and hyaluronate hydrogel, FUNDING
regenerated articular cartilage in the defects of patients was
observed (Park Y. B. et al., 2017). Bioabsorbable sirolimus- The authors are grateful to the funding support from the National
loaded PLLA stents (Xinsorb) as an alternative to metallic stents Natural Science Foundation of China (31872748, 31500779,
for coronary angioplasty showed 5 years of serial intravascular 81471790, 31530024, and 81672213), the Jiangsu Provincial
imaging in patients (Wu Y. Z. et al., 2019). There have been Special Program of Medical Science (BL2012004), the China
many commercial technologies and products such as 3D printing. Postdoctoral Science Foundation (2016M590500, 2017T100398),
Two well-known 3D bioprinters, “Life-Printer ‘X”’ and “CellJet the Jiangsu Planned Projects for Postdoctoral Research Funds
Cell Printer,” are developed in Singapore and Japan, respectively (1601269C), and the Priority Academic Program Development
(Arslan-Yildiz et al., 2016). Several examples of 3D bioprinting (PAPD) of Jiangsu Higher Education Institutions.
companies and their products and projects are shown in Table 4.
In a review on 3D-printing clinical trials for the world, 3D-
printing trials were registered in 20 different countries, most ACKNOWLEDGMENTS
commonly in China with 42 (45.65%) trials (Witowski et al.,
2018). The application of cell sheet in the clinic includes We apologize to anyone whose work was not mentioned due
heart, cornea, blood vessels, periodontal membrane, esophagus, to limited space.

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Frontiers in Bioengineering and Biotechnology | www.frontiersin.org 35 March 2020 | Volume 8 | Article 83