Kwon et al.

Biomaterials Research (2018) 22:36

https://doi.org/10.1186/s40824-018-0148-4

REVIEW Open Access

Recent advances in stem cell therapeutics

and tissue engineering strategies
Seong Gyu Kwon1, Yang Woo Kwon1, Tae Wook Lee1, Gyu Tae Park1 and Jae Ho Kim1,2*

Abstract
Background: Tissue regeneration includes delivering specific types of cells or cell products to injured tissues or organs
for restoration of tissue and organ function. Stem cell therapy has drawn considerable attention since transplantation
of stem cells can overcome the limitations of autologous transplantation of patient’s tissues; however, it is not perfect
for treating diseases. To overcome the hurdles associated with stem cell therapy, tissue engineering techniques have
been developed. Development of stem cell technology in combination with tissue engineering has opened new ways
of producing engineered tissue substitutes. Several studies have shown that this combination of tissue engineering
and stem cell technologies enhances cell viability, differentiation, and therapeutic efficacy of transplanted stem cells.
Main body: Stem cells that can be used for tissue regeneration include mesenchymal stem cells, embryonic stem cells,
and induced pluripotent stem cells. Transplantation of stem cells alone into injured tissues exhibited low therapeutic
efficacy due to poor viability and diminished regenerative activity of transplanted cells. In this review, we will discuss
the progress of biomedical engineering, including scaffolds, biomaterials, and tissue engineering techniques to
overcome the low therapeutic efficacy of stem cells and to treat human diseases.
Conclusion: The combination of stem cell and tissue engineering techniques overcomes the limitations of stem cells
in therapy of human diseases, and presents a new path toward regeneration of injured tissues.
Keywords: Tissue injury, Nanoparticle, Stem cells, Biomaterials, Tissue engineering

Background differentiation potentials of the transplanted cells [3]. To

The growing tendency of increased life expectancy as well overcome these limitations, tissue engineering technology
as increased incidence of age-related degenerative diseases has been used to improve the viability and proliferative
and tissue damage requires the use of allogenic or autolo- capacity of stem cells. Tissue engineering is the use of a
gous grafts for tissue repair. Although transplantation of combination of cells, biomaterials, biochemical and physi-
tissues or cells is innovative and has been applied to a lot cochemical factors, and engineering technologies to
of treatments, its application in clinical settings is still lim- improve or replace biological tissues [4]. In this paper, we
ited [1]. Accumulating evidence suggests that stem cells will review the types of stem cells, their use in various
can accelerate the tissue regeneration through various tissues, and tissue regeneration through stem cell engin-
mechanisms. To date, a variety of stem cells, including eering. In addition, there are many other kinds of stem
mesenchymal, embryonic, and induced pluripotent stem cells that can be used for tissue regeneration; however, in
cells, have been reported to promote regeneration of this review, we focus on the above-mentioned stem cells
damaged tissues [2]. Although stem cell therapy provides for tissue regeneration.
a new paradigm in tissue regeneration, they have limita-
tion in clinical application due to poor survival and Types of stem cells for tissue regeneration
Mesenchymal stem cells (MSCs) can be isolated from
* Correspondence: [email protected] various tissues, such as adipose tissue, tonsil, and bone
1
Department of Physiology, Pusan National University School of Medicine, marrow. MSCs show plastic adherent properties under
Yangsan 50612, Gyeongsangnam-do, Republic of Korea normal culture conditions and have a fibroblast-like
2
Research Institute of Convergence Biomedical Science and Technology,
Pusan National University Yangsan Hospital, Yangsan 50612, Republic of morphology. They express specific cell surface markers
Korea including CD73, CD90, and CD105. MSCs have the
© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Kwon et al. Biomaterials Research (2018) 22:36 Page 2 of 8

potential for self-renewal and differentiation potential into are free from ethical concerns [16]. Although iPSCs do
mesodermal lineages, including adipocytes, muscles, not negate the risk of generating tumors, transplantation
chondrocytes, and osteoblasts [2]. In addition to the differ- of autologous iPSC-derived cell therapeutics could help
entiation potential, increasing body of evidence suggests solve the immunological problem associated with
that MSCs possess immune modulatory function and transplantation of ESC-derived cells [17]. Japan’s RIKEN
pro-angiogenic activity which are beneficial for tissue re- Institute successfully transplanted the world’s first
generation [5]. MSCs interfere with dendritic cell and iPSC-derived therapy into age-related macular degener-
T-cell function and generate a local immunosuppressive ation patients [18]. However, there is a risk of neoplastic
environment by secreting various immune-modulatory development from cells differentiated from iPSCs,
cytokines [6]. Moreover, MSCs promote angiogenesis by because reprogramming factors are associated with the
secreting pro-angiogenic factors [7]. Therefore, MSC- development of tumors [19].
based clinical trials have been conducted worldwide for
various human diseases, including cardiovascular, bone Development of stem cell-activating growth factors and
and cartilage, neuronal, and inflammatory diseases [8]. peptides
Several MSC-based cell therapeutics are commercially Stem cells can differentiate into different kinds of cell
available [9], although their therapeutic efficacy is still types in response to specific ligands or growth factors
in debate. (Fig. 1) [20]. Direct transplantation of stem cells into
Embryonic stem cells (ESCs) are pluripotent stem cells injured tissues was found to be effective in animal
derived from the inner cell mass of blastocysts, and they models; however, the possibility of inducing local ische-
can differentiate to specific cell types by controlling mia or thrombosis has been raised [21]. Moreover, stem
culture conditions [10]. Recently, clinical trials were ini- cell-based cell therapy has been hampered by poor sur-
tiated to test the safety and potential efficacy of human vival of transplanted stem cells in vivo. Therefore, there
ESCs in several diseases, including spinal cord injury, is a need to develop stem cell-activating factors that
macular degeneration, diabetes and heart diseases. In enhance the survival, paracrine effects, and therapeutic
2010, Geron Corporation transplanted hESC-derived efficacy of transplanted stem cells. In particular, BMPs
oligodendrocyte precursors, GRNOPC1, into five pa- have been shown to exert novel effects on cartilage and
tients with spinal cord injury, and the clinical trial data bone regeneration in several animal experiments. It
suggest long-term safety of the therapy as well as re- has been reported that bone morphogenetic proteins
duced spinal cord cavitation in four of the five patients (BMPs) and bone-forming peptide-3 stimulated differ-
[11]. In addition, Advanced Cell Technology (MA, USA) entiation of MSCs to osteoblasts [22, 23]. Among the
tested human ESC-derived retinal pigment epithelium various types of BMPs, both BMP2 and BMP7 have
for age-related macular degeneration and Stargardt dis- been shown to play important roles in bone and car-
ease, a juvenile form of macular degeneration, and the tilage regeneration [24, 25].
clinical trial data have shown positive safety data with no Not only growth factors but also extracellular matrix
tumorigenicity and improved clinical data in some proteins have been shown to promote the regenerative
patients [12]. Although ESCs have prominent advantages potentials of stem cells. Co-transplantation of MSCs
such as pluripotency and self-renewal potential, there along with collagen matrix or fibrin to the injured tissue
are several obstacles hindering the clinical application of site is now widely used clinically [26]. Periostin, an
ESC-based cell therapeutics [13]. Because ESCs are de- extracellular matrix protein that is expressed in the peri-
rived from an embryo, they are allogenic cells to the pa- osteum and periodontal ligaments, has been identified as
tient and thus can be subjected to immune rejection. a secreted protein of MSCs. Recombinant periostin
[14]. Secondly, it is difficult to induce differentiation into protein stimulates proliferation, adhesion, and survival
a desired cell type with 100% efficiency, thus a small of MSCs in vitro, and co-implantation of MSCs and re-
fraction of undifferentiated cells might remain and form combinant periostin protein significantly accelerates
teratomas. Moreover, there are ethical issues because bone regeneration by increasing angiogenesis in a calvar-
human ESCs are derived from human embryo, which ial defect animal model [27]. Moreover, recombinant
has delayed clinical application of ESCs. periostin and its fasciclin I domain promote therapeutic
These ESC-associated issues were alleviated by the angiogenesis in a murine model of chronic limb ische-
work of Yamanaka and colleagues on somatic cell repro- mia [28]. Periostin stimulates angiogenesis and chemo-
gramming [15]. They demonstrated that somatic cells taxis of endothelial colony forming cells through a
could be reprogrammed to a primordial stem cell state mechanism involving β3 and β5 integrins. Recently, a
by introducing four pluripotency-inducing transcription short peptide sequence (amino acids 142–151), which is
factors. Since induced pluripotent stem cells (iPSCs) responsible for periostin-mediated angiogenesis, has
could be reprogrammed from adult somatic cells, they been identified by serial deletion mapping of the first
Kwon et al. Biomaterials Research (2018) 22:36 Page 3 of 8

Fig. 1 Stem cell differentiation in response to specific ligands or growth factors

fasciclin I domain [29]. These results suggest that viral expression systems is a well-known traditional
periostin can be applied for cell therapy by stimulat- method for manipulating the biological functions of
ing the pro-angiogenic and tissue regenerative poten- stem cells from “inside”. However, viral expression sys-
tials of MSCs. tems have been reported to induce immune and inflam-
In addition, it has been reported that co-transplantation matory reactions in host tissues, and genetic mutations
of N-acetylated proline-glycine-proline, a peptide pro- in host DNA can occur [31]. Therefore, development of
duced by the degradation of collagen, accelerates repair of highly efficient non-viral expression system is important
dermal wounds by stimulating migration and engraftment for stem cell research. For instance, reprogramming or
of transplanted endothelial colony forming cells [30]. direct conversion of somatic cells by using non-viral
These results demonstrate that pro-angiogenic peptides, gene expression system have great potential for clinical
including periostin and N-acetylated proline-glycine-pro- application of the reprogramming cells. Replacing
line, promote regenerative potentials of transplanted stem viruses with alternative extracellular chemicals or deliv-
cells by accelerating angiogenesis. ery systems can reduce tumor formation. Non-viral
methods include electroporation of cell membrane or
Stem cells engineered with nanomaterials delivery of genes in a form complexed with liposome or
While growth factors and cytokines can affect the bio- cationic polymers. Several types of nanoparticles have
logical functions of stem cells from “outside”, there are been developed for non-viral delivery of reprogramming
several ways to manipulate them from “inside”, as an ap- factors into cells. These nanoparticles are composed of
proach on a more fundamental level. Gene therapy using mesoporous silica, calcium phosphate, chitosan, cationic
Kwon et al. Biomaterials Research (2018) 22:36 Page 4 of 8

polymers, and magnetic nanoparticles [32]. Recently, in pre-clinical and clinical studies; however, differentiation
graphene oxide-polyethylenimine complexes have been of neural stem cells to functional neurons, reconnection
reported to be an efficient and safe system for mRNA with host neural cells, and correct transmission of nerve
delivery for direct reprogramming of somatic cells to signals are still obstacles to overcome [41]. Therefore, to
induced neurons [33]. Therefore, improvement of enhance the survival and differentiation potentials of
gene delivery efficiency using nanoparticles will be transplanted stem cells, it is necessary to combine bioma-
highly useful for direct conversion or reprogramming terials with growth factors, cytokines, and cell adhesive
of somatic cells. substances (Fig. 2).

Biomaterials enhancing the therapeutic efficacy of 3D bioprinting for tissue engineering

stem cells Biomaterial scaffolds can be used as structural compo-
Tissues are composed of two components: cells and nents for different parts of tissues, such as blood vessels,
their surrounding extracellular matrix (ECM), which is skin, and corneal tissues [42, 43]. Making 3D scaffolds
known to play an important role in cell proliferation and and culturing stem cells on them improves the regenera-
differentiation. The main function of the ECM is main- tive activity of stem cells for damaged bone and cartil-
taining cell growth and supplying essential components age. Most tissues are composed of different cell types
to cells [34]. ECM has been reported to create a frame- and multi-layered structures. Therefore, multi-layered
work for cell growth and to efficiently provide the 3D scaffolds are needed for construction of engineered
nutrients or growth factors needed for cells [35]. It is tissues using stem cells. Currently, 3D bioprinting has
difficult to naturally repair a large-size tissue defect by drawn attention in the field of biotechnology for produ-
supplying cells to the injured sites, since not only the cing multi-layered structure. Since the first technology
cells, but also the ECM are lost. Therefore, to promote for 3D bioprinting cells had been reported, there have
tissue regeneration, it is necessary to make an artificial been great advances in 3D bioprinting-based tissue en-
ECM environment for transplanted cells, and biomate- gineering [44]. Using 3D bioprinting, various cell types
rials are useful substitutes for ECM, and are also useful can be positioned in specific locations in multi-layered
in cell therapy. The biomaterial scaffold should be por- structures for constructing different tissues or organs
ous for infiltration by cells into scaffolds, and for the (Fig. 3) [45]. Bioprinting technologies include inkjet [46]
supply of oxygen and nutrients to cells. In addition, the and laser deposition [47].
scaffold should be biodegradable for proper replacement In using inkjet printer technology, however, since the
of damaged tissues with the transplanted cells [36]. cells are printed in the same manner as a commercial
In terms of biomaterials, a variety of synthetic and printer, various problems arise. For example, in order to
natural materials have been developed. In particular, print stem cells through an inkjet printer, the material
biodegradable polymers, such as collagen, gelatin, fibrin, that is added to the cells must be in a liquid form and,
hyaluronic acid, and poly(lactic-co-glycolic acid), are subsequently, have a 3D structure after injection [48].
highly useful for tissue engineering [37]. The combination However, employing crosslinking agents to form 3D
of these scaffolds and stem cells was used for skin wound structures can impair cellular viability [49]. Despite these
healing [38]. The osteogenic efficiency of MSCs was con- drawbacks, remarkable advances have been made due to
firmed in duck’s foot-derived collagen/hydroxyapatite scaf- the advantage of 3D printing cells being possible with
folds [39]. In addition, the increase of chondrogenic slight modifications to commercial inkjet printers on the
differentiation of MSCs in 3D alginate hydrogels was ex- market [50–54]. Just as laser printers have become
perimentally confirmed [40]. Neural stem cells have been popular, laser printers for 3D bioprinting have also been
used for treatment of neurodegenerative disease or stroke developed. Unlike inkjet printers, laser printers do not

Fig. 2 Stem cell engineering strategy

Kwon et al. Biomaterials Research (2018) 22:36 Page 5 of 8

Fig. 3 3D bioprinting of stem cells

apply physical stresses and do not require additives to Therefore, dECM is highly useful for 3D bioprinting of
maintain a liquid form. The viability of cells is higher stem cells, or their differentiated progeny cells.
than 95% after being printed, and apoptosis and cell pro- In the regeneration of thick tissues, not only the regen-
liferation are not affected [55]. eration of the tissue itself, but also the regeneration of
For 3D bioprinting, bioinks are needed for printing of blood vessels plays an important role in maintaining the
stem cells into 3D structures, and hydrogels are widely viability of the tissue. Artificial blood vessels applied to the
used as bioinks. Each bioink has its own characteristics human body need to have various characteristics, such as
and is used for specific purposes [56]. Natural bioinks elasticity, permeability, and biocompatibility comparable
include alginate, gelatin, collagen I, and fibrin; synthetic to the original vessels [60]. To control blood vessel fabri-
bioinks include polyethylene glycol and pluronic gels cation, the printer should have sufficient resolution, and
[57]. These materials have chemical and physical bioinks should not deform under the printing conditions
properties appropriate for bioink, and they serve as scaf- [61]. In one study, treatment with angiogenin, a stimulator
folds, similar to those of the ECM [58]. In order to mimic of angiogenesis, in a fibrin/bone powder scaffold enhanced
the ECM in vivo, de-cellularized extracellular matrix angiogenesis and bone formation, compared to a control
(dECM) scaffold has been developed. dECM is obtained group [62]. Therefore, it is possible to add pro-angiogenic
by processing original tissues with chemicals, or using en- factors during 3D bioprinting to facilitate blood vessel for-
zymatic methods to remove cellular components [59]. mation in the 3D printed tissues.
Kwon et al. Biomaterials Research (2018) 22:36 Page 6 of 8

Application of 3D bioprinting technology for tissue biomedical engineering, and nanotechnology for tissue re-
regeneration generation. Biomedical engineering and nanotechnology
Recently, application of digital light processing stereo- will be helpful for overcoming the shortcomings of stem
lithography 3D printing technology for production of cell therapeutics by supporting stem cells to grow to an
biodegradable polymeric vascular grafts has been re- appropriate concentration, offering homogeneity, and
ported [63]. Vascular grafts formed by 3D printing of resulting in proliferation at the desired location. However,
human umbilical vein cells with poly propylene fumarate biomaterials may cause toxicity when applied to the hu-
were applied for surgical grafting in patients with cardio- man body; hence, several methods have been developed to
vascular defects, suggesting that 3D bioprinting is highly increase the biocompatibility of biomaterials. Tissue en-
useful for production of patient-specific vascular grafts gineering can be applied for construction of various tis-
[63]. In addition, 3D printing is also used for bone re- sues, such as blood vessels, nervous tissue, skin, and bone.
generation. Printed calcium phosphate scaffold have For stem cell engineering, several techniques should be
been widely used for bone regeneration [64]. Transplant- developed involving new materials, new structures, and
ation of calcium phosphate scaffold has proved effective novel surface modifications of biomaterials; in addition, a
in multiple animal studies [65]. Methods for increasing deeper understanding of the interactions between cells
the osteogenicity of stem cells by applying polydopamine and biomaterials will be needed.
have also been developed [66]. In addition, 3D printing
Abbreviations
can be applied for cartilage regeneration. In one study, BMPs: Bone morphogenic proteins; dECM: De-cellularized extracellular matrix;
nanofibrillated cellulose plus alginate were used as scaf- ECM: Extracellular matrix; MSCs: Mesenchymal stem cells
folds for making ears formed with a 3D printer, and the
Acknowledgements
survival rate of chondrocytes in the scaffolds after trans- Not applicable.
plantation was 73 to 86% [67]. In the case of bone and
cartilage tissues, the size and shape of defects that occur Funding
in individual patients can be varied, therefore, 3D bio- This work was supported by a two year grant from Pusan National University.

printing technology may be highly useful for repair of Availability of data and materials
damaged skeletal tissues [68]. Not applicable.
Skin is the largest organ of the body, protecting the in-
Authors’ contributions
ternal organs from external environments, retaining The manuscript was written by contributions of all authors. All authors have
fluid, and acting as a sensory organ [69]. Thus, regener- given approval to the final manuscript.
ation of skin wounds is important for not only cosmetic
purposes but also restoration of physiologic function. In Ethics approval and consent to participate
Not applicable.
a clinical trial of treatment of burns, ulcers and other
non-healing chronic wounds, stem cells have been Consent for publication
proven to be an effective therapy for most patients [70]. Not applicable.
In the case of burns or other large skin wounds, a method Competing interests
of transplanting through artificial skin fabricated out of The author declares that they have no competing interests.
polymers or human skin is widely used nowadays [71]. Al-
though artificial skin substitutes for wound healing are Publisher’s Note
commercially available, they have disadvantages such as a Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
lack of viability, difficulty in reforming shape, and high
costs [72]. It has been reported that skin-derived dECM Received: 31 October 2018 Accepted: 7 December 2018
bioinks can used to compensate for the rapid degradation
and high contraction trends of traditional bioinks using
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