Tissue engineering; strategies, tissues, and biomaterials

Abstract

Current tissue regenerative strategies rely mainly on tissue repair by transplantation of the synthetic/natural implants. However, limitations of the existing strategies have increased the demand for tissue engineering approaches. Appropriate cell source, effective cell modification, and proper supportive matrices are three bases of tissue engineering. Selection of appropriate methods for cell stimulation, scaffold synthesis, and tissue transplantation play a definitive role in successful tissue engineering. Although the variety of the players are available, but proper combination and functional synergism determine the practical efficacy. Hence, in this review, a comprehensive view of tissue engineering and its different aspects are investigated.

Keywords:

• Tissue engineering
• biomaterials
• growth factors
• regenerative medicine
• cell therapy

1. Introduction

Nowadays, losing an organ or a tissue is a noticeable challenging in human health care. Tissue/organ transplantation, surgical operation, or mechanical device application (like dialysis) are common treatments. However, limitations of the current strategies have increased the interest in tissue engineering (Lee, Rim, Jung, & Shin, 2010). Appropriate cell type, effective cell modification, and proper supportive matrices are three main bases of tissue engineering. In this review study, a comprehensive view of tissue engineering and its different aspects are described.

2. Tissue engineering strategies

Tissue engineering strategies can be divided into two main categories: scaffold-based and scaffold-free approaches. Autologous or allogeneic cells can be used in both categories (Vapniarsky, Arzi, Hu, Nolta, & Athanasiou, 2015). On the other hand, some researchers have introduced exogenous cell-based and endogenous cell-homing approaches in tissue engineering (Li et al., 2017). Application of exogenous cellular materials in cell-based strategy has become a major concern for both economic and safety reasons with limitations such as availability of cell sources, the excessive cost of commercialization, the anticipated difficulties of clinical translation and regulatory approval. Recent insight into cell movement and homing help recruiting endogenous cells in cell-homing approach. The administration of chemokines as signals potentiates cell homing in an anti-inflammatory microenvironment (Aibibu, Hild, Wöltje, & Cherif, 2016; Andreas, Sittinger, & Ringe, 2014; Chen, Wu, Zhang, Zhang, & Sun, 2011). The cells can also be genetically or epigenetically modified (Sheyn et al., 2010), e.g. in order to enhance the efficiency of tissue regeneration (Gersbach, Phillips, & García, 2007).

2.1. Scaffold-free approaches

In scaffold-free approaches, the cells can be directly administrated, even systemically (Burra et al., 2012) or locally (Kitahara et al., 2008). Also the cells can be administrated through three-dimensional cell microsphere (Kodali, Lim, Leong, & Tong, 2014) or cell sheet techniques (Gonçalves, Rodrigues, & Gomes, 2017; Zhang et al., 2017). Due to trigger the intrinsic repair mechanisms of a tissue, co-application of the cells and some additive biomolecules seems to be more effective (Foster, Puskas, Mandelbaum, Gerhardt, & Rodeo, 2009; Luyten, Lories, Verschueren, de Vlam, & Westhovens, 2006).

2.1.1. Biomolecules

Growth factors are soluble diffusible signaling polypeptides that regulate different kinds of cell processes inducing cell survival, migration, differentiation, and proliferation. Platelet-rich plasma is rich in a variety of growth factors with wide application in cartilage and skeletal disorders (Kon et al., 2010). It has been shown that applying growth factors could facilitate tissue regeneration. For instance, basic fibroblast growth factor (J. W. Yang, Zhang, Sun, Song, & Chen, 2015), insulin-like growth factor-1 (Mullen et al., 2015), and bone morphogenetic protein-2 (Kim et al., 2015) have been used for different tissue engineering purposes (Table 1).

Table 1. Growth factors used in tissue engineering along with their functions.

Growth Factor	Abbreviation	Function
Angiopoietin-1	Ang-1	Blood vessel maturation and stability
Angiopoietin-2	Ang-2	Endothelial cells disassociation from surrounding tissues
Basic fibroblast growth factor-2	bFGF-2	Endothelial cells survival, migration and proliferation
Bone morphogenetic protein-2	BMP-2	Osteoblasts differentiation and migration
Bone morphogenetic protein-7	BMP-7	Osteoblasts differentiation and migration, renal development
Fibroblast growth factor	FGF	Angiogenesis and embryonic development
Epidermal growth factor	EGF	Epithelial cell growth, proliferation and differentiation
Insulin-like growth factor-1	IGF-1	Cell proliferation and inhibiting cell apoptosis
Nerve growth factor	NGF	Neural cells survival and proliferation
Platelet-derived growth factor	PDGF	Embryonic development, proliferation, migration, growth of endothelial cells
Transforming growth factor-α	TGF-α	Basal cells or neural cells proliferation
Transforming growth factor-β	TGF-β	Bone-forming cells Proliferation and differentiation, anti-proliferative factor for epithelial cells
Vascular endothelial growth factor	VEGF	Endothelial cells survival, migration and proliferation

2.2. Scaffold-based approaches

In scaffold-based approaches, both topological and biochemical aspects of the scaffold should be investigated for differentiation, adhesion, or viability of the cells (Kilian, Bugarija, Lahn, & Mrksich, 2010; Mansouri & SamiraBagheri, 2016). The geometrical properties and fabrication methods of the scaffolds have remarkable influences on cellular behavior (Norman & Desai, 2006; Parker et al., 2002). Many of these methods were established in other research areas, but their usage was further demonstrated in biology, like photolithography (Su, 2007), electrospinning (Hasan, Alam, & Nayem, 2014), and soft lithography (Kim et al., 2008).

Another approach is to utilize the natural extracellular matrix (ECM) entitled whole-organ tissue engineering. In this method, the cellular and nuclear content of a tissue is removed by chemical agents or enzymes and the remaining can be used as a scaffold. These naturally occurring scaffolds can then be seeded with certain cell populations (Dahl, Koh, Prabhakar, & Niklason, 2003; Petersen, Calle, Colehour, & Niklason, 2012).

Although some promising results have been achieved in animal models, many challenges such as in vivo viability and functionality remain to be solved. Interestingly, it has been shown that the repopulation of the organ by patient’s own cell is possible in vivo.

In order to de novo synthesize of a natural ECM scaffold, sheets of cells can be cultured and wrapped into tubes (L’Heureux et al., 2006) or other 3D structures (Tsuda et al., 2007). After removing the cells, there would be a scaffold in the desired shape made of the secreted ECM. Some common steps of scaffold-based approach are described as follows:

2.2.1. Scaffold pretreatments

In order to improve the efficiency, some peptides and biomolecules can be simply loaded on the surface of the scaffolds (Mohamadyar-Toupkanlou, Vasheghani-Farahani, Bakhshandeh, Soleimani, & Ardeshirylajimi, 2015; Reis et al., 2012) or can be chemically immobilized through covalent bonds (Chiu & Radisic, 2010; Karageorgiou et al., 2004). There are also other surface treatments such as plasma treatment (Martens, Bronckaers, Politis, Jacobs, & Lambrichts, 2013), wet chemical method (Madhumathi et al., 2009), co-electrospinning of surface active agents and polymers (Lelkes et al., 2007). The surface treatment methods are used to maximize absorption of bioactive molecules on the scaffolds (Bose & Tarafder, 2012; Yoo, Kim, & Park, 2009).

2.2.2. Scaffold fixation

In tissue engineering of large defects, the construct has to be fixed at the site of interest. The sterilization step has to be done very carefully, in a way that neither bioactivity of the scaffold nor the viability of the cells is affected (Ferraris et al., 2012). The scaffold can be fixed using mechanical strength, through fibrin glue, pins, or magnetic force (Bekkers et al., 2010; Knecht et al., 2007; Russo et al., 2012). Using a biocompatible magnetite-based Ferro fluid, the scaffold becomes a soft ferromagnetic material; application of internal magnet pins or external magnet ring can fix the scaffold at the site.

2.2.3. Cell seeding and infiltration

In preparation of the cells, prior biochemical or biomechanical inductions could be applied (Ahvaz et al., 2012; Sadeghi, Bakhshandeh, Dehghan, Mehrnia, & Khojasteh, 2016). Seeding the cells using gravity can be accounted as the first approach, but sometimes it is insufficient for penetration of the cells into the scaffold (Jaiswal, Haynesworth, Caplan, & Bruder, 1997). The efficiency of cell seeding is further improved using biological glues like fibronectin (Salacinski, Tiwari, Hamilton, & Seifalian, 2001). However, using fibronectin has its own disadvantages, such as thromboembolic events and clot formation in vivo (Ramalanjaona, Kempczinski, Rosenman, Douville, & Silberstein, 1986).

The dynamic cell seeding has been also applied (Hsu, Tsai, Lin, & Chen, 2005), however, applying centrifugal systems may have some negative effects on cell morphology (Godbey, Hindy, Sherman, & Atala, 2004). In addition, exerting shear stress on cells, uneven distribution of the cells in the scaffold, and the inability to transfer nutrients completely are among the other disadvantages of this approach (Carrier et al., 1999).

Vacuum seeding can be accounted as the current leading method since it is straightforward and rapid with inexpensive devices and low contamination risk (Udelsman et al., 2011). It exerts external (Nieponice et al., 2008) or internal (Williams & Wick, 2004) pressure on cells to penetrate the scaffolds.

Electrostatic seeding is another approach that induces a temporary positive charge on the graft. This approach may cause some morphological problems like cell retention in vivo (Bowlin et al., 2001). In magnetic seeding methods, some homogenous magnetic nanoparticles are added to the cells; then, applying temporary magnet forces the cells through the scaffold (Shimizu et al., 2007). Incorporating cationic iron oxide liposomes into the cells would have the same result (Perea, Aigner, Hopfner, & Wintermantel, 2006). For more efficiency, the previously mentioned methods can be combined (Soletti et al., 2006).

Pre-seeding scaffolds by fibroblast or endothelial cells can be helpful because these cells secrete some growth factors or ECM components (Radisic et al., 2008). For example, seeding keratinocytes on basal lamina analogous topography formed by laser in soft lithography caused the advanced formation of the epidermis (Pins, Toner, & Morgan, 2000).

2.2.4. Computational modeling and controlling

The features of the scaffold or its situation in the bioreactor have to be controlled, considering the rate of nutrient consumption of the cells, their count, and growth. One of the ways to investigate all factors as a whole is using computational fluid dynamics (CFD) analysis (Pok, Dhane, & Madihally, 2013). CFD analysis is done through solving partial differential equations. The CFD procedure starts by setting up the geometry of the system. It divides the system into some grids, where numerical calculations are carried on. Then, it selects a mathematical model (like defining the porous structure details or modeling nutrient distribution) to run mathematical calculations (Patrachari, Podichetty, & Madihally, 2012). As a whole, CFD can be useful in scaffold characterization (Toh et al., 2007) or bioreactor design (Sucosky, Osorio, Brown, & Neitzel, 2004).

In the rest of this article, we will discuss the important issues in tissue engineering in more details, including cells, tissues, and scaffolds.

3. Practiced cell types

Several cell types have been used for engineering tissues, but of the most promising ones are stem cells. Because of self-renewal ability, stem cells can be expanded in vitro and then be transplanted into the desired site (Ramsden et al., 2013). Moreover, these cells have the capability of differentiating into most cell lineages, which can be beneficial for regenerating various types of tissues (Shafiq, Jung, & Kim, 2016).

Adult stem cells (ASCs) are multipotent, easy to isolate, and autologous administrative, however, limited self-renewal capacity and decreased proliferation level with aging should be addressed as their major disadvantages. Bone marrow-derived stem cells and adipose-derived stem cells (ADSCs) are among the most commonly used adult stem cells in tissue engineering (Karam, Muscari, & Montero-Menei, 2012; Sadeghi et al., 2016). ADSCs, harvested with a low-invasive procedure and high yield, are widely used for bone (Kao et al., 2015), cartilage (Wu, Cai, Zhang, Karperien, & Lin, 2013), neural (Ferrero-Gutierrez, Menendez-Menendez, Alvarez-Viejo, Meana, & Otero, 2013), and cardiac (Carvalho et al., 2013) regenerations.

Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are considered promising cell sources for cell therapy. Human iPSCs (hiPSCs) are generated from various differentiated adult cells by direct reprogramming (Ohmine et al., 2012) and have many advantages over human embryonic stem cells. Compared to human ESCs, hiPSCs are not associated with ethical concerns and immunological rejection of allogeneic grafts are lower (Hosoya; Ohmine et al., 2012). Human iPSCs can proliferate indefinitely in vitro (Farzaneh, Pournasr, Ebrahimi, Aghdami, & Baharvand) and have the potential to differentiate into a variety of cell types including definitive endoderm (DE), hepatocyte, and pancreatic beta cells (Christodoulou et al., 2011; Hosoya et al.; Illing et al., 2013; Liu, Zhang, Chen, Li, & Wang).

Embryonic stem cells (ESCs) have the major advantages of pluripotency and very high self-renewal capacity with low tumorigenicity concern, hence are widely used for regenerating almost all types of tissues (Havasi, Soleimani, Morovvati, Bakhshandeh, & Nabiuni, 2014; Kuo & Chang, 2013; Sirabella, Cimetta, & Vunjak-Novakovic, 2015).

Extra-ESC sources are isolated from tissues discarded after birth. Having to be stored cryogenically, they are not cost effective and the freezing procedure often results in deleterious effects. Several studies have successfully used stem cells derived from umbilical cord (Longo et al., 2012), amniotic fluid (Petsche Connell, Camci-Unal, Khademhosseini, & Jacot, 2013), and placenta (Jin et al., 2014) for tissue engineering purposes.

Induced Pluripotent stem cells (iPSCs) derived from somatic cells make patient-specific cell therapies possible, which bypass immune rejection and ethical concerns. The unlimited expansion potential of iPSCs also makes them a valuable cell source for tissue engineering (Havasi et al., 2014). However, many important issues remain to be addressed, such as the differences among various iPSC lines in differentiation and expansion abilities, and the appropriate differentiation stage of the cells for specific tissue engineering applications (Havasi, Nabioni, Soleimani, Bakhshandeh, & Parivar, 2013; Wu & Hochedlinger, 2011).

4. Engineered tissues

The aim of tissue engineering is to create functional and patient-specific tissues for transplantation or in vitro screening systems. While the potential promise of tissue engineering holds a great success, nowadays, only in vitro engineered tissues like skin and cartilage are used in clinics.

The lack of in vitro engineered tissues is partially due to the current inability to create engineered blood vessel systems known as vascularized systems (Lovett, Lee, Edwards, & Kaplan, 2009). In vivo vascular systems supply tissues with nutrients and oxygen through blood vessels and small capillaries in tissues. Only in a few tissues like skin, cartilage, or cornea, cells can be supplied via diffusion from far blood vessels. In this regard, employment of endothelial cells for neoangiogenesis and prevascularization by biomolecules is a common approach (Andreas et al., 2014). Current approaches to improve in vitro oxygen diffusion includes perfusion bioreactors (Grayson et al., 2008), cell co-cultures (Borges et al., 2003; Wenger et al., 2004), channeled scaffolds (Radisic et al., 2006), and modular assembly (Kelm et al., 2006; McGuigan & Sefton, 2006). Meanwhile, after implantation, the diffusion process is still complicated (Rouwkema, Boer, & Blitterswijk, 2006). Herein, recent progress and challenges in each engineered tissue are briefly discussed.

4.1. Cartilage

Due to inability to grow and reform (Bakhshandeh, Soleimani, Paylakhi, & Ghaemi, 2012), cartilage tissue engineering is one of the most advanced fields of tissue engineering. On this point, significant success is obtained for treatment of osteoarthritis and rheumatic diseases (Kafienah et al., 2007). However, since progressively cartilage diseases need a different repair approach and cooperation of immune system, many of cartilage repair strategies focus on cartilage defects induced by trauma (Moreira-Teixeira, Georgi, Leijten, Wu, & Karperien, 2011). Autologous chondrocyte implantation (ACI) (Brittberg et al., 1994), matrix-associated autologous chondrocyte transplantation (MACI) (Grigolo et al., 2002), microfracture technique (Steadman, Rodkey, Briggs, & Rodrigo, 1999), and subchondral bone drilling (Beiser & Kanat, 1989) are common clinical treatments. None of these procedures are universal, regarding the type and the size of defects (Cucchiarini et al., 2014). For instance, although ACI and microfracture treat smaller defects similarly (Van Assche et al., 2010), when it comes to defects larger than 3 cm² ACI has superior results (Basad, Ishaque, Bachmann, Stürz, & Steinmeyer, 2010), (Saris et al., 2014). MACI has also shown more efficacy in treating large defects (larger than 3 cm²) than microfracture (Basad et al., 2010).

Recently, mesenchymal stem cell-based treatment has received attention as a potential technique for treatment of cartilage defects (Qi, Feng, & Yan, 2012). In 2013, there were 18 clinical trials focusing on cartilage regeneration concerning the use of mesenchymal stem cells (Filardo et al., 2013). Presently, MACI is the most popular scaffold-based technique in clinical trials (Makris, Gomoll, Malizos, Hu, & Athanasiou, 2015).

4.2. Bone

Despite the capacity of the human skeletal system to rejuvenate itself, non-union bone fractures remain a major clinical challenge. Shortage of bone grafts and risks of infection for allografts, as well as low healing rate and lack of remodeling capacity for synthetic grafts, make tissue engineering approaches better and safer options (Luyten & Vanlauwe, 2012).

Human bone marrow stromal cells (hBMSCs), human adipose tissue-derived mesenchymal stem cells (hAD-MSCs), and umbilical cord-derived mesenchymal stem cells (hUC-MSCs) are reliable sources for bone tissue engineering (Bakhshandeh, Soleimani, Ghaemi, & Shabani, 2011; Wen et al., 2013). Stem cells have demonstrated proper efficacy for fracture healing in several animal models as well as in a number of clinical trials (Chen et al., 2016).

It has been demonstrated that mechanical stimulations such as tensile stretch (Haasper et al., 2008; Qi et al., 2008) and fluid flow-(Kreke, Huckle, & Goldstein, 2005) induced shear stress. Electromagnetic field stimulation (Tsai, Li, Tuan, & Chang, 2009), chemical stimulation (Pittenger et al., 1999), scaffold architecture (Schofer et al., 2009) may enhance osteogenic differentiation.

Despite current advances in bone tissue engineering, lack of effective vascularization methods still remains an obstacle (Amini, Laurencin, & Nukavarapu, 2012). To overcome this issue, a few methods have been under investigation (Liu, Chan, & Teoh, 2015). One approach is based on using smart scaffolds with the ability to control the release of growth factors, for example, growth factors can be encapsulated in scaffold as a delivery system (Lee, Silva, & Mooney, 2011). The other approach involves generation of prevascularization in grafts either in in vivo or in vitro situation. Based on in vivo approach, the grafts are implanted into a well-vascularized region by implantation into the defect site. On the other hand, in vitro approach is based on co-culturing the graft with endothelial cells. Due to some advantages such as bypassing multiple surgeries required for in vivo approach and reducing the time needed to generate effective vascularized implant, co-culture systems have received much more attention in recent years (Liu et al., 2012).

4.3. Cardiovascular

An increasing number of clinical trials in cardiac cell therapy have provided encouraging results for cardiac repair (Frey et al., 2014).

Stem cell-mediated cardiac repair follows three main strategies: The first aims at recruiting or promoting the homing of endogenous or circulating stem cells at the periphery or inside the damaged zone with locally injected factors. The next is based on the local scaffold-based transplantation of stem cells to replace the dead cells. The last approach involves constructing scaffold-free transplant either using spheroids (multicellular aggregates) or through cell-sheet engineering (Y. S. Zhang et al., 2015). Cell-sheet engineering involves generation of confluent cell sheets and using them as a single layer or stacking several layers to produce multilayer (Haraguchi et al., 2014).

Human myocardium has been formed recently in infarcted rodent hearts after injection of ESC-derived cardiomyocytes (Hadjipanayi & Schilling, 2013). Currently, limited in vivo heart valve tissue engineering (HVTE) studies on sheep showed the good functionality of tissue-engineered valves (Schmidt, Stock, & Hoerstrup, 2007). A vascular network in 3D cardiac constructs was developed from primary cardiac myocytes, with (Stevens et al., 2009) or without (Zimmermann et al., 2002) the addition of endothelial cells.

Recently, in situ tissue engineering has emerged as a promising route to create living heart valves within the body at the site of destination (Funayama et al., 2015). However, a slight progress has been made toward developing biocompatible, tissue-engineered scaffolds for heart valve leaflets that can withstand the dynamic pressure inside the heart. Reproducing the native alignment of cardiomyocytes in engineered graft is also another obstacle (Zhang et al., 2015).

4.4. Neural system

Various promising studies have been performed in order to provide clinical approaches for the treatment of Parkinson’s disease (Ramos-Gomez & Martinez-Serrano, 2016), Huntington and Alzheimer (Srinageshwar, Maiti, Dunbar, & Rossignol, 2016). In addition, several protocols are available for neural differentiation (Hafizi, Bakhshandeh, Soleimani, & Atashi, 2012; Zare et al., 2015) and some clinical trials are under investigation (He et al., 2015; Kappos et al., 2015).

Spinal cord treatment is another interesting area of tissue engineering. Application of stem cells has improved the motor and sensory function (Elliott Donaghue, Tator, & Shoichet, 2016). Recent studies have focused on the production of specific cellular populations for treatment of spinal cord injury (Ye et al., 2016).

Another approach for nerve injury treatment is based on nerve conduits. Nerve conduits enclose proximal and distal stump of the injured nerve and provide a cylindrical environment to promote nerve regeneration on the principle of entubulation. To optimize this approach, several aspects such as satisfying basic principles of design, adding lumen fillers, providing growth factors, supplementing with support cells, applying electrical stimulation have been under investigation (Ezra, Bushman, Shreiber, Schachner, & Kohn, 2016; Gu et al., 2016).

4.5. Skin

As a protective layer, the skin maybe injured or burned harshly. Adult skin consists of three layers: epidermis, dermis, and hypodermis. Mostly, scientists have been trying to construct dermis and epidermis replacements. However, containing sweat glands along with nerve and blood vessels, constructing hypodermis layer is very important. In recent studies, it has been demonstrated that incorporating sweat glands in vitro can enhance skin quality and preserve homeostasis during skin regeneration (Mahjour, Ghaffarpasand, & Wang, 2012; Mohd Hilmi & Halim, 2015).

Skin stem cells play an important role in wound healing. So, maintaining homeostasis among self-renewal, proliferation, and differentiation of skin stem cells is crucial in skin regeneration (Poojan et al., 2015). Although there are some significant advances in skin tissue engineering due to its simplicity with respect to other fields, there is still a long way to construct bioartificial skin resembling the normal skin in all aspects.

4.6. Liver

As a detoxifying organ, the liver is constantly exposed to different toxins and chemicals which may cause liver failure. The common treatment for end-stage organ failure is orthopedic transplantation, which is limited by donor shortage (Szkolnicka & Hay, 2016). Bioartificial livers can lead to overcoming this issue and provide a treatment for certain metabolic diseases. A few bioartificial livers are now in clinical trials, and several in vitro micro-liver models are in development (Soldatow, LeCluyse, Griffith, & Rusyn, 2013).

In addition to constructing liver replacements, there is another frontier of liver tissue engineering, which concerns constructing functional liver units for drug toxicity assessment and metabolism evaluation (Lee, Kim, & Choi, 2015; Soldatow et al., 2013).

4.7. Tooth

Dental tissue encounters mechanical, microbial, and chemical stresses. The main incentive to dental tissue engineering is the limited repair capacity of dental structures; Enamel is not able to regenerate, and dentin has a low capability to regenerate (Gong, Heng, Lo, & Zhang, 2016).

Dental pulp, dental follicle, exfoliated deciduous teeth, apical papilla, and periodontal ligament can be used as MSC sources needed for dental tissue engineering. Of course, each cell source is suitable for the regeneration of specific tooth structure: stem cells from dental pulp and apical papilla can be used for dentin or pulp tissue engineering, those from dental follicle and periodontal ligament can be used for periodontal tissue engineering, and stem cells from exfoliated deciduous teeth are useful for pulp tissue engineering (Liu et al., 2015).

Since dentin is produced by dental pulp, regeneration of dentin depends heavily on having vital and functional pulp. It has been reported that isolated pulp cells can produce dentin in vitro by differentiation to dentin-like cells and forming dentin-like mineral construction (Cao et al., 2015).

Considering the complex structure of the tooth, regenerating a whole tooth remains a demanding task. Moreover, vascularization and innervation remain elusive just like other organs. The potential to differentiate into nerve cells has been reported for dental pulp- and dental follicle-derived stem cells, however, managing nerve differentiation, especially in dentin-pulp complex, is still problematic (Martens et al., 2013).

5. Scaffolds

The scaffold is a temporary structure for cell growth support, tissue formation, and cell inspiration (Murugan & Ramakrishna, 2007). To fulfill this crucial task, scaffolds should have some essential characteristics including cell adhesion permission, biocompatibility and biodegradability, sufficient mechanical integrity and porosity, processability for adapting the environment, and sufficient optional characteristics such as electrical conductivity.

Different types of scaffolds are used in tissue engineering including but not limited to porous, microsphere, hydrogel, fibrous, polymer–bioceramic composite, and acellular scaffolds (Dhandayuthapani, Yoshida, Maekawa, & Kumar, 2011). In order to synthesize proper scaffolds, different methods such as thermally induced phase separation, solvent casting and particulate leaching, solid freeform fabrication techniques, phase separation and electrospinning are applied (Ravichandran, Sundarrajan, Venugopal, Mukherjee, & Ramakrishna, 2012).

5.1. Different types of Scaffolds according to the materials

5.1.1. Natural Scaffolds

5.1.1.1. Hyaluronic acid

In 1934, Karl Meyer and John Palmer isolated a novel glycosaminoglycan from the vitreous humor of bovine eyes (Meyer & Palmer, 1934). They proposed the name ‘hyaluronic acid’ (HA) for this substance due to its composition from a uronic acid and an amino sugar. Because of biodegradability, HA-based scaffolds have been extensively used in the forms of hydrogels (Place et al., 2012), meshes (Park, Lee, & Kim, 2011), and sponges (Perng, Wang, Tsi, & Ma, 2011) in tissue engineering.

Several chemical modifications and crosslinking reactions have been used to improve HA short residence time and low mechanical integrity in an aqueous environment (Freymann et al., 2012; Lei, Rahim, Ng, & Segura, 2011). HA-based scaffolds have been applied in wound healing (D’Agostino et al., 2015), cell delivery (Perng et al., 2011), bone (Cui, Qian, Liu, Zhao, & Wang, 2015), and cartilage (Erickson et al., 2012) tissue repair.

5.1.1.2. Chitosan

Chitosan is a copolymer of β-(1→4) glucosamine and N-acetyl-D-glucosamine (George & Abraham, 2006). Chitosan-based scaffolds are biocompatible, biodegradable (Huang, Onyeri, Siewe, Moshfeghian, & Madihally, 2005), nontoxic, and non-antigenic (Khor & Lim, 2003). Their properties are often tailored by several modifications, e.g. crosslinking by glyoxal (Monier, Ayad, & Abdel-Latif, 2012), glutaraldehyde (Wilson, Pratt, & Kozinski, 2013),and natural crosslinkers like genipin (Frohbergh et al., 2012) could modify the properties of chitosan-based scaffolds for bone, (Peng et al., 2012), cartilage (Song et al., 2015), skin (Prasad, Shabeena, Vinod, Kumary, & Anil Kumar, 2015), and cardiac (Pok, Myers, Madihally, & Jacot, 2013) tissue engineering.

5.1.1.3. Collagen

Collagen is the major protein constituent of the extracellular matrix (Yang et al., 2004). Collagen molecules consist of three fibers, twined around one another, made up of Gly-X-Y three peptide repeats (Berisio, Vitagliano, Mazzarella, & Zagari, 2002). Collagen is mainly isolated from animal tissues, which raises concerns about viral and prion contaminants (Friess, 1998). However, nowadays there are some developed ways for synthetic collagen scaffolds preparation (Kew et al., 2012).

High mechanical stability, biocompatibility, and low antigenic effects are some of the major properties of collagen-based scaffolds. Collagen could be crosslinked by glutaraldehyde (Chandran, Paik, & Holmes, 2012), genipin (Mu, Zhang, Lin, & Li, 2013), and citric acid with glycerol (Jiang, Reddy, Zhang, Roscioli, & Yang, 2013). Collagen-based scaffolds have been widely applied in bone (Lee et al., 2013), cartilage ( Zhang et al., 2013), neural (Elias & Spector, 2012), and cardiac (Shafy et al., 2013) tissue engineering.

5.1.1.4. Alginate

Alginate is an anionic polysaccharide abundantly found in the cell wall (Narayanan, Melman, Letourneau, Mendelson, & Melman, 2012). Alginate hydrogel formation occurs with physical gelation (i.e. ionic interaction), thermal gelation, or crosslinking (Lee & Mooney, 2012). Due to its biocompatibility and biodegradability, alginate has been widely used in bone (Li, Ramay, Hauch, Xiao, & Zhang, 2005), cartilage ( Li & Zhang, 2005), and cardiac (Sapir, Kryukov, & Cohen, 2011) tissue engineering.

5.1.1.5. Agar-Agarose

Agarose is a natural polymer formed by β-D-galactopyranose (1–3linked) and 3,6-anhydro-α-L-galactopyranose (1–4 linked) unit alternation. Agarose scaffolds have been used for central (Lynam et al., 2015) and peripheral (Labrador, Buti, & Navarro, 1995) nerve regeneration.

5.1.1.6. Xanthan

Xanthan is a secreted polysaccharide from bacterium Xanthomonas campestris (Rehm, 2010). It has been used as skin (Almeida, Mueller, Hirschi, & Rakesh, 2014) and bone (Sehgal, Roohani-Esfahani, Zreiqat, & Banerjee, 2015) tissue engineering scaffolds and a wound dresser (Bellini et al., 2015).

5.1.1.7. Cellulose

The bacterial form of cellulose polysaccharide is used for bone (Shi et al., 2012), cartilage (Svensson et al., 2005), and cardiac scaffolds (Entcheva et al., 2004) and a wound healer (Czaja, Krystynowicz, Bielecki, & Brown, 2006). In addition, the methylcellulose hydrogel with agarose has been used for nerve repair (Martin, Minner, Wiseman, Klank, & Gilbert, 2008).

5.1.1.8. Starch

Starch and its derivate are widely used as bone tissue engineering scaffolds (Gomes et al., 2008; Martins et al., 2009). Silva et al. used starch blend scaffold with Schwann and olfactory ensheathing cells to repair spinal cord injury (Silva et al., 2012).

5.1.1.9. Dextran

Dextran is a bacterial polymer that consists of α-1,6-linked D-glucopyranose residues with a few percent of α-1,2-, α-1,3-, or α-1,4-linked side chains (Lévesque, Lim, & Shoichet, 2005). It has been used as a wound healer, skin (Sun et al., 2011) and neural scaffolds (Lévesque & Shoichet, 2006), and a drug delivery carrier (Lévesque et al., 2005).

5.1.2. Synthetic Scaffolds

5.1.2.1 Polylactic Acid (PLA)

PLA-based scaffolds have been widely used in regenerative medicine (Pertici et al., 2014). PLA consists of lactic acid produced by fermentation of Lactobacillus. Polymerization of lactic acid is performed by direct condensation process under vacuum (Garlotta, 2001). This biocompatible and biodegradable polymer could be modified by coating (Chen, Mak, Wang, Li, & Wong, 2008), entrapment (Cordeiro & Hincke, 2011), and chemical conjunction via wet chemistry (Cai et al., 2002). Nevertheless, poor toughness (Rasal & Hirt, 2009), slow degradation rate (Bergsma, de Bruijn, Rozema, Bos, & Boering, 1995), and hydrophobicity (Burg et al., 1999) are some of PLA drawbacks. PLA-based scaffolds have been broadly used in regenerating bone (Abdal-hay, Sheikh, & Lim, 2013), cartilage (Izal et al., 2013), nerve (Pertici et al., 2014), and bladder (Ahvaz et al., 2012).

5.1.2.2. Polycaprolactone (PCL)

Due to its biocompatibility, biodegradability, and suitable mechanical strength, PCL is applied broadly in tissue engineering (Kijeńska, Prabhakaran, Swieszkowski, Kurzydlowski, & Ramakrishna, 2012; Reddy, Venugopal, Ramakrishna, & Zussman, 2014). PCL is synthesized via ring-opening polymerization of a lactone or polycondensation of hydroxycarboxylic acid (Kim et al., 2015; Labet & Thielemans, 2009). Blending or copolymerization modifications could improve PCL stiffness for proper cell attachment (Ahvaz et al., 2013; Reddy et al., 2014), thus rendering them to be the supporter of various cell types such as osteoblasts (Bakhshandeh et al., 2011), cardiomyocyte (Reddy et al., 2014), neurons (Kijeńska et al., 2012).

5.1.2.3. Polyglycolic acid (PGA)

PGA is the aliphatic polyester synthesized with ring-opening polymerization or polycondensation (Xue et al., 2012). Because of its proper compatibility and low toxicity, PGA scaffolds has been widely used in tissue engineering (Bernardini, Chellini, Frediani, Spreafico, & Santucci, 2015). Due to 45–55% crystallinity, PGA is insoluble in water, however, having the ester linkage, it is completely degradable (Wang, 2013).

5.1.2.4. Poly (lactic-co-glycolic acid) (PLGA)

This FDA-approved copolymer is widely utilized in tissue engineering because of good biodegradability and biocompatibility features (Yin et al., 2015; Yu et al., 2014). PLGA is synthesized by ring opening and copolymerization of glycolic acid and lactic acid monomers (Qian, Wohl, Crow, Macosko, & Hoye, 2011). PLGA is also an appropriate scaffold for hollow organs (Horst et al., 2013). Its crystallinity can vary from amorphous to crystalline, depending on the monomer composition (Loo, Ooi, & Boey, 2005). The higher percentage of glycolide reduces the PLGA degradation time (Samadi et al., 2013). PLGA scaffolds are used for cartilage (Yin et al., 2015), bone (Yoshida et al., 2015), and cardiac (Yu et al., 2014) tissue regeneration.

5.1.2.5. Conductive polymers

Conductive polymers such as polyaniline, polypyrrole, polythiophene, and their derivations are applied in nerve conduits and cardiac scaffolds. Due to low processability, solubility, and high toxicity, their applications in tissue engineering is limited. Some groups synthesized low toxic and highly soluble conductive polymers (Balint, Cassidy, & Cartmell, 2014). In addition, copolymerization of aniline oligomer with other biocompatible polymers such as gelatin improves biodegradability (Liu et al., 2012).

5.2. Different types of Scaffolds according to fabrication methods

5.2.1. Three-dimensional (3D) printed scaffold

The advent of 3D printers has revolutionized the tissue engineering (Murphy & Atala, 2014). The 3D bioprinters use spherical or cylindrical cellular aggregates as bioinks. Each bioprinter has two extruders, one for the cells and another for a hydrogel as a temporary non-adhesive support for the printed structure. The hydrogel will be removed after one or more days of incubating the structure in a bioreactor (Campbell & Weiss, 2007; Nakamura et al., 2005). There are also similar devices for direct cell writing using pneumatically powered nozzle systems (Chang, Nam, & Sun, 2008) or laser guidance (Catros et al., 2011).

5.2.2. Hydrogel scaffold

Hydrogels are the 3D network of polymer that can absorb a large amount of water. Hydrogels, made from natural or synthetic polymers (Tsuda et al., 2007), could be sorted into different categories such as pH sensitive (Udelsman et al., 2011), thermos sensitive (Van Assche et al., 2010), injectable and biodegradable (Vapniarsky et al., 2015).

5.2.3. Fiber scaffold

Preparing the environmental needs of tissues resembling the natural ones, fiber scaffolds play an important role in tissue engineering (Wang, 2013). Fibers have different shape and size. For example, aligned fiber causes better cell migration compared to non-aligned (Wen et al., 2013). The nano-sized fibers have the better improvement for motor neuron other than micro ones (Wenger et al., 2004). There are different methods for fiber spinning such as electrospinning (Williams & Wick 2004), wet spinning (Wilson et al., 2013), jet spinning (Wu et al., 2013), melt spinning (Wu & Hochedlinger, 2011).

5.2.4. Leached scaffold

Enough porosity has a vital role in the scaffold for better cell differentiation, proliferation, and migration. Other method used to fabricate porous scaffold is leaching (Xue et al., 2012) such as salt leaching (Yang et al., 2004) and porogen leaching (Yang et al., 2015).

6. Conclusion

Bioartificial tissue engineering is an interesting and essential challenge in recent decades. It is clear that the variety of cells, inducers, scaffolds, and strategies are available, thus the combination of these parameters is supposed to have a profound knowledge about the interactions in in vitro and in vivo. Selection of appropriate methods for cell stimulation, scaffold synthesis, and tissue transplantation play a definitive role in successful tissue engineering; hence these factors were introduced in this review to overcome the difficulties in choosing parameters.

Disclosure statement

No potential conflict of interest was reported by the authors.