Tissue engineering, a branch of regenerative medicine, refers to the application of supporting cells, material scaffolds, bioactive molecules, or their combinations to repair and reconstruct tissues and organs.
Tissue engineering is a promising strategy for the repair and regeneration of damaged tissues or organs. Biomaterials are one of the most important components in tissue engineering. Recently, magnetic hydrogels, which are fabricated using iron oxide-based particles and different types of hydrogel matrices, are becoming more and more attractive in biomedical applications by taking advantage of their biocompatibility, controlled architectures, and smart response to magnetic field remotely.
In this literature review, the aim is to summarize the current development of magnetically sensitive smart hydrogels in tissue engineering, which is of great importance but has not yet been comprehensively viewed.
Hydrogels have been shown to be one of the most applicable biomaterials in tissue engineering (Kabu et al., 2015; Madl et al., 2017, 2019; Deng et al., 2019) mainly attributed to their inner 3D network microstructures, moderate biocompatibility, and good water content feature, which are analogous with those of the natural tissue (Cui Z.K. et al., 2019; Zhu et al., 2019).
Meanwhile, hydrogel-based drug delivery systems for numerous therapeutic agents, with high water content, low interfacial tension with biological fluids, and soft consistency, have been shown to be more stable, economical, and efficient in comparison with conventional delivery systems (Li and Mooney, 2016; Moore and Hartgerink, 2017; Cheng et al., 2019; Fan et al., 2019; Zheng et al., 2019).
Considering the above advantages, hydrogels have been conducted into the biomedical application to provide a tunable three-dimensional scaffold for cell adhesion, migration, and/or differentiation, and they could also be designed as the platform for the controlled release of cytokines and drugs in tissue engineering and drug delivery (Huang et al., 2017; Jiang et al., 2017; Hsu et al., 2019; Wei et al., 2019; Zheng et al., 2019).
Hydrogel first appeared in a literature as early as in 1894 (Van Bemmelen, 1894); however, the “hydrogel” described at that time was not the same form of hydrogels used nowadays; it was a type of a colloidal gel made from inorganic salts. Later on, the term “hydrogel” was applied for describing a 3D network of hydrophilic native polymers and gums by physical or chemical crosslinking approaches, and its application heavily relied on water availability in the environment (Lee et al., 2013).
The current generation of hydrogel in the biological field was first performed by Wichterle and LÍm (1960), indicating that glycoldimethacrylate-based hydrophilic gels exhibited adjustable mechanical properties and water content. From then on, more and more hydrogels have been developed, and the smart hydrogels were then introduced in different fields of biological science, such as drug delivery, bioseparation, biosensor, and tissue engineering.
Smart hydrogels are described as they respond directly to the changes of environmental conditions (Wichterle and LÍm, 1960), and numerous studies of smart hydrogels in the applications of nanotechnology, drug delivery, and tissue engineering have been put into effect in the last few decades (Li X. et al., 2019; Li Z. et al., 2019; Zhang Y. et al., 2019).
Recently, magnetically responsive hydrogel, as one kind of smart hydrogels, has been introduced into biomedical applications in improving the biological activities of cells, tissues, or organs. This is mainly attributed to its magnetic responsiveness to external magnetic field and obtaining functional structures to remotely regulate physical, biochemical, and mechanical properties of the milieu surrounding the cells, tissues, or organs (Abdeen et al., 2016; Antman-Passig and Shefi, 2016; Rodkate and Rutnakornpituk, 2016; Bannerman et al., 2017; Omidinia-Anarkoli et al., 2017; Xie et al., 2017; Silva et al., 2018; Tay et al., 2018; Wang et al., 2018; Bowser and Moore, 2019; Ceylan et al., 2019; Luo et al., 2019).
Recent studies have represented that magnetic hydrogel could act as an excellent drug release and targeting system. For example, Gao et al. (2019) fabricated a magnetic hydrogel based on ferromagnetic vortex-domain iron oxide and suggested that this unique magnetic hydrogel could significantly suppress the local breast tumor recurrences.
Manjua et al. (2019) developed magnetic responsive poly(vinyl alcohol) (PVA) hydrogels, which could be motivated by ON/OFF magnetic field and non-invasively regulated protein sorption and motility, indicating a promising application for tissue engineering, drug delivery, or biosensor system.
Moreover, a composite magnetic hydrogel prepared by a combination of a self-healing chitosan/alginate hydrogel and magnetic gelatin microspheres could be used as a suitable platform for tissue engineering and drug delivery (Chen X. et al., 2019a). In comparison with magnetic hydrogels, various kinds of smart biomaterials (e.g., scaffolds, biofilms, other smart hydrogels), which are activated by external stimuli, such as light, pH, temperature, stress, or charge, have great potential in biomedical applications (Chen H. et al., 2019; Cui L. et al., 2019; Wu C. et al., 2019; Zhao et al., 2019; Yang et al., 2020).
However, the long response time and less precisely controlled architectures of these stimuli-responsive smart biomaterials are the two main limitations.
Magnetic hydrogels are usually made of a matrix hydrogel and a magnetic component that was incorporated into the matrix. Recently, superparamagnetic and biocompatible iron oxide-based magnetic nanoparticles (MNPs) are most commonly incorporated into polymer matrices to prepare magnetically responsive hydrogels for their application in tissue engineering, such as γ-Fe2O3, Fe3O4, and cobalt ferrite nanoparticles (CoFe2O4) (Zhang and Song, 2016; Rose et al., 2017; Ceylan et al., 2019).
Magnetite (Fe3O4) is a compound of two kinds of iron sites with 1/3 of Fe2+ and 2/3 of Fe3+. The intervalence charge transfer between Fe2+ and Fe3+ induces absorption throughout the ultraviolet–visible spectral region and the infrared spectral region, which generates a black appearance in color (Barrow et al., 2017). Maghemite (γ-Fe2O3), with a brown-orange color pattern, is an oxidative product of magnetite (Fe3O4) when the temperature is below 200°C (Tang et al., 2003).
In terms of CoFe2O4, previous studies have shown that the concentration of 20% was toxic, whereas at 10% the toxicity was insignificant. Moreover, 10% (w/w) of CoFe2O4 could maximize magnetic response because of numerous amounts of nanoparticles, developing biocompatible biomaterials (Goncalves et al., 2015; Brito-Pereira et al., 2018). For example, Hermenegildo et al. (2019) designed a novel CoFe2O4/Methacrylated Gellan Gum/poly(vinylidene fluoride) hydrogel, which created a promising microenvironment for tissue stimulation.
n this literature review, we aim to summarize the preparation methods and current development of magnetically sensitive smart hydrogels in tissue engineering, especially in bone, cartilage, and neural tissue engineering, which are of great importance but have not yet been comprehensively reviewed.
The Fabrication Processing Of Magnetic Hydrogels
Magnetic hydrogels are made of composite materials that possess biocompatibility, biodegradation, and magnetic responsiveness. The characteristics of magnetic hydrogels depend upon several issues, including the magnetic particles and the component of hydrogels used, the magnetic particles and hydrogels’ concentration, and the size and uniformity of magnetic particles within the hydrogels.
There are mainly three preparation methods of fabricating magnetic hydrogels: (i) blending method; (ii) in situ precipitation method; (iii) grafting-onto method. The scheme for the main three syntheses of the magnetic hydrogels is shown in Figure 1.
The Blending Method
In the blending approach, magnetic particles, and hydrogels are fabricated separately. The magnetic particles are normally synthesized using a coprecipitation process. The resulting magnetic particles are then stored in an aqueous or oily liquid to prevent aggregation and oxidization. Finally, the solution of magnetic particles is mixed with the hydrogel solution for crosslinking, and the magnetic particles are encapsulated into the hydrogels.
Tóth et al. (2015) modified the surface of MNPs (magnetite) with biocompatible chondroitin-sulfate-A (CSA) to develop CSA-coated MNPs. Then, CSA-coated MNPs were dispersed into hyaluronate (HyA) hydrogel to prepare the HyA-based magnetic hydrogel. It was found that the HyA-based magnetic hydrogel could be conducted in the treatment of osteoarthritis by the intra-articular injection approach.
Shi et al. (2019) fabricated bisphosphonate (BP)-modified hyaluronic acid (HA)/Fe3O4 magnetic hydrogel. This novel magnetic hydrogel showed outstanding compatibility and slow degradation in vivo and held the expectation of safety in clinic usage.
The blending method has several advantages in the preparation of magnetic hydrogels. Firstly, magnetic particles (e.g., MNPs, micrometer-iron oxides) with homogenous size in hydrogels can be obtained by modifying the stirring speed, the concentration of the substances, and the fabrication period. Secondly, the preparation process is easy to be performed since the preparation and crosslinking of magnetic particles are conducted separately.
However, there are also some limitations that could be addressed in the future, including the asymmetric distribution of magnetic particles within the hydrogels and the diffusion of magnetic particles when the magnetic hydrogels were submerged in a solution.
In Situ Precipitation Method
In the process of the in situ precipitation, the network of the hydrogels acts as a chemically reactive substance, within which the iron ions from inorganic salts in hydrogels react with alkali solutions (e.g., NH3·H2O, NaOH; Arias et al., 2018; Liu et al., 2019) to prepare the magnetic particles. In detail, the hydrogels are firstly prepared through polymerization, temperature change, or a crosslinking reaction.
Then, magnetite precursors containing iron(III) and iron(II) at a molar ratio of 1:2 are added into the hydrogels to obtain a homogenous solution. Finally, the mixture is immersed in an alkali solution to induce the crystallization of magnetite. The magnetic particles are incorporated into the hydrogels according to the following hydrolytic reaction (2 Fe3+ + Fe2+ + OH– → Fe3O4 + 4 H2O). Wang et al. (2018) designed a magnetic chitosan hydrogel by adding MNPs via in situ synthesis during chitosan hydrogel formation.
The resulting magnetic hydrogel showed a magnetic response and improved morphological and mechanical features, including the homogenous distribution of MNPs and excellent wettability. Moreover, the mechanical properties (such as the compression strength, the yield strength, and the probe displacement) of the magnetic hydrogel was enhanced with the rising concentration of MNPs from 0 to 15 wt%, which was attributed to the crosslinking role of MNPs in the process.
Under low-frequency alternating magnetic field (LAMF) exposure, the magnetic hydrogel laden with drugs exhibited a pulsatile drug release profile. In addition, the in situ fabricated MNPs in the magnetic hydrogel had excellent biocompatibility and no acute toxicity on MG-63 cells (human osteosarcoma cell line). Liu et al. (2019) fabricated polydopamine (PDA)-chelated carbon nanotube (CNT)-Fe3O4 (PFeCNT) nanohybrids into the acrylamide hydrogel via an in situ precipitation method to generate the PFeCNT hydrogel.
This magnetic hydrogel formed an anisotropic morphology under a low static magnetic field (SMF) (30 mT) and showed conductive and mechanical features. Interestingly, under external electrical stimulation, the myoblasts cultured on the magnetic hydrogel exhibited oriented outgrowth. Arias et al. (2018) designed a magnetic bacterial cellulose (MBC) hydrogel by an in situ synthesis approach that mixed the dextran-coated Fe3O4 nanoparticles with bacterial cellulose pellicles.
The resulting MBC hydrogel could be activated with saturation magnetization and exhibited a moderate Young’s modulus (200−380 kPa), which was appropriate for vascular tissue engineering. Under an external magnetic field (0.3 T) stimulation, the produced gradient magnetic fields resulted in higher cell retention for the magnetically activated MBC hydrogel.
With the in situ precipitation method, numerous kinds of inorganic substances could be applied in the fabrication of the hydrogel networks, with good dispersion in the hydrogel matrix. Moreover, the synthesized approach is straightforward and economical. However, this method is only appropriate for limited hydrogels that possess stable networks. This is because the alkali solution used in the process might destroy the hydrogel network and limit the application of cell encapsulation (Wang et al., 2009).
The Grafting-Onto Method
In the grafting-onto methodology, there are covalent bonds formed between the magnetic particles and the hydrogel network. In detail, several functional groups are grafted onto the surface of the magnetic particles, which act as micro- or nanocrosslinkers to generate covalent bonds with the hydrogel monomers. Hu et al. (2019) designed a magnetic hydrogel made from non-toxic polyacrylamide (PAAm) hydrogel and 3-(trimethoxysilyl)propyl methacrylate coated Fe3O4 via the grafting-onto approach.
This novel magnetic hydrogel exhibited relatively high mechanical properties, including tensile strength and fracture toughness. In addition, polydimethylsiloxane (PDMS) was introduced to modify the surface of the magnetic hydrogel, and the resulting product exhibited excellent underwater performance. The PDMS-coated magnetic hydrogel kept stability even under fatigue loading, which highlighted significant potentials in the applications of artificial muscles.
Messing et al. (2011) firstly fabricated methacrylic groups functionalized magnetic CoFe2O4 nanoparticles. Then the magnetic hydrogels were fabricated by adding this kind of magnetic nanoparticles into a polyacrylamide hydrogel network.
An advantage of the grafting-onto approach is that the covalent bonds are capable of encapsulating the magnetic particles within the hydrogels, which promote the stability of the magnetic hydrogel. However, the long fabrication time, the high-cost protocol, and the complicated fabrication process restrict its broader applications in the biomedical field.
Applications In Bone Tissue Engineering
The repair of large bone defects caused by traumas, infections, cancers, or other diseases is still a thorny clinical problem (Herberg et al., 2019). Previous studies have shown that osteo-inductive growth factors played a significant role in bone regeneration (Cui L. et al., 2019; Ruehle et al., 2019) however, autologous bone graft remains the gold standard in the treatment of bone defects (Bouyer et al., 2016).
Considering the donor site morbidity and limited source of the donor area, the development of bone tissue engineering biomaterials is becoming more and more attractive for researchers. Most endeavors have been applied for the evaluation of MNPs-incorporated hydrogels in bone repair. As hydroxyapatite (HAP) is one of the most important components in natural bone inorganic substances, exhibits excellent biocompatibility and osteo-conductivity, and plays a key role in biomineralization (Moncion et al., 2019; Zhou et al., 2019), the magnetic HAP composite hydrogel was designed.
For example, nano-HAP coated γ-Fe2O3 nanoparticles (m-nHAP) were synthesized and then added into poly(vinyl alcohol) (PVA) solution to fabricate m-nHAP/PVA hydrogels. The PVA showed excellent biocompatibility, high mechanical properties, and slow biodegradation, which were crucial for its application (Iqbal et al., 2019; Venkataprasanna et al., 2019). The pore sizes of hydrogels rose gradually followed by the increased content of m-nHAP, which was accessible for nutrient exchange.
Meanwhile, the adhesion and proliferation of human osteoblasts were dramatically promoted as the m-nHAP concentration increased (Hou et al., 2013). However, the magnetic field was not introduced in this study, which might be considered as a potential promoter in improving bone tissue regeneration using this magnetic hydrogel.
Cells, such as stem cells, neural cells, and osteoblasts, are an important component in tissue engineering (Cerqueira et al., 2018; He et al., 2018; Ahmad et al., 2019; Chen M. et al., 2019; Midgley et al., 2019); therefore, MNP labeled cells are becoming more and more available in magnetically bioinspired hydrogels. Henstock et al. (2014) first added TREK1-MNPs or Arg-Gly-Asp (RGD)-MNPs into human mesenchymal stem cells (hMSCs) to fabricate MNP labeled cells, which were then seeded into either collagen hydrogels or poly(D, L-lactide-coglycolide) (PLGA) encapsulating bone morphogenetic protein-2 (BMP-2)-releasing collagen hydrogels (as shown in Figure 2A).
The RGD-binding sites of cell-surface mechanoreceptors (i.e., integrins) play an important role in transferring the external stimulus into the intracellular cytoskeleton (Cartmell et al., 2002). It was worth mentioning that hydrogels containing TREK1 or RGD-MNP labeled hMSCs showed significantly more mineralization than controls; moreover, hydrogels containing functionalized MNPs and BMP-2 had thicker and more numerous mineralized domains compared to those without BMP-2 (Figures 2B–K).
In order to maintain the stem cell phenotype and multiple differentiation potential ex vivo, a magnetic cell levitation method was used to label the MSCs with MNPs and then fabricated multicellular spheroids, which were implanted into type I collagen to form a magnetic hydrogel. Biological analyses showed that the 3D spheroid hydrogel system retained the functionality of MSCs, maintained the expression of stem cell markers, produced hematopoietic factors, and decreased cell-cycle progression genes, which could be able to establish an attractive platform for osteogenesis and drug delivery (Lewis et al., 2017).
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