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Advanced Fiber Materials

, Volume 1, Issue 1, pp 32–45 | Cite as

Construction of Electrospun Organic/Inorganic Hybrid Nanofibers for Drug Delivery and Tissue Engineering Applications

  • Wei Huang
  • Yunchao Xiao
  • Xiangyang ShiEmail author
Review
  • 504 Downloads

Abstract

Electrospun nanofibers hold a great potential in biomedical applications due to their advantages of large specific surface area, good biocompatibility, easy fabrication and surface modification. In particular, organic/inorganic hybrid nanofibers exhibit enhanced mechanical properties and long-term sustained release or controlled release profile of encapsulated drugs, which enables hybrid nanofibers to serve as desired platform for drug delivery and tissue engineering applications. This review summarizes the recent progresses in the preparation, performances and applications of hybrid nanofibers as drug delivery vectors for antibacterial and antitumor therapy, and as nanofibrous scaffolds for bone tissue engineering or other types of tissue engineering applications. Nanofibers doped with various types of inorganic nanoparticles (e.g., halloysite, laponite®, nano-hydroxyapatite, attapulgite, carbon nanotubes, and graphene, etc.) are introduced and summarized in detail. Future perspectives are also briefly discussed.

Graphic Abstract

Keywords

Electrospun nanofibers Hybrid nanofibers Drug delivery Tissue engineering 

Introduction

In the past decades, electrospun nanofibers have been explored for various applications in energy, catalysis, environment, and biological sciences due to their outstanding properties such as large specific surface area, high porosity, good biocompatibility, and easy fabrication and surface modification [1, 2, 3, 4]. Furthermore, electrospun nanofibers possess the ability to mimic native extracellular matrix (ECM) [5, 6], making electrospinning a powerful tool for fabricating functional nanomaterials for biomedical applications, especially in the fields of tissue engineering and drug delivery [3, 7, 8].

Generally, electrospun nanofibers could effectively carry both hydrophobic and hydrophilic drugs and achieve a sustained drug release profile, which enables them to serve as desired platform for biomedical applications, including wound dressing [9, 10], anti-bacterial [11, 12] and antitumor drug delivery [7, 13, 14]. However, conventional drug-loaded nanofibers were simply prepared by directly doping drugs within polymer solutions before electrospinning to form the nanofibers, and always exhibit a burst drug release profile [15]. In addition, electrospun nanofibers are known as prospective tissue engineering scaffolds due to their ECM-mimicking topologies and excellent biocompatibility. For better applications in tissue engineering, multifunctionality of nanofibrous scaffold is required, such as enhanced mechanical property and positive stimulation for improved cellular response.

Numerous studies have shown that inorganic nanoparticles (NPs) such as halloysite nanotubes (HNTs) [16, 17, 18], carbon nanotubes (CNTs) [19, 20, 21], graphene [22, 23], nano-hydroxyapatite (n-HA) [24, 25, 26], laponite® (LAP) [27, 28], and mesoporous silica (MMS) [29, 30], etc., have large specific surface area, high surface activity and good biocompatibility. The large specific surface area and high surface energy endow inorganic NPs with good loading capabilities for a variety of drugs and biologically active macromolecules. Moreover, inorganic nanomaterials have been validated to be able to reinforce the mechanical properties of polymeric matrix [31], and simultaneously promote cell functionality in the tissue engineering domain, especially in bone tissue engineering [32].

Combining the outstanding merits of inorganic NPs and electrospun nanofibers, organic/inorganic hybrid nanofibers exhibit improved performances in catalysis [33], mechanical property [34], drug encapsulation ability [35], and cellular response [36], which is beneficial for their tissue engineering and drug delivery applications. Much effort has been devoted to fabricate a series of organic/inorganic hybrid nanofibers. On one hand, the hybrid nanofibers prolong the drug release profile effectively; on the other hand, the loaded inorganic component can significantly enhance the mechanical properties of the nanofibers and promote cell adhesion, migration, proliferation and differentiation.

In this review, we aim to provide an overview of organic/inorganic hybrid electrospun nanofibers for drug delivery and tissue engineering applications. The strategy that combines a series of inorganic NPs including HNTs, LAP, n-HA, attapulgite (ATT) and CNTs with biocompatible organic polymers to fabricate functional hybrid nanofibers will be elaborated in detail. The biomedical applications in drug delivery and tissue engineering of organic/inorganic hybrid nanofibers are introduced. This review starts with a brief introduction of the area of research, details the formation and properties of hybrid inorganic/organic electrospun nanofibers, and then introduces the application of the materials for drug delivery and tissue engineering applications, and ends with a brief discussion of future outlooks.

Fabrication and Performance of Hybrid Nanofibers

Till now, various approaches have been exploited to fabricate organic/inorganic hybrid nanofibers with desired morphologies and enhanced mechanical properties. Especially, the blended electrospinning, Layer-by-layer (LbL) self-assembly, in situ fabrication, and co-axial electrospinning methods (Fig. 1) have been employed for the fabrication of hybrid nanofibers, which is detailed in this section.
Fig. 1

Schematic illustration of four approaches to fabricate organic/inorganic hybrid nanofibers: a blended electrospinning, b Layer-by-layer self-assembly, c in situ fabrication, and d co-axial electrospinning methods

Blended Electrospinning

Directly mixing inorganic NPs with polymer solution for electrospinning is a simple and versatile method to prepare hybrid nanofibers. The simple mixing of two materials in their pristine forms renders the formed hybrid nanofibers with improved mechanical property or biological activity, which is essential for their biomedical applications. The solid inorganic NPs were first added to the polymer solution with stirring to form a uniform and stable colloidal solution for subsequent electrospinning process [37]. A long-time and vigorous stirring process usually ends to a homogeneous composite solution and an evenly distributed nanoparticles-nanofibers composite. In our group, a series of inorganic NPs (e.g., CNTs [38, 39, 40, 41, 42], HNTs [40, 41, 43, 44, 45, 46], LAP [47, 48], n-HA [43, 48], GO [49], ATT [50], etc.)/PLGA hybrid electrospun nanofibers were fabricated. For instance, Zhao et al. [40] reported CNTs/PLGA and HNTs/PLGA hybrid nanofibers prepared using blended electrospinning. In their study, PLGA was dissolved in a mixture of tetrahydrofuran (THF)/dimethyl formamide (DMF) at a concentration of 25% (g/mL) and then different concentrations of CNTs or HNTs (1 wt%, 3 wt% or 5 wt% relative to PLGA) were mixed with PLGA solution for subsequent electrospinning. We showed that the doped CNTs or HNTs were well distributed within the nanofibers in a coaxial manner and the incorporation of inorganic NPs does not significantly change the morphology of the PLGA nanofibers (Fig. 2). In another study, the same blended electrospinning approach was adopted to acquire PVA/CS/MWNTs hybrid nanofibers [41]. The representative stress–strain curves of PVA/CS and PVA/CS/MWNTs hybrid nanofibers clearly show that mechanical properties of PVA/CS fibrous mat are significantly improved with the incorporation of CNTs (Fig. 3).
Fig. 2

Transmission electron microscopy (TEM) micrographs of a PLGA nanofibers, b HNTs-doped PLGA nanofibers with 5% HNTs relative to PLGA, and c CNTs-doped PLGA nanofibers with 5% CNTs relative to PLGA. The arrows indicate the nanotubes embedded within the PLGA nanofibers. Reprinted from Ref. [40]. Copyright 2012 Wiley–VCH Verlag GmbH & Co. KGaA, Weinheim

Fig. 3

Stress–strain curves of non-crosslinked electrospun PVA/CS (a) and PVA/CS/CNTs (b) nanofibers, and crosslinked PVA/CS (c) and PVA/CS/CNTs (d) nanofibers. Reprinted from Ref. [41]. Copyright 2011 Elsevier

Similarly, Zheng et al. [43] fabricated n-HA/PLGA and HNTs/PLGA hybrid electrospun nanofibers. With the increase of the incorporated n-HA, the average diameter of hybrid n-HA/PLGA nanofibers decreased. For the HNTs/PLGA nanofibers, the average diameter increased with the increase of the incorporated HNTs. It is generally accepted that the properties of the electrospinning solution could be affected by the addition of anionic or cationic species [51]. The smaller diameter of the n-HA/PLGA hybrid nanofibers than that of pure PLGA nanofibers is presumably due to the increase of the solution conductivity or viscosity caused by the introduction of n-HA [52]. In addition, the introduction of negatively charged HNTs may result in a decrease of the surface charge density of the spinning jet, thus increasing the diameter of the hybrid nanofibers.

Layer-by-Layer (LbL) Self-Assembly

As one of the most important surface modification techniques, LbL self-assembly has been widely utilized to deposit multilayers onto nanofiber surfaces [53]. For the fiber surface functionalization, electrospun nanofibrous mats are first formed and then used as a substrate for subsequent deposition of inorganic/organic multilayers via electrostatic self-assembly [54, 55]. For instance, Luo et al. [56] prepared CNTs-containing nanofibrous polysaccharide scaffolds by combining electrospinning and LbL self-assembly techniques, where electrospun cellulose acetate (CA) nanofibers were first fabricated and then chitosan (CS)/CNTs multilayers were deposited on the CA nanofibrous mats via electrostatic LbL self-assembly. Meanwhile, for comparison, CS/sodium alginate (ALG) multilayers were also deposited onto CA nanofibers (Fig. 4). The mechanical durability characterization showed that CA nanofibers assembled with CS/CNTs multilayers displayed higher tensile stress and ultimate strain than those assembled with similar numbers of CS/ALG multilayers. Furthermore, with increase in the number of the deposited CS/CNTs bilayers, the tensile stress of the CA nanofibers did not change significantly, and the ultimate strain started descending, which is probably due to the increased brittleness of the mats with more CNTs assembled onto the fiber surfaces. Therefore, less layers of CS/CNTs deposition onto the CA nanofibers were beneficial to reserve the improved mechanical property of the nanofibrous scaffold including tensile stress, ultimate strain, and Young’s modulus. Overall, the LbL self-assembly method enables the generation of controllable and uniform inorganic layer on the surface of nanofibers, but the adopted inorganic NPs are required to be either positively or negatively charged, which limits its versatility.
Fig. 4

Schematic illustration of the preparation of multilayered CA/(CS/CNTs) and CA/(CS/ALG) scaffolds. Reprinted from Ref. [56]. Copyright 2013 Elsevier

In-Situ Fabrication Method

The hybrid nanofibers can be obtained through in situ fabrication method. The inorganic NPs can be formed in situ in the polymer solution for subsequent electrospinning to generate hybrid nanofibers. In addition, polymer nanofibers doped with inorganic NP precursors (e.g., metal ions) can be firstly generated, followed by in situ growth of the inorganic NPs. For both cases, the in situ methods are helpful to avoid particle aggregation and to generate hybrid nanofibers with uniform particle distribution within the fibers. However, considering the in situ generation of the inorganic NPs, this method is mainly applicable for fabricating hybrid nanofibers doped with metal or metal oxide NPs. For example, Bai and co-workers fabricated Fe3O4-doped polyvinyl alcohol (PVA) nanofibers [57]. The authors of the study first mixed Fe(II) and Fe(III) salts with 6 wt% PVA solution at 60 °C under N2 for 20 min. After adjusting the pH to 11 with sodium hydroxide solution, the mixture was stirred vigorously for 1 h at 80 °C under N2 atmosphere to create magnetic Fe3O4 NPs. Afterwards, the mixture was cooled down to room temperature and directly electrospun to get Fe3O4-PVA hybrid nanofibers. In another study, Pan et al. [58] fabricated Ag NPs/PVA and Ag NPs/(PVA/PEI) hybrid nanofibers through the same in situ fabrication method. To prepare AgNPs/PVA hybrids, AgNO3 was mixed in the PVA electrospun solution, followed by epigallocatechin gallate (EGCG) reduction to form Ag NPs/PVA solution, and then the Ag NPs/PVA nanofibrous mat was obtained through electrospinning.

Alternatively, in situ reduction method combined with electrospinning technology is another approach to obtain organic/inorganic hybrid nanofibers with uniform distribution of the inorganic NPs. In this method, the NPs-containing nanofibers can be formed through the electrospinning of a polymer and metal salt mixture solution, followed by chemical reduction or physical treatment [59, 60]. For instance, to prepare the Ag NPs/(PVA/PEI) hybrid nanofibers, PVA/PEI electrospun nanofibers were firstly obtained, and then were functionalized by 3-mercaptopropyl triethoxysilane to introduce thiol groups along with the PVA hydroxyl groups on the surface of nanofibers. After that, the functionalized nanofibers were immersed in the AgNO3 solution, and reduced by EGCG to acquire the Ag NPs/(PVA/PEI) nanofibers. TEM images showed that Ag NPs with uniform size were well distributed on the surface of PVA/PEI nanofibers.

In another work, Son and coworkers [60] proved that polymer nanofibers containing Ag NPs could be produced by UV irradiation of nanofibers electrospun from a CA/silver nitrate mixture solution. Briefly, CA solution containing 0.5 wt% of AgNO3 was electrospun to form composite CA nanofibers, followed by UV irradiation to obtain the Ag NPs/CA nanofibers. Ag NPs were predominantly generated on the surface of the CA nanofibers, likely due to the fact that the Ag+ ions and Ag clusters diffused and aggregated on the surface of the CA nanofibers during the UV irradiation.

Co-Axial Electrospinning

In addition, co-axial electrospinning has also been used to prepare hybrid nanofibers, where a coaxial spinneret composed of an outer and an inner needle is commonly used. By adjusting the flow rate of inner and outer polymer solution with different compositions, various hybrid nanofibers with varied morphologies can be obtained [61]. It is possible to develop composite fibers with desirable mechanical properties. For instance, Song and coworkers employed coaxial electrospinning to encapsulate FePt NPs in poly (ε-caprolactone) (PCL) nanofibers. In the electrospinning process, FePt/hexane solution and PCL/2, 2, 2-trifluoroethanol (TFE) were used as inner and shell fluid, respectively. TEM and X-ray photoelectron spectroscopy analyses confirmed that the FePt NPs were completely encapsulated within the PCL nanofibers [62, 63]. Compared with blended electrospinning, the co-axial electrospinning method requires more accurate control on electrospinning parameters (e.g., voltage, flow rate and concentration of electrospinning solution) since both core and shell fluids are electrospun at the same time.

Drug Delivery Applications

The high surface area and tunable surface functionality of inorganic NPs make them suitable drug carriers for sustained release of drug molecules [70]. It is reasonable to combine the advantages of inorganic particles with electrospun polymer nanofibers to control the drug release rate or avoid burst release of the encapsulated drugs from the hybrid nanofibers. Eletrospun hybrid nanofibers have been used to encapsulate various types of drugs for different biomedical applications, in particular for antibacterial or antitumor applications (summarized in Table 1).
Table 1

Fabrication methods and applications of organic/inorganic hybrid nanofibers

Inorganic NPs

Organic polymer

Fabrication method

Applications

References

CNTs

PVA/CS

Blended electrospinning

Enhanced cellular response

[41]

 

PLGA

Blended electrospinning

Antitumor

[42]

 

CA/CS

LbL assembly

Enhanced cellular response

[56]

 

PU

Blended electrospinning

Neural tissue engineering

[64]

HNTs

PLGA

Blended electrospinning

Enhanced cellular response

[43]

 

PLGA

Blended electrospinning

Enhanced cellular response

[44]

 

PLGA

Blended electrospinning

Antibacterial

[45, 46]

LAP

PLGA

Blended electrospinning

Antibacterial

[47]

 

PLGA

Blended electrospinning

Antitumor

[48]

n-HA

PLGA

Blended electrospinning

Enhanced cellular response

[43]

 

PLGA

Blended electrospinning

Antibacterial

[48]

GO

PLGA

Blended electrospinning

Differentiation of MSCs

[49]

Au

PCL/gelatin

Blended electrospinning

Neural tissue engineering

[65]

TiO2

PU

Blended electrospinning

Skin tissue engineering

[66]

Fe3O4

PLA/PCL

Blended electrospinning

Antibacterial

[67]

MMS

PLLA

Blended electrospinning

Antibacterial

[68]

ATT

PLGA

Blended electrospinning

Differentiation of MSCs

[50]

Ag

CA

In situ fabrication

Antibacterial

[60]

 

PVA

In situ fabrication

Antibacterial

[69]

FePt

PCL

Coaxial Electrospinning

N/A

[62, 63]

NPs nanoparticles, CNTs carbon nanotubes, LAP laponite®, HNTs halloysite nanotubes, MMS mesoporous silica, ATT attapulgite, Ag silver, FePt iron-platinum, GO graphene oxide, PVA polyvinyl alcohol, CS chitosan, PLGA polylactic-co-glycolic acid, CA cellulose acetate, ALG sodium alginate, PU polyurethane, PCL polycaprolactone, PLA polylactic acid, LbL layer-by-layer, N/A not available

Antibacterial Drug Delivery

Through the combination of inorganic NPs and electrospinning technique, antibacterial drugs such as amoxicillin (AMX) and tetracycline hydrochloride (TCH) can be encapsulated to form drug-loaded nanofiber systems. Qi et al. [46] reported the use of HNTs/PLGA composite nanofibers for encapsulation and release of a model drug TCH. In this study, the TCH was first loaded into the lumen of HNTs by a vacuum infusion process and then the electrospun HNTs/PLGA composite nanofibers were formed. Results showed that both electrospun TCH/PLGA nanofibers and TCH/HNTs powders exhibited an obvious initial burst release, around 83.8% and 89.4% of TCH was released from TCH/PLGA nanofibers and TCH/HNTs powders, respectively within the first day. In comparison, the medicated TCH/HNTs/PLGA composite nanofibers showed a relatively sustained TCH release profile. Only about 18.6% and 16.3% of TCH were released from the TH-1/PLGA and TH-2/PLGA nanofibrous mats within the first day (TH-1 and TH-2 represent 1% and 2% of TCH relative to PLGA, respectively) and after 42 days, about 77.6% and 68.5% of the TCH were released, respectively (Fig. 5). Therefore, the TCH release rate could be controlled by the content of TCH in the drug-loaded electrospun mats. In addition, the TCH/HNTs/PLGA nanofibrous mats also possess excellent cytocompatibility, and importantly display effective antibacterial activity to inhibit bacterial growth both in liquid medium and on solid medium.
Fig. 5

In vitro release profiles of TCH from a TH-1/PLGA, b TH-2/PLGA, c TCH/PLGA nanofibers, and d TCH/HNTs powders. The samples were incubated in PBS buffer (pH 7.4) at 37 °C. Reprinted from Ref. [46]. Copyright 2013 Elsevier

Wang et al. [47] prepared PLGA/LAP/AMX composite electrospun nanofibers by encapsulating an antibiotic drug AMX. In this study, AMX was incorporated into the interlayer space of LAP in an intercalation manner, and the AMX-loaded LAP nanodisks with an optimized loading efficiency of 9.76 ± 0.57% were incorporated within PLGA nanofibers. With the coexistence of both the reservoir-type of LAP interlayer space and the matrix-type of PLGA nanofibers, the release speed of AMX was significantly suppressed with a biphasic and sustained manner. Furthermore, PLGA/LAP/AMX nanofibers displayed effective antibacterial activity and noncompromised cytocompatibility in comparison with LAP-free PLGA/AMX nanofibers. This fabrication strategy may be applied for other drug encapsulation and release in various biomedical applications in the fields of tissues engineering and pharmaceutical science.

Similarly, Zheng et al. [48] designed and prepared a hybrid n-HA-incorporated PLGA nanofiber system, where both polymer nanofibers and the n-HA were containers and barriers of AMX, affording the drug with a sustained release profile. Different from HNTs and LAP, n-HA could easily load AMX via a simple adsorption of drug onto the surface of NPs. The results of in vitro release experiments showed that both AMX/n-HA drug-loaded powder and AMX/PLGA drug-loaded fiber exhibited an obvious initial burst release, while the initial burst release of AMX from the AMX/n-HA/PLGA system was alleviated, showing sustained release effect. In vitro antibacterial activity assay data revealed that electrospun AMX/n-HA/PLGA fiber mat exhibited immediate, long-lasting and drug-loading-dependent antibacterial activity to inhibit the growth of staphylococcus aureus (Fig. 6).
Fig. 6

Left panel: inhibition of bacterial (S. aureus) growth as a function of the AMX concentration after 24 h incubation of free AMX, AMX/n-HA particles, AMX/PLGA nanofibers, and AMX/n-HA/PLGA nanofibers, respectively. Right panel: Growth inhibition of bacteria (S. aureus) on agar plate at the incubation time of 6 h (a), 12 h (b), 18 h (c), and 24 h (d). Spots 1, 2, 3, and 4 represents PLGA, n-HA/PLGA, AMX/n-HA/PLGA, and AMX/PLGA nanofibers, respectively. Reprinted from Ref. [48]. Copyright 2013 Elsevier

In addition, organic/inorganic hybrid nanofibers based on polymer/magnetic NPs or polymer/MMS NPs have also been reported to load and release antibacterial drugs. For instance, Haroosh et al. [67] prepared and characterized PLA/PCL/magnetic NP hybrid nanofibers loaded with TCH. Hu et al. [68] combined ibuprofen (IBU) with MMS to prepare PLLA-MMS-IBU composite nanofibers. The electrospun PLLA-MMS-IBU composite fibrous membranes showed significantly lower initial burst release (6% release in the first 12 h) compared with that of electrospun PLLA-IBU fibrous membranes (46% release in the first 12 h). Moreover, the IBU release from the PLLA-MMS-IBU fibers was significantly longer than that from the MMS-free PLLA-IBU fibers (100 vs. 20 days). This study may be extended to fabricate various fibrous membranes with long-term sustained drug release characteristics for long-term anti-inflammation and anti-adhesion to prevent peritendinous adhesions.

Besides antibiotic drugs, Ag NPs have been intensively investigated as antibacterial agents due to the outstanding merits of broad-spectrum antibacterial activity and low toxicity to human body [71, 72, 73, 74]. As an example, Addisu et al. [69] fabricated an Ag NP-doped PVA nanofibrous mat via electrospinning method combining with in situ reduction. The antibacterial effect was visually evaluated by inhibition zone test. Results revealed that the agar plate had a clear circular zone of inhibition because the slowly released Ag(I) ions diffused out of the fibrous mat and inhibited the growth of the Escherichia coli in a certain diameter outward. The antimicrobial activity of the Ag NP-doped PVA nanofibers was also investigated by spraying bacterial suspension onto the nanofibers. Large bacteria colonies were observed around the edges of fibrous mat for the control, while no colonies growing was observed around the Ag NP-immobilized PVA nanofibers, which suggests a good antibacterial efficacy of Ag NPs/PVA nanofibers.

Anti-Tumor Drug Delivery

Besides antibacterial drug delivery, anticancer drugs have also been incorporated into hybrid nanofibers for therapeutic applications. Doxorubicin (DOX) is known as a highly efficient anti-neoplastic agent commonly used in the treatment of various types of cancer such as leukemia, ovarian cancer and breast cancer [75, 76, 77]. The clinical use of DOX is often limited because of its undesirable cardiac toxicity, short half-life and low solubility in aqueous solution [78]. In our previous work [48], we combined biocompatible inorganic n-HA with biodegradable PLGA polymer to form electrospun composite nanofiber-based drug delivery system. Since both the n-HA and electrospun nanofiber matrix can act as drug delivery carriers, the developed double-container drug delivery system has been proven to be able to reduce the drug release rate and significantly suppress the initial burst release. Therefore, Zheng et al. [48] reported the development of n-HA-doped PLGA nanofibers for DOX encapsulation, release, and antitumor activity evaluation. The in vitro drug release experimental results showed that under both pH conditions (pH = 5.4 and 7.4), the release of DOX from both DOX/n-HA powders and DOX/PLGA fibrous mats was significantly faster than that from the DOX/n-HA/PLGA fibrous mats. Furthermore, PLGA/n-HA/DOX fiber had a good sustained release profile with a release period over 30 days. For drug delivery applications, KB cells were treated with medium containing free DOX, and medium containing released DOX from the DOX/n-HA powder, DOX/PLGA nanofibers and DOX/n-HA/PLGA nanofibers, respectively. Cell viability assessments showed that the therapeutic efficacy of DOX/n-HA/PLGA composite nanofibers was lower than that of free DOX, DOX/n-HA powder and DOX/PLGA nanofibers, which is due to the slow release rate of DOX from the composite n-HA/PLGA nanofibers. Similarly, Qi et al. [42] prepared DOX-loaded CNTs (DOX/CNTs) with an optimized drug encapsulation percentage and mixed them with PLGA solution for subsequent electrospinning to form DOX-loaded composite nanofibrous mats. This system demonstrated the same performance in terms of the controlled release of DOX, since DOX can be properly incorporated into the interior or onto the surface of CNTs.

Tissue Engineering Applications

Inorganic NPs doped into nanofibers can enhance both the physical properties (e.g., mechanical property and surface stiffness) and biological functionality (e.g., absorption and transport of nutrition) of the host nanofibers. Considering the main drawbacks of the traditional electrospun nanofibers such as poor mechanical properties in tissue engineering, organic/inorganic hybrid nanofibers are much more advantageous, allowing nanofibers to have desirable mechanical durability. Furthermore, inorganic NPs such as CNTs [79], GO [80], LAP [81], and ATT [82] can also facilitate cell adhesion, migration, proliferation and differentiation. In this section, cellular response, differentiation of mesenchymal stem cells, and some other tissue engineering applications of hybrid electrospun nanofibers will be introduced.

Hybrid Nanofibers for Enhanced Cellular Response

In our previous studies [47, 48], we showed that CNTs, LAP, or n-HA could be incorporated into PLGA nanofibers to enhance their tensile strength and elasticity without compromising the uniform fibrous morphology. In another work, Liu et al. [39] and Liao et al. [41] proved that the unique properties of CNTs doped in the polymer nanofibers could enhance the cellular responses. In particular, PVA/CS nanofibers incorporated with CNTs were able to promote cell attachment and proliferation, thereby providing a unique fibrous scaffolding material for tissue engineering applications. The improved cellular response should be derived from the superior protein absorption property due to the existence of the CNTs, thereby providing sufficient nutrition for the cell growth and proliferation. The same scenario is applicable for CA nanofibers self-assembled with CS/CNTs multilayers [56], LAP/PLGA [47] and HNTs/PLGA [44] nanofibers all prepared for improved cell responses (Fig. 7).
Fig. 7

SEM micrographs of mouse fibroblasts grown onto a coverslips, electrospun b PLGA, c HNTs (3%)/PLGA, d HNTs (5%)/PLGA, e CNTs (3%)/PLGA, and f CNTs (5%)/PLGA nanofibrous mats, respectively, after culture for 3 days. Reprinted from Ref. [83]. Copyright 2012 Royal Society of Chemistry

Hybrid Nanofibers for Differentiation of Mesenchymal Stem Cells

Human mesenchymal stem cells (hMSCs) are multi-potential stem cells, which have an inherent ability to differentiate into many kinds of lineages, such as osteogenic [84], chondrogenic [85], myogenic [86], adipogenic [87], and neurogenic lineages [88]. The ECM mimicking property affords electrospun polymer nanofibers to be an ideal scaffold material for differentiation of hMSCs for various tissue engineering applications. For example, Martins et al. [57] reported that dexamethasone (DEX), an osteogenic inducing factor incorporated within electrospun PCL nanofibers, was able to be sustainably released and the electrospun DEX-incorporated PCL nanofibers were able to induce osteogenic differentiation of human bone marrow stem cells for bone tissue engineering purposes. However, in this case the inducing factor of DEX has to be added to promote the differentiation.

GO sheets have been demonstrated to enrich the proliferation and differentiation agent on their surface [89], which may be useful to promote the stem cell differentiation. Luo et al. [49] fabricated GO-incorporated electrospun PLGA nanofibers for bone tissue engineering applications. Doping of GO into nanofibers led to a slight increase in their hydrophilicity, and significant improvement in their absorption ability and preconcentration capacity. The GO-doped PLGA nanofibrous mats could afford ECM biomimetic microenvironment for human hMSCs adhesion and proliferation, therefore were recognized as a biocompatible scaffold for tissue engineering. Meanwhile, the authors demonstrated that the GO-doped PLGA fibrous substrate could induce expression of osteogenic marker genes such as alkaline phosphatase (ALP), collagen type I (Col I), and osteocalcin (Ocn), which promoted ALP activity and osteocalcin secretion. The PLGA nanofibers incorporated with GO not only promoted the attachment and proliferation of hMSCs but also enhanced the hMSCs differentiation toward osteoblast.

In addition, Wang et al. [47] prepared hybrid LAP-doped electrospun PLGA nanofibers and investigated the possibility of inducing the osteogenic differentiation of hMSCs. The incorporation of LAP led to the increase of the surface hydrophilicity and protein absorption capacity of PLGA nanofibers. Importantly, LAP-doped PLGA nanofibers were able to induce the osteoblast differentiation of hMSCs in growth medium without any inducing factors, which is primarily due to the significant role played by LAP, an Si- and Mg-rich nanoclay material with good biodegradability [90]. With the proven hemocompatibility, the fabricated smooth and uniform organic/inorganic hybrid LAP-doped PLGA nanofibers may find many tissue engineering applications. Similarly, Wang et al. [50] reported electrospun ATT-incorporated PLGA nanofibers for osteogenic differentiation of stem cells in the absence of any inducing factors such as DEX. They demonstrated that ATT incorporation did not appreciably change the hemocompatibility of the PLGA nanofibers, instead improved their surface hydrophilicity and mechanical durability, and facilitated cell adhesion and proliferation of hMSCs. The results of alkaline phosphatase activity, osteocalcin secretion and calcium content revealed that the doped ATT within PLGA nanofibers was able to induce the osteoblastic differentiation of hMSCs in growth medium without the inducing factor of DEX (Fig. 8).
Fig. 8

a ALP activity of hMSCs cultured onto TCP, PLGA, and PLGA-3%ATT nanofibers in growth medium (left part of the figure) and osteogenic medium (right part of the figure, labeled with “+DEX”) at different culture times. b Osteocalcin secretion of hMSCs cultured onto TCP, PLGA, and PLGA-3%ATT nanofibers. c Calcium content (normalized for the protein content) of hMSCs cultured onto TCP, PLGA, and PLGA-3%ATT nanofibers. Reprinted from Ref. [50]. Copyright 2015 Royal Society of Chemistry

Hybrid Nanofibers for Neural and Skin Tissue Engineering

Depending on the specific properties of inorganic NPs, organic/inorganic hybrid nanofibers also hold a great potential for applications in neural and skin tissue engineering [91]. For example, metal NPs, serving as anchoring sites for the small filopodial projections on 2D surfaces, could improve the neurite-substrate interactions, leading to controlled growth of the neurons [92, 93]. Baranes et al. [65] demonstrated the beneficial effect of Au NPs on the differentiation, growth, and the maturation of neurons on 3D PCL-gelatin nanofibrous scaffolds. Morphometric analyses of primary and neuronal cell line behavior on nanocomposite electrospun fibers revealed elaborated neuronal growth and axonal elongation, leading to more complex neuronal networks. Additionally, electrical conductivity is very important in neural tissue engineering, as this property can allow CNTs to increase the neural signal transfer ability [91]. Hasanzadeh et al. [64] reported polyurethane (PU)/CNTs hybrid nanofibers that enhanced neural stem cells attachment, proliferation and differentiate toward mature neural cells.

Organic/inorganic hybrid nanofibers can also be explored for skin tissue engineering applications. For instance, Yan et al. [66] prepared TiO2-doped electrospun PU membranes with no toxic effect, showing a high and immediate adherence to L929 cells (mouse fibroblast cells). At the same time, TiO2/PU nanofibers could control the evaporation of water from wound beds at an optimal level and absorb exudates, keeping the wound beds moist without dehydration or exudates accumulation. Therefore, electrospun TiO2/PU nanofibers hold a great potential to be applied as wound dressing in skin tissue engineering.

Concluding Remarks and Outlooks

In summary, we systematically introduced the construction of organic/inorganic hybrid nanofiber systems for drug delivery and tissue engineering applications. In terms of drug delivery, organic/inorganic hybrid nanofibers contribute to the long-term sustained release or controlled release profile and mitigate burst release of encapsulated drug without compromising the therapeutic efficacy of the encapsulated drugs. Meanwhile, addition of inorganic NPs (HNTs, LAP, n-HA, ATT, CNTs, and GO, etc.) not only enhances the mechanical properties of the nanofiber scaffolds, but also promotes the cell adhesion, proliferation, migration and differentiation for tissue engineering applications.

With the deepening research of organic/inorganic hybrid nanofiber systems, their potential applications have been widely recognized. However, the further in vivo application of the organic/inorganic hybrid nanofibers is still a challenging subject. For instance, fabrication of controllable and stable organic/inorganic hybrid nanofibers in a large scale is currently quite limited. More animal experiments are required to thoroughly study the long-term biosafety and stability of inorganic NPs as well as in vivo degradation or metabolic pathways prior to clinical applications. Besides bone tissue engineering applications, the organic/inorganic hybrid nanofibers can be explored for the utility in cartilage, nerves, skin and muscle tissue engineering. Additionally, the formed hybrid nanofibers are able to be processed into injectable nanofibers for expanding their in vivo biomedical applications through homogenization and cryocutting treatment. Moreover, hybrid nanofibers can be further functionalized for targeted or interventional therapy. These future directions will lead to further research of organic/inorganic hybrid nanofiber systems for various applications in the biomedical domain.

Notes

Acknowledgements

We thank the financial supports from the Shanghai Education Commission through the Shanghai Leading Talents Program (ZX201903000002), the National Natural Science Foundation of China (81761148028 and 21773026), and the Science and Technology Commission of Shanghai Municipality (17540712000 and 18520750400). X. Shi also acknowledge the supports by FCT-Fundação para a Ciência e a Tecnologia (project PEst-OE/QUI/UI0674/2019, CQM, Portuguese Government funds), and through Madeira 14-20 Program, project PROEQUIPRAM-Reforço do Investimento em Equipamentos e Infraestruturas Científicas na RAM (M1420-01-0145-FEDER-000008) and by ARDITI-Agência Regional para o Desenvolvimento da Investigação Tecnologia e Inovação, through the project M1420-01-0145-FEDER-000005-Centro de Química da Madeira-CQM+ (Madeira 14-20).

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Copyright information

© Donghua University, Shanghai, China 2019

Authors and Affiliations

  1. 1.State Key Laboratory for Modifcation of Chemical Fibers and Polymer Materials, International Joint Laboratory for Advanced Fiber and Low-dimension Materials, College of Chemistry, Chemical Engineering and BiotechnologyDonghua UniversityShanghaiPeople’s Republic of China
  2. 2.CQM-Centro de Química da MadeiraUniversidade da MadeiraFunchalPortugal

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