Design of Composite Fibers for Brain

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1		Vincenzo Guarino	--	5780	2024-01-26 10:30:50	\|
2	format	Jason Zhu	Meta information modification	5780	2024-01-29 03:30:08	\|

This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics16010134

The brain consists of an interconnected network of neurons tightly packed in the extracellular matrix (ECM) to form complex and heterogeneous composite tissue. According to recent biomimicry approaches that consider biological features as active components of biomaterials, designing a highly reproducible microenvironment for brain cells can represent a key tool for tissue repair and regeneration. Indeed, this is crucial to support cell growth, mitigate inflammation phenomena and provide adequate structural properties needed to support the damaged tissue, corroborating the activity of the vascular network and ultimately the functionality of neurons. In this context, electro-fluid dynamic techniques (EFDTs), i.e., electrospinning, electrospraying and related techniques, offer the opportunity to engineer a wide variety of composite substrates by integrating fibers, particles, and hydrogels at different scales—from several hundred microns down to tens of nanometers—for the generation of countless patterns of physical and biochemical cues suitable for influencing the in vitro response of coexistent brain cell populations mediated by the surrounding microenvironment.

electro-fluid dynamics nanofibers nanoparticles fibrogels brain

1. Blended Fibers

Researchers can produce materials with specialized and synergistic qualities by manufacturing nanofibers with multiple components, which makes them ideal for a wide range of applications. In the context of tissue engineering, fibers play a crucial role, and blended electrospun fibers have shown promise for various biomedical applications, including brain tissue engineering. Neural cells have been shown to locate and utilize the cues provided by fibers for migration into hybrid matrices, indicating the potential for tailored fibers to guide cellular behavior ^[1].

The specific components used rely on several variables, including mechanical qualities, biocompatibility, chemical properties, conductivity, and the intended use of the neural tissue engineering scaffold ^[2]. By altering the mechanical properties of the final product, blend materials can be created to incorporate a variety of capabilities for uses like controlled drug delivery. It is possible to introduce extra characteristics like conductivity to affect biological activity by modifying fiber chemical features. Moreover, other components enable the delivery of topographic signals to CNS cells, hence broadening the scope of possible uses. Moreover, multicomponent integration can improve the overall stability and strength of nanofibers and by applying it with different collector assemblies, alignment as well as fiber morphology can be controlled.

For instance, the fabrication of electrospun scaffolds for neural tissue engineering that blend hydrophilic and hydrophobic materials enable the creation of a balance of features, including enhanced cell contact and structural stability. Lins et al. described the fabrication process and emphasized the possible applications of poly(lactic acid) (PLA)–poly(lactide-b-ethylene glycol-b-lactide) block copolymer (PELA) and PLA–polyethylene glycol (PEG) blends on the morphology, wettability, and mechanical properties of the material and the behavior of neural stem cells (NSCs). The findings suggested that electrospun blend of PLA and PELA have favorable surface characteristics, potentially resembling brain structures ^[3]. According to another study, composite nanofibers of polyhydroxyphenylvalerate–PCL (PHPV/PCL) improve the mechano-responsiveness and life span of hiPSC-derived cortical neurons ^[4]. It is possible to create a material with enhanced or balanced performance qualities by blending synthetic and natural components. Proteins and polysaccharides are examples of natural materials that frequently show great biocompatibility, indicating that living cells can tolerate them well. The overall biocompatibility of a material can be improved by blending them with synthetic materials. Saracino et al. examined how the physical characteristics of PCL-based blended fibers affect astrocyte behavior. Blending PCL with a gelatin protein has shown a favorable effect on spreading and alignment of the cell along the fibers, and this sheds light on the way astrocytes interact with the electrospun scaffold and suggests possible uses for PCL–gelatin blended materials with aligned and randomly oriented morphology in regenerative medicine and neural tissue engineering ^[5].

Blended nanofibers with conductive elements, like graphene or carbon nanotubes, can be developed for use in brain tissue or bioelectronic device applications. This gives the nanofiber electrical conductivity, enabling it to be used as an interface with CNS cells. For example, with an emphasis on neurological prosthesis, Bianco et al. investigated the application of single-walled carbon nanotubes (SWNTs) and high-purity carbon nanofibers (CNFs) in electrospun PCL scaffolds. Rat cerebral-microvascular endothelial cells (CECs) were used for an in vitro cytocompatibility study, and the results showed that carbon nanocompounds in the fibers enhanced cell vitality, indicating that they might be used as an environment that is conducive to endothelial cell growth ^[6]. Furthermore, in order to explore the possibility of using SWNT-CS/PVA nanofibers for brain tissue engineering, Shokrgozar et al. fabricated the blended electrospun nanofibers and confirmed increased proliferation rate of both human brain-derived cells and U373 cell lines ^[7]. The development of NSCs can be enhanced by electrical stimulation; however, this is dependent on a stable nanopatterned electroconductive substrate. Garrudo et al. aimed to optimize the electroconductivity of polyaniline–PCL electrospun nanofibers by using the pseudo-doping effect. There were favorable impacts on doublecortin (DCX) and microtubule-associated protein 2 (MAP2) gene expression and cell alignment. The newly developed optimized platform has potential uses in the development of in vitro drug screening platforms, deep brain electrode interfaces, and transplanting fully developed and functioning neurons ^[8].

Every component of a composite nanofiber can be functionalized in blend systems to fulfill a particular role. For instance, one component may provide structural support, and another may contain bioactive chemicals, thereby granting the material controlled release capability. Multiple capabilities may be included into a single nanofiber system thanks to this functionalization. They have been widely studied for a drug delivery system for brain tumors. Ramachandran et al. showed a novel approach that uses a blend of PLGA–PLA–PCL polymers to target glioblastoma. This approach facilitated the delivery of the chemotherapeutic drug temozolomide (TMZ) directly to tumors in an orthotopic brain tumor model and demonstrated effective, long-term control on glioblastoma multiforme (GBM) ^[9]. Similarly, in different research, carmustine, a drug used in interstitial chemotherapy for GBM, was tested in coaxially electrospun fiber membranes made of the sheath polymer PCL and the core polymer poly(1,3-bis-(p-carboxyphenoxy propane)-co-(sebacic anhydride) (PCPP-SA). The use of multilayered membranes composed of core–sheath fibers can result in carmustine long-term release ^[10]. Also, synthetic and natural polymer composites, such as PCL and gelatin, have been successfully developed as an antitumor SN-38 loaded drug delivery platform for brain tumors and fibers, showing good biodegradation and antitumor function ^[11].

2. Particle-Decorated Fibers

In tissue engineering, the design of scaffolds with biomimetic and bioactive properties is highly desirable to improve the regeneration capacity of tissues. In particular, research on neural tissue regeneration has been focused on the development of biomaterials with particular topography to mimic the ECM ^[12]^[13]. Additionally, bioactive factors, such as proteins and growth factors, should be considered to promote the formation of the new tissue ^[14]. In this regard, the use of EFDTs can offer the possibility of combining both electrospinning and electrospraying to generate hybrid scaffolds with a controllable topography and a delivery system of bioactive molecules by adapting some parameters of process ^[15]^[16]. This technological approach, inspired by additive manufacturing, allows functionalizing a fibrous network by the deposition of nanoparticles that can be optimized independently upon the surrounding substrate ^[17]. The large versatility of both the processes—electrospinning and electrospraying—can allow switching among different modes to integrate nanoparticles into the fibrous network (i.e., sequential or simultaneous ^[16]), providing different solutions to match the release mechanisms to the specific applicative demands.

More recently, a fiber scaffold decorated with collagen nanoparticles with a density gradient was fabricated by electrospraying of collagen onto aligned fibers of PCL ^[18]. In detail, collagen nanoparticles with a density gradient were collected onto radially aligned fibers via electrospraying by the use of a size-tunable aperture working as a mask between the needle and the grounded collector ^[19]. Once the hole was gradually opened, particles tended to be distributed onto more extended portions of the surrounding substrates, thus altering the particle density in time, from the center to the periphery. It was demonstrated that this peculiar configuration can promote cell migration, due to the synergic contribution of radially aligned nanofibers (e.g., topographic signal) and nanoparticle density gradient (e.g., haptotactic cue) ^[19].

Overall, synthetic polymers, including PCL, PLA, and PVA, are generally used for the fabrication of micro- or nanofibers due to their high mechanical stability and recognized biocompatibility, while natural polymers—being the major constituent of the ECM—are usually preferred for the fabrication of nanoparticles with relevant advantages respect to other approaches suitable to support cell–material interaction ^[20]^[21]. For instance, the combination of synthetic and natural polymers into blends can reduce the ultimate mechanical properties of the fibers ^[22]. In particular, wool–keratin dispersed in PCL solution tend to form an inhomogeneous mixture as a function of relative concentration (higher than 20%), thus generating heterogeneous fibers ^[23]. Conversely, keratose—keratin from hair oxidation—nanoparticles deposited via co-electrospraying onto PVA nanofibers do not compromise the mechanical properties of fibers, also improving adhesion and proliferation of neural cells when compared with PVA fibers ^[24]. From this perspective, nanoparticle-coated nanofibers may represent a potential application for neural tissue engineering. Moreover, the versatility of electrospraying allows the formation of core–shell nanoparticles able to protect and release bioactive molecules properly loaded under the fiber shell. For instance, neurotrophic factors have been loaded in poly(d,l-lactide-co-glycolide) core–shell nanospheres, then electrosprayed onto PCL aligned fibers, to obtain an integrated platform with potential use for guiding neural tissue growth and regeneration by combining both physical guidance and molecular delivery ^[25].

Modulation of cell migration and neurite extension play important roles in CNS cell repair ^[26]^[27]. Hence, to regulate cell migration, a class of uniaxially aligned nanofibers with nerve growth factors (NGFs) loaded into PCL microparticles was designed ^[28]. In this case, the long-term and sustainable release of NGF from microparticles and aligned topography were able to guide the growth of axons and migration of neural stem cells. Moreover, the modification of surface roughness by changing the deposition time of loaded microparticles influenced the axon outgrowth of PC12 and SH-SY5Y cells and the alignment of Schwann cells. To evaluate the influence of surface roughness on neurite extension, aligned fibers decorated with a moderate density of electrosprayed fatty acid microparticles provided an optimal surface roughness to promote the neurite extension of PC12 and dorsal root ganglial (DRG) cells ^[29].

By combining electrospinning and electrospraying, hybrid scaffolds composed of highly aligned fibers of PCL coated with electrosprayed collagen and polypyrrole nanoparticles were fabricated. The aligned topography induced the orientation and neurite/axon extension of PC12 cells along the fibers, whereas the conductive microenvironment enhanced the outgrowth of neurite/axons. The combination of both topography and conductivity enhanced neurogenesis due to the increase in voltage-gated calcium channel protein (VGCC) expression, which activated intracellular signaling ^[30].

3. Particle-Loaded Fibers

Nanoparticle (NP) loading within electrospun micro/nanofibers allow the obtainment of functional hybrid fibers with empowered features provided by both NPs (guest) and polymer mats (host). This strategy results in a synergistic combination between the functional features of NPs (e.g., small size, high surface:volume ratio and chemical reactivity), along with flexibility and porosity of the polymer mats. Viscosity, spinnability and resultant composite nanofiber morphology are among the main parameters affected by NP loading and distribution within the polymer solution. Therefore, an NP clustering effect needs to be avoided by means of physical methods (e.g., stirring, sonication), chemical modification (e.g., surfactants) to improve colloidality of NPs, or dissolution of NPs and polymers in different solvents. Several NPs have been successfully embedded within micro/nanofiber mats, including metal ^[31]^[32], metal oxide ^[32], and carbon-derived ^[33] and polymer-based NPs ^[34]. NPs can be incorporated within electrospun micro/nanofibers by three main routes. The most used is direct blending electrospinning, where the NPs are directly added to the polymer solution prior to electrospinning ^[34]^[35].

However, the distribution of NPs within the polymer solution may affect the spinnability and the resultant hybrid composite fiber morphology, leading to fewer mechanical properties and loss of functional sites in composite fiber mats. Another way to encapsulate nanoparticles is through coaxial electrospinning, creating core–shell like fibers. This approach allows the uniform embedding of pharmaceutical agents and/or NPs into the core materials, preserving them from the surrounding environment by a shell layer and leading to a sustained and kinetically controlled release over a long time. The third option involved in situ NPs growing directly within nanofibers, which can be used as substrates. This approach is typical of inorganic NP-loaded electrospun composite fibers. The process involves the dissolution of metal salt (precursors) into the polymer solution, followed by composite nanofibers mat by electrospinning and NP formation by thermal (e.g., sintering, calcination) or chemical (e.g., redox agents) means or a combination of them. The physicochemical conditions of the post-treatments, like calcination temperature and concentration of redox agents, may influence both the crystalline phase of NPs and surface morphology of the nanofibers. The latest advancements in particle-loaded electrospun composite nanofibers intended for neuronal tissue engineering and/or DDSs for brain disease treatment have been focused on improving conductivity features and functional healing. Carbon-derived NPs have been widely used as conductive fillers within electrospun composite fibers in neural engineering applications. Steel et al. described a nanofibrous conductive composite based on an ultralow concentration of carboxylated multiwalled carbon nanotubes (MWCNTs) electrospun within methacrylated hyaluronic acid (MeHA) nanofibers (MeHA/MWCNTs) ^[36]. The incorporation of an ultralow concentration of MWCNTs (0.01% v/v) resulted in a better dispersion within HA, a lower impedance and a higher charge capacity of HA fibers. HA-MWCNT substrates proved to firmly sustain neuron growth, as evidenced by neurite length and neuron number, for 72 h, with only 1 h of an applied 20 Hz biphasic alternating current (AC) waveform 24 h post-seeding, owing to the activation of voltage-sensitive ion channels. Additionally, da Silva, D.M. and co-workers recently explored the inclusion of poly-dopamine functionalized reduced graphene oxide (PDA@rGO) within adipose tissue-derived extracellular matrix (adECM) assisted by a lactide–caprolactone copolymer and processed into a bidimensional (2D) nanofiber platform by electrospinning intended for guiding NSC fate ^[37]. adECM/PLA-PDA@rGO was electrospun into a dense arrangement in a uniform and bead-free 2D nanofibrous platform, with PDA@rGO sheets homogeneously integrated within the membrane, as confirmed by SEM. PDA@rGO incorporation resulted in a reduction in the average fiber diameter from 564 ± 238 nm (undoped) to 377 ± 158 nm (PDA@rGO doped), probably due to an improved conductivity of the electrospinnable solution. In fact, an increase in the electrical conductivity from 5.5·10⁻⁶ S·cm⁻¹ (undoped) to 2.3·10⁻⁵ S·cm⁻¹ was recorded by adding PDA@rGO. The metabolic activity/proliferation of NSCs was highly dependent on PDA@rGO presence on bidimensional platforms. NSCs exhibited the typical clustered round-shaped morphology (undifferentiated cells) after 7 days and a further growing reaching confluence after 14 days, as confirmed by phalloidin/DAPI staining, whereas in the absence of exogenous diffusible signaling differentiation-inductive factors (e.g., retinoic acid and brain-derived neurotrophic factor), the presence of PDA@rGO boosts spontaneous NSC differentiation toward the neuronal lineage in 2D adECM–PLA platforms.

Other attempts have exploited hybrid electrospun composite nanofibers as delivery systems for brain cancer treatment. In this regard, Unal, S. and colleagues developed PCL–gelatin nanofibrous encapsulating bacterial cellulose nanocrystal (BCNC) as a platform for mimicking the GBM tumor ECM ^[38]. BCNC loading increased the fiber diameters within the nanofibrous matrix and changed the fiber morphology towards the beaded formation. PCL–gelatin–BCNC nanofibers promoted axon growth and elongation of glioblastoma cells (U251 MG), making it a potential 3D platform to support cell proliferation and adhesion. Additionally, Rasti Boroojeni et al. looked into the synergistic effect of scaffold conductivity and sustained release of thyroid hormone triiodothyronine (T3) on selective NSC differentiation toward oligodendrocyte-like cells ^[39]. T3-loaded CS NPs were synthesized by ionic gelation and introduced within the PCL solution, while a polyaniline–graphene (PAG) nanocomposite was prepared and incorporated into gelatin nanofibers. The two solutions were co-electrospun using two different needles on opposite sides of the electrospinning device, resulting in a composite PCL–T3@CS–gelatin–PAG nanofibers. The electrospun composite nanofibers loaded with 2% PAG and 2% T3@CS NPs exhibited the best biocompatible cellular support and proliferation with good electrical conductivity of 10.8·10⁻⁵ S·cm⁻¹. Furthermore, PCL–T3@CS–gelatin–PAG nanofibers efficiently induced in vitro differentiation of bone marrow-derived NSCs (BM-NSCs) into oligodendrocyte-like cells, as confirmed by high level of oligodendrocyte marker expression, like O4, oligodendrocyte transcription factor (Olig2), platelet-derived growth factor receptor-alpha (PDGFR-α), O1, myelin/oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP), which might be related to sustained release of T3 over time. Molina-Peña, R. and co-workers ^[40] proposed a strategy for trapping GBM cells by means of a 40 μm-thick CS electrospun membrane encapsulating SF-1α-loaded PLGA-based NPs (CS/SF1-α@PLGA), showing an average fiber diameter of 261 ± 45 nm. SF1-α@PLGA NPs were clearly visible along nanofibers length as “bulges” on SEM analysis. Although the membranes lost over 10% of their initial mass after 5 weeks, they also provided a sustained release of SDF-1α. Furthermore, high cytocompatibility was confirmed in vitro by using several cell lines in particular rat primary astrocytes, showing excellent anchoring sites to support the adhesion of human GBM cells by extension of their pseudopodia. Recently, Jiang et al. exploited the possibility of developing curcumin (Curc)-loaded zeolite Y NPs (nZY) integrated into hybrid PCL–gelatin (PG) electrospun nanofibers (Curc@nZY-PG NFs) as an implantable DDS for potential post-surgical GBM treatment ^[41]. Curc@nZY-PG NFs exhibited slightly rough and randomly oriented fibers with a mean diameter of 640 nm. PCL, gelatin and Cur@nZY NPs strongly interacted among them by means of hydrogen bonds, which resulted in a rigid intermolecular interactive network formation. This translates to a more stable nanofibrous mat exhibiting a controlled biodegradability (63% of mass loss within three months), a steadier drug release profile over a relatively long time (47% of Curc release within 14 days) and higher tensile strength (2.75 ± 0.1 MPa) and Young’s modulus (151.3 ± 5.5 MPa). Curc@nZY-PG NFs exhibited superior cytotoxicity, anti-cell-migratory activity, and proapoptotic effect in the first 72 h against U87-MG cells compared to normal human astrocytes (NHAs). A Curc@nZY-PG NFs proapoptotic effect was also confirmed by nuclear fragmentation and upregulation of Bax, CASP-3, and CASP-9 expression levels along with a downregulation of hTERT and antiapoptotic BCL-2 expression levels in U87-MG cells. Concurrently, Yang et al. proposed near-infrared (NIR)-II-triggered composite electrospun nanofibers based on CS embedding copper-selenide (CuSe) NPs to simultaneously reach rapid intracranial hemostasis, killing superbug and residual cancer cells associated with GBM post-surgery ^[42]. This approach represents a prompt strategy to shorten craniotomy time, significantly reducing tumor recurrence and accelerating incision repair, through a minimally invasive surgery. Bazzazzadeh and co-workers exploited the incorporation of magnetic MIL-53 nanometal organic framework particles (NMOFs) into poly(acrylic acid) (PAA)-grafted CS–PU (PAA-g-CS/PU) core–shell nanofibers for controlled release of TMZ and paclitaxel (PTX) against U-87 MG cells in a dual chemo/hyperthermia therapy ^[43]. NMOF-CS-g-PAA-PTX-TMZ/PU core–shell nanofibers with an average fiber diameter of 250–300 nm were produced by coaxial electrospinning. NMOF loading increased the Brunauer–Emmett–Teller (BET) surface area of core–shell fibers from 123 to 178 m²·g⁻¹. The nanofibers exhibited an encapsulation efficiency of TMZ and PTX higher than 80%, which were released with a maximum release rate under pH of 5.5 at 43 °C and minimum release rate under pH of 7.4 at 37 °C. The co-delivery of TMZ and PTX from the nanofibers resulted in U-87 MG cell necrosis of 56.3% (−AMF) and 68.9% (+AMF), respectively, compared to the same nanofibers without TMZ/PTX: 3.2% (CS-g-PAA/PU) and 15.2% (NMOF-CS-g-PAA/PU). In addition, the flow cytometry results indicated that 31.3% and 49.6% of apoptotic cell death occurred for U-87 MG glioblastoma cells treated with NMOF-CS-g-PAA–TMZ-PTX/PU in the absence and presence of AMF, respectively.

4. Neat and Nanocomposite Fibrogels

Over the last few years, biomaterials and hydrogels, either natural or synthetic, have been widely investigated for potential use in the brain, not only as growth factors, cell or therapeutic drug delivery carriers, but also in the development of injectable formulations and scaffolds to support and guide the growth of endogenous or exogenous cells after implantation into damaged areas of brain tissue ^[44]^[45]^[46]^[47]^[48]^[49]^[50]. Even though hydrogels can change the degree of swelling and/or cross-linking in their structure, they are often reported to have poor mechanical properties, with high degradation rates and with a low modulus matching the brain, which may limit their final application. However, for brain applications, they may provide a biocompatible 3D matrix with interconnected pores that fairly mimics the native ECM, with highly controlled properties like biodegradation. As a delivery platform, they may offer chemical and biological smart responsiveness to external stimuli like pH or temperature ^[51]^[52]^[53]. It is important to remember that the hydrogel composition can restrict the ability of cells to adhere and proliferate. Nevertheless, this can be avoided by covalently attaching peptide sequences to the polymer chains of hydrogel, which may affect the activity of embedded cells ^[54]. However, with the right modification, some hydrogel limitations might be easily overcome. Indeed, hydrogels can be suitably chemically modified to improve the mechanical properties and increase their residence time ^[55]^[56]^[57]^[58]. Hydrogels can be also modified by using electrospun nanofibers. In addition to mechanically strengthening the hydrogel, electrospun nanofibers provide ECM-mimicking substrates, creating an environment that perfectly replicates the organization of collagen fibers and proteoglycans in the original ECM to enhance cell adhesion and differentiation ^[59]^[60]. Indeed, due to their ability to withstand contractile stresses, they are a preferred material for cell attachment sites. Electrospun fibers are also composed, scaled, and topographically manufactured in a tailored way. Compared to other materials, electrospun nanofibers can be easily prepared using a wide range of materials, and they are characterized by good surface chemical properties of adsorbing drugs, high drug loading efficiency, and controlled drug delivery ^[61]^[62]. Above all, to meet the specific requirements for the final application, the design of injectable formulations, 2D mats or 3D scaffolds based on electrospun nanofibers involves varying their physical/topographical cues, such as diameter, alignment, density, surface chemistry, and load composition, to endow the nanofibers with different and peculiar properties ^[63]. Indeed, the structure and morphology of electrospun nanofibers are important factors that support and guide cell growth. At present, a variety of hydrogels and electrospun nanofibers have been widely used in brain research. Natural and synthetic materials with high biocompatibility have been applied for the fabrication of electrospun nanofibers, including collagen, HA, CS, silk, fibronectin, fibrinogen, PLLA, poly(L, D-lactide) (PLA), PCL, PLGA, polystyrene (PS), and polypyrrole (Ppy). There are two different ways to add electrospun fibers into the hydrogels. The first involves building a sandwich model by laminating layers of hydrogel and nanofibers. This technique allows creating a multilayered fibrous hydrogel in a repeatable, predesigned manner, but it does not offer injectability for such approach. The morphology and mechanical properties of the structure can be fine-tuned by varying the layout, classes of fibers and hydrogels employed. To increase the mechanical integrity, hydrogels are typically directly cross-linked with electrospun fibers. Hydrogel precursor solutions can be used as soak solutions to submerge fiber mats or dropped onto previously constructed fiber meshes ^[64]^[65]. The second method of hydrogel functionalization with electrospun fibers is simpler and more common. Physical methods, such as solution blending, can be applied to produce neat hybrids and nanocomposite fibrous hydrogels with homogeneous properties by dispersion of the electrospun-fibers within a hydrogel solution. Electrospun fibers—cut into short fibers—can be homogeneously dispersed in a solution using an ultrasonic homogenizer to interpenetrate and entangle through the walls and pores of the hydrogels and became completely integrated in the matrix. Afterwards, the mixture can be successively freeze-dried to obtain porous 3D sponges or aerogels ^[66]. Chemical cross-linking or temperature-mediated cross-linking among short fibers can be further adopted to modulate multifunctional structure features ^[67]. It is essential to adjust the composition of electrospun fibers to facilitate fiber dissolution and dispersion with a well-defined architecture in injectable or noninjectable hydrogel solutions ^[68]. Injectable therapies are beneficial because they are less invasive, which lowers the risk of infection and shortens the recovery period. In addition, injectable hydrogels play a critical role when material needs to be quickly injected into otherwise inaccessible parts of the body, such as neural tissue. Another interesting approach is adding nanofillers, such as inorganic or organic particles, to the hydrogel matrix or decorating/loading fibers with such nanoparticles. In such fibrous nanocomposite systems, hydrogels are the perfect medium for nanofiller dispersion. By boosting bioactivity, mechanical stiffness, magneto-electric features, or enabling regulated release of drugs or growth factors, nanofillers may provide a supportive role. The next sections will independently address each approach, summarizing the latest research on brain tissue applications.

4.1. Multilayers

The lamination method was used by Kaixiang Huang et al. ^[69]. The authors electrospun PS nanofibers onto one face of a Matrigel-coated paper as a BBB model. The addition of astrocytes (iPS-Astros) increased the barrier properties of induced pluripotent stem cells (hiPSCs)-derived endothelial cells (iPS-ECs), indicating positive regulation of astrocytes to the BBB model. Further RNA-sequencing gene analysis highlighted that the introduction of iPS-Astros regulated the gene expression of the tight junction protein family and vascular endothelial (VE)-cadherin in iPS-ECs, explaining the increased trans-endothelial electrical resistance ^[69]. In the field of brain tissue engineering, PLLA, CS and gelatin were used to design a triple-layered biocomposite substitute of dura mater ^[70]. Initially, PLLA films were produced with varying w/v concentrations (7%, 8.5%, and 10%). PLLA–CS solution was directly spun on the PLLA film surface at different ratios (10/90, 20/80, and 30/70, w/w) to create the intermediate layer. Afterwards, a mixture of equivalent gelatin solution (15 w/v%) and CS at different concentrations (0, 1, 2, and 3 wt%) was prepared as hydrogel precursor. Small intestine submucosa (SIS) powders (0.5%, w/v) were also added. The hydrogel precursor was poured into the template ^[70]. Then, the double-layered electrospun membrane was cut into strips and placed on the hydrogel precursor with the CS–PLLA layer facing down. One layer of gelatin–CS hydrogel with and without acellular SIS powders was prepared for in vitro and in vivo study, respectively. Results showed that the three-layer structure was stable after 30 days in vitro. In vivo, the structure showed good stability over 14 days. Even though the tensile strength (366 ± 2 kPa) was lower than values reported for the natural tissue, it is important to remember that the dura can only withstand a maximum of 6.66 kPa of cerebrospinal fluid pressure. The PLLA layer offered excellent leakage prevention property, due to the hydrophobic properties conferred by methyl enrichment on the surface obtained during electrospinning process. In the present study, in vitro results revealed that fibroblasts were only present on the top surface of the PLLA film after 5 days of cell culture, thus indicating a satisfactory cell barrier function. The in vivo study also revealed that after 14 days, cells expanded into the hydrogel pores and occupied the degradation area, forming new tissue with newly formed vessels. In contrast, very few cells passed through the double-electrospun layer and very little collagen was deposited at the cellular infiltration sites of PLLA film. Furthermore, no overt inflammatory responses were observed against the PLLA film, ruling out the possibility of adhesion brought on by a strong inflammatory response. Additionally, the in vivo experiments demonstrated the bioactivity of hydrogels to support tissue regeneration, most likely because of the comparatively slow rate of disintegration of high-molecular-weight PLLA films and the prolonged release of SIS powders. Additionally, SIS powders induced M2-like macrophage polarization ^[70]. A unique technique for building a layered three-dimensional scaffold was presented by Honkamaki et al. to improve the artificial microenvironment for neurons produced from human pluripotent stem cells (hPSCs) ^[71]. The invention of a revolving dual-electrode collector and the assembly of fibers onto a substrate that was horizontally positioned between the electrodes were the basis for the Honkamki method’s originality. The apparatus allowed electrospinning well-aligned PLA fibers directly on top of type 1 collagen hydrogel embedding hPSC neurons. The three parallel fiber layers arranged within a 3D hydrogel matrix comprised the 3D scaffold. After 2 weeks of cell culture, the orientation of the individual neurons close to the fiber layer was analyzed to study the influence of the fibers on the directed growth of neurons. The findings demonstrated that in the absence of further functionalization, the fiber layers enhanced directed cell proliferation and neurite extension ^[71]. Recently, enzymatically cross-linked gelatin hydrogels with stiffness varying from 8 to 80 kPa were coupled with a sparse monolayer of PCL electrospun fibers ^[72]. Using electrospinning as a method to introduce anisotropic characteristics to the hydrogels, PCL fibers were spun on top of the gel in either a random or aligned way without appreciably changing the stiffness of the hydrogel substrate. On the fibrous hydrogel scaffolds, a human neural progenitor cell line attached, proliferated, and differentiated ^[72].

Microscale integration of electrospun fibers and hydrogels via a proper integration of electrospraying and air brush-spraying to deposit nanocomposite hydrogel solutions on the same collection for electrospun fibers have been also investigated ^[73]. For example, tri-layered zein–PVP–graphene oxide–zein nanofiber mats have been obtained by Lee et al. ^[74] in sandwich-layered structures with biphasic drug release behavior. In particular, the presence of graphene oxide in PVP nanofibers results in improved mechanical performance of mats and tailored release features.

4.2. Injectable/Scaffold Systems

Hsieh et al. investigated the incorporation of electrospun fibers in hyaluronic acid and methylcellulose blended fibrous hydrogels as a potential injectable cell delivery vehicle for repair of the CNS ^[75]. The authors fabricated two types of electrospun fibers: genipin cross-linked collagen and a co-polymer of poly(ε-caprolactoneco-DL-lactide) (PCL-PLA). The fibers in the collected fiber mats were broken up into smaller pieces using sonication, and then the fragments were mixed with the hydrogel (5 mg/mL). With a 30 G needle, the blended fibrous hydrogel could still be injected. In fact, the hydrogel contained a good distribution of the electrospun fibers. Cells seemed to aggregate and concentrate around the fibers when mixed with neural stem/progenitor cells. The evaluation of cell proliferation revealed that the collagen electrospun fibers had a negative impact on cell viability, as evidenced by a decrease in the number of cells after 7 days in culture. Synthetic fiber composites seemed to influence cell differentiation more than their natural equivalent ^[75]. A hydrogel composed of 1.5% SeaPrep agarose and 7.0% Methocel methylcellulose was produced by Rivet et al. ^[76]. PVA electrospun fibers mats fragments were dispersed into the hydrogel matrix ^[76]. The agarose–methylcellulose combination was selected because of biocompatibility, physiologically relevant thermogelation characteristics, and injectability. Moreover, the materials based on cellulose did not undergo considerable degradation during the investigation, which allowed the researchers to study and distinguish the infiltration induced by hydrogel degradation from that induced by electrospun fiber topography. To demonstrate the injectability of the hybrid scaffold and determine whether the presence of fibronectin improved cellular recognition of the injected fibers, the scaffold was implanted into the rat striatum. When injected into the rat striatum, infiltrating macrophages/microglia and resident astrocytes were able to locate the fibers and use their cues for migration into the hybrid matrix ^[76]. Ting-Yi Wang et al. developed a composite scaffold incorporating electrospun PLA short nanofibers embedded within a thermoresponsive xyloglucan hydrogel, which could be easily injected into the injured brain ^[77]. Moreover, glial-derived neurotrophic factor (GDNF), a protein known to support axonal growth and cell survival, was embedded within the fibrous hydrogel or covalently bonded to it to offer regulated administration and enhance the trophic qualities of the host brain. The materials’ ability to sustain ventral midbrain (VM) dopamine progenitors, continuously release GDNF, and have an impact on cell survival and dopaminergic axon formation was validated in vitro. In Parkinsonian mice, these fibrous blended hydrogels were shown to improve VM graft survival and striatal re-innervation in without adversely affecting the host immune response. This result was further increased by GDNF administration. All these findings offered a way to greatly modify the environment of the damaged brain, promoting improved graft neuron integration and survival ^[77]. Bruggeman et al. used self-assembling peptide (SAP) hydrogels based on a well-known peptide epitope from laminin, a common ECM protein, particularly within the CNS: fluorenylmethyloxycarbonyl (Fmoc) capped aspartic acid–isoleucine–lysine–valine–alanine–valine (DIKVAV) ^[78]. The peptide generated around 10 nm-diameter nanofibers, forming a macroscale supramolecular hydrogel with easily adjustable assembly-derived stiffness to suit different types of soft tissues. This is a crucial factor in guiding the survival, integration, and differentiation of endogenous cells. PLA was electrospun into nanofibers with diameters of approximately 100–2000 nm. Short fibers with a length of approximately 20–100 μm were combined with the DIKVAV hydrogel. The resulting hybrid fibrous hydrogel conserved the macroscopic characteristics of the SAP hydrogel, particularly its injectable, shear-thinning feature, which is crucial for microinjection into the brain ^[78]. At the nanoscale, the hybrid fibrous hydrogel highlighted a hierarchical architecture at multiple length scales, due to the range of nanofibers found in each component of the materials. The addition of short fibers to the hydrogel had only a minor impact on the mechanical properties of hydrogel, with a slight increase in stiffness observed with increasing short-fiber concentration, suggesting that the well-dispersed short fibers were only loosely interacting with the SAP network. The stability of the peptide structures was largely preserved. Multiple growth factors, including the neurotrophic growth factor GDNF and brain derived neurotrophic factor (BDNF), were able to be temporally/spatially released in controlled fashion by the SAP hydrogels. Through the combination of these materials, the authors were able to provide a range of nanofiber diameters and hence improved structural biomimicry of the ECM ^[78]. Recently, bone marrow mesenchymal stem cells (BMSCs) were loaded into rigid–flexible fibrous hydrogels made of electrospun nanofibers and self-adapting, injectable hydrogel. The effects of these loaded BMSCs on ischemia insult were studied ^[79]. Firstly, coaxial electrospinning was performed using 10% w/v solutions of PCL and gelatin methacryloyl (GelMA). Subsequently, 1% dibenzaldehyde-terminated polyethylene glycol (DF-PEG4000) and 3% glycol chitosan (GC) were combined (1:3) to produce a hydrogel. The concentration of nanofibers in the gel was 5 mg/mL. Based on an in vitro examination of BMSC survivability, migration, neurite growth, angiogenic potential, and paracrine effects, it was found that BMSCs loaded into fibrous hydrogels exhibited superior therapeutic efficacy to saline-laden BMSCs. Additionally, in vivo, BMSCs improved neurological impairments, decreased microglial and astrocyte overactivation, and enhanced neuronal proliferation and vascular expansion. They also greatly reduced the amount of brain edema and the infarct volume. According to bioinformatic analysis, BMSCs embedded into fibrous hydrogels were able to raise the activity of the PI3K/AKT signaling pathway by decreasing the quantity of exosomal miR-206e3p. In summary, BMSCs loaded in innovative blended fibrous hydrogels exhibited clear neuroprotective effects, reducing ischemia injury by promoting angiogenesis and neural regeneration in the brain following ischemic stroke. These findings offered a promising strategy for using cell transplantation to treat CNS diseases in clinical settings ^[79].

Karimi et al. developed complex structures obtained via the incorporation of magnetic short nanofibers (M.SNFs) and olfactory ecto-mesenchymal stem cells (OE-MSCs) into alginate hydrogels ^[80]. Wet-electrospun gelatin and superparamagnetic iron oxide nanoparticle (SPION) nanocomposite fibers were chopped and subsequently embedded in alginate hydrogels containing OE-MSCs derived from a neural crest. The results highlighted an accelerated neural-like differentiation of OE-MSCs due to the presence of SPIONs ^[80].

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