4.1 Classification of Stimuli-Responsive Polymers

This chapter focuses on the fabrication, characterization, and applications of stimuli-responsive fiber-based materials, which are composed of polymers responsive either solely or multiply to temperature, light, or electric/magnetic field. Stimuli-responsive polymers could be classified as either physical or chemical stimuli-responsive ones (Figure 4.1). The physical stimuli such as temperature, electric, or magnetic fields will affect the level of various energy sources and alter molecular interactions at critical onset points. Physical stimuli are sometimes favorable because they allow local and remote control. On the other hand, the appearance of numerous bioactive molecules is tightly controlled to maintain a normal metabolic balance via the feedback system called homeostasis in human body. Therefore, chemical or biochemical stimulus such as pH, ionic factors, or biomolecules has been considered as another important stimulus. Some systems have been developed to combine two or more stimuli-responsive mechanisms into one polymer system, the so-called dual- or multi-responsive polymer systems. One of the most widely used stimuli-responsive polymers is poly(N-isopropylacrylamide) (PNIPAAm) and its derivatives. A PNIPAAm solution, which undergoes a sharp yet reversible phase transition from monophasic below a specific temperature to biphasic above it, generally exhibits the so-called lower critical solution temperature (LCST) behavior. PNIPAAm has an LCST of 32°C in aqueous solution. There have been several studies on the electrospun PNIPAAm nanofibers [1–3]. These temperature-responsive nanofibers show much quicker response times than the corresponding bulk materials because the nanofibers have an extremely larger external surface area (Figure 4.2). However, one of the major challenges in the development of PNIPAAm nanofibers is that they are not stable in water and disperse easily; therefore, an incorporation of non-soluble components or cross-linkable moieties into PNIPAAm nano-fibers is required. Therefore, careful choice of polymers and rational design of nanofiber are crucial to fabricate dynamic and responsive fibers. Also, use of different precursor materials makes it possible to fabricate fibers, which respond to other stimuli such as pH, light, temperature, or magnetic, that could better meet the demands of the desired applications. The following sections will review some of the varieties of stimuli-responsive nanofibers and their key fabrication methods as well as some of their applications in biomedical fields.

4.2 Fiber Fabrication

Polymeric nanofibers can be processed by diverse techniques such as phase separation, self-assembly, electrospinning, drawing, and microfluidic devices (Figure 4.3).

Phase separation is a method that has long been used to fabricate porous polymer fibrous membranes or sponges by inducing the separation of a polymer solution into two different phases, namely, the polymer-poor phase (low polymer concentration) and the polymer-rich phase (high polymer concentration). This enables the preparation of a three-dimensional nanofibrous structure with interconnected pores.

Self-assembly by a bottom-up method for the preparation of nanofibers from polymers, peptides, and macromolecules is a versatile and powerful technique to construct well-defined nanostructures. This is accomplished by spontaneous and automatic organization of molecules into desired structures through various types of intermolecular interactions [4]. Lipid membranes, which control cellular processes, assemble from a hydrophobic tail group and a hydrophilic head group [5]. This natural organization of life is driven by noncovalent forces. It is known that polymer fibers and liquid crystals (LCs) all self-assemble in solutions based on the same principles that drive natural molecular assembly [4]. Recently, Saito et al. [6] have developed a stimuli-responsive self-assembled system from lyotropic LCs composed of cyclic ethynylhelicene oligomers. Through careful control of temperature, the LCs were able to be dynamically changed from anisotropically aligned fibers to turbid gels. It is thought that these systems have potential biological applications in mimicking actin. Bitton et al. [7] have used peptide amphiphiles in combination with hyaluronic acid in dynamic self-assembly of hierarchical nanofibers under electrostatic control. Heparin was found to drive the self-assembly process by the formation of a dense diffusion barrier.

Electrospinning is considered to be a simple technique to produce micro-sized or nano-sized fibers. Nevertheless, controlling fiber alignment by electrospinning has not been a simple task [8]. In electrospinning, the “Taylor cone” of a polymer solution droplet forms at the end of a capillary tip when electrical forces are applied [9]. When the electric field reaches a critical level at which the repulsive electric force overcomes the surface tension force, a charged jet of the solution is ejected from the tip of the “Taylor cone.” As the jet diameter decreases when the jet flies to the collector, the radial forces from charged ions exceed the cohesive forces of the jet solution, causing it to split into many fibers. Furthermore, these divided fibers repel each other, leading to chaotic trajectories and bending instability. At the same time, the solvent is evaporated and the polymer solidifies on the collector. Thus, continuous fibers are laid to form a nonwoven sheet. With the increased control over spatial alignment and fiber diameters, electrospinning will play a key role in the development of future smart fibers. A recent example where control over the fiber diameter by tuning the electrospinning conditions had an influence on the fiber properties was shown using PNIPAAm/polystyrene [10]. Here electrospun fiber mats were fabricated with superhydrophilic and superhydrophobic properties. The large surface area of the fibers and the temperature-responsive PNIPAAm contributed to the fast wettability switching of these electrospun fiber mats.

Drawing is an optimized method for the fabrication of single fibers using a viscous polymer solution with volatile organic solvents. A continuous long linear fiber can be obtained by the drawing method, and the fiber diameter relies on the size of the needle (micropipette), polymer solution flow rate, and temperature, which affect the viscosity of the polymer and the evaporation rate of the solvent. The fabrication of fibers by the drawing process has been understood since Carothers et al. [11] reported it in the 1930s. Yuan et al. [12] have recently shown that 3D structures can be directly written using a programmable micro-milling machine. These precisely fabricated biodegradable arrays can be used for endothelial cell growth and are an exciting precursor to a functional microvascular network. Polymer fibers for microfluidic devices are also not a new concept, but recently, Yildirim et al. [13] have shown that microfluidic devices can be assembled from drawn polymer fibers, with the microfluidic channels incorporated into the individual fiber. Microfluidic devices fabricated by this method have the potential to be applied in a high-throughput, low-cost, point-of-care analysis, which can be used for early-stage detection of diseases in the field.

The fabrication of fibers using microfluidic devices is also being explored. By controlling the internal morphology of nanofibers using expansion flow in a coaxial microfluidic channel, a broad range of fibers with chemical and mechanical properties have been realized [14]. The control over fiber morphology has implications for tissue engineering, as cell proliferation is known to be dependent on the scaffold morphology. Often one of the limitations of other techniques used to fabricate fibers is the choice of materials. Yu et al. [15] have recently combined droplet microfluidics with wet spinning to fabricate hybrid bamboo biomimetic fibers, which have multiple functionalities. Calcium alginate was used to bind polymer microspheres composed of poly(lactic-co-glycolic acid) (PLGA) into a bamboo-like architecture. The authors also demonstrated the flexibility of their method by incorporating hydrophobic droplets and cell microspheroids into the calcium alginate fiber. The advantage of this method is the flexibility and the choice of materials that can be used in the fabrication of new fibers.

4.3 Biomedical Application

4.3.2 Drug Delivery Systems (DDSs)

DDSs are quite interesting applications that have evolved over the years, long before sustained DDSs were developed. Recently, many researchers have focused on controlled DDSs because these have become possible with the use of smart materials with remotely controllable properties. Therefore, drugs can be released to targeted regions on demand.

In this regard, temperature-responsive polymer-grafted chitosan (CTS) nanofibers were reported [23]. First, CTS-graft-PNIPAAm copolymer was also synthesized by using 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide and N-hydroxysuccinimide (NHS) as grafting agents to graft carboxyl-terminated PNIPAAm chains onto the CTS biomacromolecules. And then, CTS-g-PNIPAAm with or without bovine serum albumin (BSA) was fabricated into nanofibers through electrospinning using poly(ethylene oxide) (PEO) as a fiber-forming facilitating additive. The CTS-g-PNIPAAm/PEO nanofibers showed a pH- and temperature-dependent swelling/deswelling behavior. The drug release study showed that the nanofibers provided controlled release of the entrapped protein.

Zhang and Yarin [24] introduced two types of smart nanofibers for the study of the release of a dye rhodamine 610 chloride (rhodamine B) as a drug model. The electrospun nanofibers were fabricated from poly (NIPAAm-co-methylmethacrylate (MMA)) and poly(NIPAAm-co-MMA-co-acrylic acid (AAc)) copolymers, which are temperature-responsive and pH/temperature dual-responsive copolymers, respectively. In the case of a dye release study using poly(NIPAAm-co-MMA) nanofibers, a relatively low cumulative release rate (on the order of 1%) was observed below LCST, which resembled that of pure PMMA nanofibers. By the time the temperature crossed the LCST, however, the corresponding cumulative release rate had rapidly reached about 10% and saturated at about 12%. Moreover, the release rate demonstrated the largest thermal response. It is emphasized that poly(NIPAAm-co-MMA) nanofibers exhibited a positive thermoresponsive release profile, that is, a higher release rate when the nanofibers shrink above LCST than when the nanofibers swell below LCST.

Cui et al. [25] fabricated pH-responsive nanofibers for a local drug delivery system by introducing acid-labile acetal groups into a biodegradable backbone. The drug (paracetamol)-incorporated nanofibers were prepared by electrospinning [25]. The profile of drug release from the electrospun nanofibers prepared from an acid-labile polymer was evaluated in buffer solutions of different pHs (4.0, 5.5, and 7.0). In the absence of an acid group in the polymer, there were no significant differences in the profile among the buffer solutions of different pHs. Following the introduction of an acid group, significantly different drug release profiles were observed. The total amounts of the drug released were about 67% and 78% after incubation in pH 5.5 and pH 4.0 buffer solutions, respectively, and only 26% after incubation in pH 7.4. Moreover, the amount of the drug burst-released depended on the contents of acid-labile segments and the polymer nanofibers incubated in pH 4.0 medium. Additionally, when the pHs of buffer solutions were 5.5 and 4.0, the amount of drug released from pH-sensitive nanofibers increased owing to the pH-induced structural changes of the polymeric nanofibers and the degradation of the matrix polymer.

Kim et al. [26] fabricated novel temperature-responsive nanofibers for “on–off” drug release systems (Figure 4.4). They synthesized the nanofibers using the temperature-responsive polymer, poly(NIPAAm-co-N-hydroxylmethylacrylamide(HMAAm)), and fluorescein isothiocyanate (FITC)-dextran was directly embedded into these nanofibers as the drug model. The prepared nanofibers showed “on–off” switchable swelling–shrinking behavior in response to temperature alternation cycles upon crossing the LCST; correspondingly, the dextran release profile showed the “on–off” switchable behavior. After the first heating, approximately 30% of the loaded dextran was released from the nanofibers. The release stopped after cooling below LCST, but the release restarted upon the second heating. In this system, the dextran is released by it being squeezed out of the collapsed interconnected cross-linked polymer network. The release of dextran stops upon cooling because of the suppressed diffusion of the dextran molecules, which have high molecular weight. Almost all of the dextran was released from the nanofibers after six temperature cycles. This kind of “on–off” drug release system can release a certain amount of a drug within a short time after an off period that can be programmed according to the circadian rhythm of the disease being treated. They also showed temperature- and magnetic-field-responsive electrospun nanofibers containing an anticancer drug (doxorubicin, DOX) and magnetic nanoparticles (MNPs). Upon alternating magnetic field (AMF) application, the temperature-responsive nanofibers shrank in response to the increased temperature triggered by MNPs [27]. The incorporated DOX was released from nanofibers owing to the hyperthermic effect. These nanofibers demonstrated the synergic effect of hyperthermia and chemotherapy for cancer cell therapy with the hyperthermic treatment time being less than 5 min, which can reduce the side effects on normal tissues or cells.

On the other hand, Fu et al. [28] studied the development of a novel photoresponsive “on–off” release system for a prodrug, based on host–guest interaction on the photoresponsive and cross-linked nanofiber surface. The nanofibers with stimuli-responsive surfaces were electrospun from the block copolymer via controlled radical polymerization, and then the surfaces were modified with photosensitive 4-propargyloxyazobenzene by “click chemistry.” Followed by UV irradiation at a wavelength of 365 nm, the prodrug was released quickly from nanofiber surfaces, as the photosensitive group transformed from the trans to the cis form configuration. In the dark, however, there was almost no release of the prodrug from the nanofiber surfaces, or between the host and the guest, that is, between the prodrug and the surfaces. Furthermore, this system showed a quick response and controllable release of the prodrug, as revealed by the multistep “on–off” release profile under UV irradiation. The concentration of the prodrug in solution increases gradually in the next 10 min upon UV exposure. The concentration of the prodrug ceases to increase upon removal of the UV irradiation after 20 min. The concentration of the prodrug remains almost constant in the next 20 min, in the absence of UV irradiation. When UV irradiation is resumed after that, the concentration of the prodrug in solution increases again.

4.3.3 Cell Application

The stimuli-responsive nanofiber meshes have been also explored as cell manipulation/storage systems. Maeda et al. [1] envision the temperature-responsive nanofiber meshes in a cell storage application. The cryopreservation of mammalian cells was demonstrated without loss of viability during freezing process by using a PNIPAAm mesh because dehydrated PNIPAAm chains suppressed the formation of large extracellular ice crystals during the freeze/thaw process (Figure 4.5). Sur et al. [29], on the other hand, prepared peptide amphiphile nanofiber matrices by incorporation of a photolabile artificial amino acid to control bioactivity. The peptide amphiphiles self-assembled into cylindrical nanofibers. Cell adhesion was dynamically controlled by rapid photolytic removal of the RGDS peptide from the nanofiber. This dynamic temporal control of cell-material interactions can become an important component in the design of new artificial matrices based on nanostructures for regenerative medicine research studies.

Fukunaga et al. [30] and Sawada et al. [31] developed calcium ion (Ca²⁺)-responsive hydrogels composed of designed β-sheet peptides. As the novel designed peptide, E1Y9, has a glutamic acid residue to interact with Ca²⁺, the peptide in the sol-state self-assembled into hydrogels in the presence of Ca²⁺. The hydrogels showed a high cell-adhesive ability that was similar in magnitude to fibronectin. Thus, the novel peptide-based nanofiber hydrogels can facilitate development studies for 3D cell cultures for tissue engineering.

On the other hand, the authors have innovated a nanofiber mesh for the removal of toxins from the blood, which they are hopeful to incorporate into wearable blood purification systems for kidney failure patients [32]. We made our nanofiber mesh using two components: a blood-compatible primary matrix polymer made from polyethylene-co-vinyl alcohol, or EVOH, and several different forms of zeolites. Zeolites have microporous structures capable of adsorbing toxins such as creatinine from the blood. Different zeolites have different pore sizes, meaning they can be used to selectively adsorb specific solutes. Our result demonstrated that a 16-g mesh is enough to remove all the creatinine produced in one day by the human body. Although the new design is still in its early stages and not yet ready for production, nanofiber-based biomaterials will soon be a feasible, compact, and cheap alternative to dialysis for kidney failure patients across the world.

Kim et al. [33] prepared a temperature-responsive fibrous hydrogel that was used as a cell capture and release membrane. The fibrous hydrogel captured and released cells by self-wrapping, encapsulation, and shrinking in response to temperature changes. In the cell culture medium at 37°C, a droplet of cells was dropped on a fiber web, and the web immediately started to fold up and wrap around the droplet. The folding of the fiber web was very fast and was completed within 30 s. After 10 min at 37°C, the fiber web was transferred to a refrigerator at 4°C and allowed to swell for another 10 min. The fiber web became transparent with a hydrogel-like morphology, and the fibrous structure was maintained. When the web was heated again to 37°C, the hydrogel-like fibrous web shrank and became opaque. After three cycles of temperature alternations, almost all of the cells (>95%) seeded on the web were released, whereas only a few cells were released upon swelling during the cooling from 37°C to 4°C. Live/dead assay of the cells released from the web showed that almost all of the cells were alive, and the condition and proliferation of the cells were determined. The most interesting application of magnetic-field-responsive fibers is in the hyperthermic treatment of cancer cells. Huang et al. [34] reported MNP-incorporated polystyrene (PS-MNP) nanofibers that showed the hyperthermic effect on cultured SKOV-3 cells. When the PS-MNP nanofibers were exposed to the AMF for 10 min or longer, all of the cancer cells were destroyed, and the association of the cancer cells with the nanofibers was also demonstrated. Here, improved hyperthermic smart fibers are introduced.

4.4 Filters

Owing to the high specific surface area and high porosity of nanofibers, they have been developed as filter media, which are very useful for the separation or purification of not only waste water but also biomolecules. Furthermore, filtration has been improved and new types of nanofibers have been developed, such as hollow fibers. pH-responsive hollow fibers for protein antifouling were developed by Zou et al. [35]. The hollow fibers were prepared by a dry-wet spinning technique based on a liquid–liquid phase separation technique. Poly(MMA-co-AAc-co-vinylpyrrolidone (VP)) terpolymer was synthesized to modify polyestersulfone hollow fiber membranes. When the pH changed from 2.0 to 11.0 in pH-responsive filtration, the fluxes increased under acid conditions owing to the increased hydrophilicity and showed pH dependence, that is, fluxes decreased with increasing pH. These results indicated that the flux variation increased with the increase in the amount of the terpolymer, and the pH sensitivity was caused by the dissociation of AAc in the terpolymers. In a further study by the same group, they used another type of terpolymer (poly (St-co-AAc-co-VP)), and two mechanisms underlying the functions of the pH-sensitive flat-sheet membranes (FSMs) and hollow fiber membranes were clarified, namely, the pore size change theory and electroviscous effect [36]. Firstly, regarding the pore size change theory, the swelling–shrinking effect of the ionized–deionized AAc chain was deemed to be the main reason for the water flux change and solute rejection of the pore-filled pH-sensitive FSM. Secondly, regarding the electroviscous effect, the carboxylic acids of AAc could dissociate to carboxylate ions at pH 12.0 to provide a high charge density in the copolymer, resulting in the swelling of the terpolymer. Furthermore, the solution flowing through the pores in the membranes was affected by the electroviscous effect during the filtration. The electroviscous effect is a physical phenomenon that occurs when an electrolyte solution passes through a narrow capillary or pore with charged surfaces.

4.5 Conclusion

Fibers produced from various types of responsive polymers at various production stages have already been explored for a wide range of applications in diverse fields, including nanotechnology, textiles, industry, fuel cells, tissue engineering, regenerative medicine, and biomaterials. These fibers, particularly well-defined nanofibers, have astounding features compared with other types of materials, for instance, high specific surface area, high porosity, and biomimetic properties, providing promising potential applications. Therefore, fibers have been explored as cell culture scaffolds, DDSs, and other biomedical applications. Among these types of fibers, those that combined well with stimuli-responsive media are called smart fibers. They can be turned on and off remotely (“on–off” controllable) by applying external stimuli while the fiber characteristics remained. The applications of smart fibers are not limited in vitro or in vivo. Thus, the smart fibers have gained much attention from researchers because their remotely controllable characteristics can be used to match the circadian rhythm of a disease, which could be a good candidate for the treatment of cancer, damaged tissues, or chronic diseases. Unfortunately, the most serious limitation of fibers is their lack of direct injectability into the body. Hence, they are normally used in the form of mats, sheets, or webs of bulk size. Nevertheless, mat- or sheet-type smart fibers offer an opportunity to develop their unique applications, for example, dressings or anti-adhesion membranes for wounds. Further functionalization of smart fibers could also be used for the separation, purification, and preservation of biomolecules or cells. Taking together all these merits of smart fibers, they can be utilized as key tools in a wide range of applications with switchable properties in response to external remote control.

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