Biomedical application of responsive ‘smart’ electrospun nanofibers in drug delivery system: A minireview

3.1 pH-responsive electrospun nanofibers

Acid-base homeostasis, which keeps the pH of the arterial blood between 7.38 and 7.42, regulates the human body. Therefore, for proper bodily function, certain tissues or cell compartments have their own distinctive pH environments (Weng & Xie, 2015). For instance, the gastric acid pH is 1.5–3.5 and 4.5–5.0 for lysosomes and 8.0 for the secretions of the pancreas. The advancement of pH-responsive systems is largely focused on polymers that have weak acids, such as carboxylic acid or base groups, such as primary, secondary or tertiary amines, that have a pK_a that allows for sharp changes in the state of ionization at the pH of interests. The significant increase in the degree of ionization will cause an adjustment in the conformational chains and the affinity for the solvent and the interactions between them, resulting in disassembling, swelling or shrinking of the components (Alvarez-Lorenzo & Concheiro, 2014). An ideal scenario is the release of pH-responsive, drug-loaded electrospun nanofibers (pH-RDLEF) depending on the characteristic pH of the disease, and the release of such nanofibers decreases or fully stops when the condition has been improved and the pH shifts to the normal value (Weng & Xie, 2015). In a study conducted by Da Costa et al. (2015), an enteric polymer of Eudragit L-100 has been incorporated with additives block co-polymers, PE-b-PEO, loaded with nifedipine as the model drug. At pH 6.8, the release of the drug was prolonged after the introduction of PE-b-PEO into the electrospun fibers. The results indicate that pH-responsive nanofibers can serve as effective drug carriers since the release of nifedipine could be controlled by changing the pH of the environment, and therefore these drug-loaded pH-responsive nanofibers might have potential applications in the biomedical field.

3.2 Thermoresponsive electrospun nanofibers

Temperature changes can trigger and alter the release of the drug according to the circadian rhythm of the disease being treated. Temperature-responsive drug-loaded electrospun is made of polymers that undergo sudden solubility shifts or water affinity. Thermosensitive drug delivery systems, typically based on polymers such as poly(N-isopropylacrylamide) (PNIPAM) or poly(N-vinylcaprolactam) (PNVCL) are well known in the literature (Li, Sang, et al., 2018; Yadavalli et al., 2015). At a given temperature, these materials undergo distinct hydrophilic or hydrophobic phase transitions. In a study conducted by Li et al., 2017, the thermosensitive polymer poly(di(ethylene glycol) methyl ether methacrylate) (PDEGMA) was synthesized and electrospun into fibers by blending with ethyl cellulose (EC) loaded with model drug KET. The drug release studies showed that KET was released over a prolonged period of time with the fibers having different release profiles at 25 and 37 °C, reflecting their thermosensitive properties. Thus, the fibers prepared in this work have potential as smart stimuli-responsive drug delivery systems.

3.3 Light responsive electrospun nanofibers

Photo-responsive nanofibers are derived from the modified polymer with photochromic molecules using the electrospinning method (De Sousa et al., 2010). Photochrome is the ability to undergo a light-induced reversible colour change based on a chemical reaction (Nakatani et al., 2016). There are two main types of photoisomerization behaviours that have been used in light-responsive electrospun nanofibers: open-closed ring transformation and cis–trans conversion (Weng & Xie, 2015). De Sousa et al. (2010) successfully fabricated electrospun fibers using poly (methacrylic acid) with open-closed ring transition which was a spiropyran (SP) or cyclodextrin-SP inclusion complex. The presence of the SP on the nanofiber surface was confirmed in which vibrational modes of the photochromic molecule were detected in the nanofiber's material. The photochromic properties of the mixture of polymer and SP demonstrated in the study open new possibilities for light-driven nanomaterials as spiropyrans themselves can be potentially incorporated into different organic and inorganic matrices in applications ranging from optical devices to biocompatible materials.

3.4 Electric field responsive electrospun nanofibers

There are three categories of electric field responsive polymers: electroactive polymers, ion-doped conducting polymers, and polymer composites/bends/coatings (Smela, 2003). In a series of studies

by Lee et al., electric fields have been shown to influence the growth and orientation of neurons in vitro. A piezoelectric polymer polyvinylidene fluoride–trifluoroethylene(PVDF–TrFE) was used to fabricate electrospun aligned and random scaffolds were having nano or micron-sized fiber dimension. The electrospun piezoelectric membranes of PVDF-TrFE were fabricated and different cell lines were tested for neuroregeneration capability. The effect of fiber alignment and piezoelectricity on neurite extension of dorsal root ganglion neurons was investigated, and it was discovered that annealed and aligned fibers, which also exhibited the greatest piezoelectric effect, supported the cell growth and neurite extension well. (Lee et al., 2011). The results obtained in vivo and in vitro supported the use of piezoelectric conduits to repair nerve injuries using the electrospinning technique.

3.5 Multiple stimuli-responsive electrospun nanofibers

In order to expand the already broad tunability over drug delivery, multi-stimulus-responsive electrospun fiber systems that respond to a combination of two or more signals have been developed. The study conducted by Li et al. (2018b) adopted a more straightforward, effective, and low-cost twin-jet electrospinning process to fabricate dual- or multi-responsive DDSs by using easily obtained polymers, such as poly(N-vinylcaprolactam) (PNVCL), ethyl cellulose (EC) and Eudragit L-100 containing KET. The study focused on dual temperature and pH-responsive nanofiber. As a result, homogeneous fiber was obtained, successfully showing a thermoresponsive effect when the PNVCL-containing fiber mats changed from being hydrophilic to hydrophobic above the lower critical temperature of 33 °C. A hydrophilic carrier tends to give faster release than a hydrophobic analogue. At 37 °C and pH 4.5, the lowest extent of KET release is observed, just 15% after 60 h. In contrast, the greatest amount of release and the most rapid rate at 25 °C and pH 7.4. Therefore, the study demonstrated the potential for combining multiple stimuli in electrospun nanofibers for sustained release.

4.1 Cancer drug therapy

The fact is that most typical administrations of chemotherapeutic medicine can harm body tissues and cells. Therefore, developing a targeted drug delivery system is crucial to avoid systemic toxicity which can cause the failure of the main organs (Pour Khalili et al., 2020; G. Yang et al., 2015). The nanofibers have higher efficiency in encapsulation and drug-loading capabilities because of the higher surface area of the nanofibers (Cheng et al., 2017). The various types of drugs, such as antiviral, proteins, antibiotics, DNA and RNA, have been successfully encapsulated in the pH-dependent nanofibers; thus, the efficiency of the drug release kinetics has been analyzed (Hu et al., 2014). This non-woven nanofiber network is similar to the human extracellular matrix (ECM), influencing its outstanding performance because it increases the possibility of resembling the ECM matrices (Hu et al., 2014).

The earliest fabrication of the fibers using the electrospinning method was conducted by Li et al. (2002). In a study conducted by Ardeshirzadeh et al. (2015), the electrospun fibers were developed via an electrospinning approach by using DOX loaded nanofiber for a successful drug delivery system (Ardeshirzadeh et al., 2015). The development of fiber using polymers has been demonstrated, including polyethylene oxide (PEO), chitosan (CS) and graphene oxide (GO). The drug release kinetics from the DOX loaded in electrospun nanofibers scaffold showed strong pH-dependent release capacity, with pH 5.3 marking the highest drug release in comparison with the pH 7.4 release profile. The results showed a decreasing rate of interaction between DOX and polymer mixtures at higher pH conditions, suggesting this method as a potential candidate for the targeted cancer drug delivery to treat lung cancer.

Besides that, another study used electrospinning-electrospraying methods for DOX by using a polymer solution, which was polycaprolactone (PCL) to provide a substrate for the nanofiber network formulation with boron nitride nanotubes (BNNTs) in DOX nanocapsules (Pour Khalili et al., 2020). The drug release profile at lower pH of 4.0 exhibited the highest DOX release rate by using the electrospinning approach. The results of the formulation of DOX with BNNTs clusters and DOX with BNNTs plus PCL nanofiber mats showed that both methods had appropriate applicability characteristics in cancer drug targeting (Pour Khalili et al., 2020).

Nowadays, more effective and safe drug therapies of the local treatments for colonic diseases have been demanded because of the tremendous increase in the prevalence of colonic diseases. It was estimated that some 1,096,000 new cases of colon cancer and 704,000 new cases of rectal cancer were diagnosed in 2018, totalling to 1,8 million new cases of colon cancer (Rawla et al., 2019). The effective diagnosis of colonic diseases has since been a global public health issue worldwide. In a study conducted by Jia et al. (2017), an active pharmaceutical ingredient and anti-inflammatory drug, indomethacin, has been formulated into fibers (Jia et al., 2017). The fibers were manufactured with Eudragit S100 polymer, which was categorized as the pH-dependant polymer that made up the shell. At the same time, the drug-loaded core was based on the mucoadhesive PEO, which permited the release of the drug in a pH 7.4 environment. The pH results in shell dissolution after the polymer sticks mostly to the wall of the digestive system, providing prolonged indomethacin withdrawal to treat local irritable intestinal syndrome (Jia et al., 2017).

Besides that, another potential controlled drug delivery system of nanofiber mat is formulated by using chemotherapeutic agent RB for postoperative cancer treatments (Sayin et al., 2019). In the postoperative applications for cancer treatment, controlling the immediate drug release as well as adjusting the fiber rate of drug release are the most significant concerns that need to be resolved (Thakkar & Misra, 2017). In a study, the electrospinning method was used to synthesize a thin layer of pH-responsive crosslinked polymer P(4VP-co-EGDMA) with water-soluble polyvinyl alcohol (PVA) nanofibers coated via initiated chemical vapor deposition (iCVD) where iCVD is an all-dry, free-radical polymerization method which allows polymerization directly occur on the substrate surface, by reacting thermally decomposed radicals with the monomer molecules adsorbed on the substrate. Slower release kinetics was detected when the pH declined, and the more acidic pH marked the average release rate by the end of 6 h, with 98% of RB being released at pH 9.0. In contrast, 55% of drugs were released at pH 4.0. The coated nanofibers demonstrated better stability at slightly acidic and specific pH values after 72 h of prolonged incubation (Sayin et al., 2019).

Moreover, a new application of biomedical nanofibers involves treatment for wound infections and local chemotherapy by using functionalization of graphene oxide that contains siloxane and curcumin as their crosslinking agent in the nanofibers (Sedghi et al., 2017). In an in vitro cell toxicity test performed on MCF-7, HEP G2 and L929 cell lines, curcumin anti-cancer activity remained intact even after loading into nanofibers. (Sedghi et al., 2017). The rate of the combination drug release increased after ten days of incubating in an increase in temperature and a decline in pH, with the highest performance at pH 5.4 (Sedghi et al., 2017).

Besides that, prebiotics is also a preferred substrate other than the conventional anti-cancer drugs for colonic-targeted delivery (Fernández et al., 2016). Wen et al. (2020) formulated a polysaccharide-based electrospun fiber mat containing a bioactive compound called Phycocyanin (PC) and galactooligosaccharide-based prebiotics (Wen et al., 2020). A water-soluble biliprotein, PC, exhibited anti-cancer activity against a variety of cancer cell types (Jiang et al., 2017) based on the evaluation of formulations' efficiency using UV–visible PC absorbance under different pH conditions (Wen et al., 2020). The highest record for absorbance at 620 nm was at pH 6.0 and 7.0, signifying the stability of the conformational structure in the formulation. Though the transmission density was slightly influenced at pH 9.0, and the PC spectrum changed significantly at pH 3.0, indicating the instability of the formulation at the specified pH compared to pH 6.0 or 7.0 (Wen et al., 2020). In summary, the electrospun fiber mats formulated with bioactive compounds and prebiotics work together to block the cell cycle and induces apoptosis in cancer cells. As a consequence, it is theoretically a useful agent for chemopreventive or colon cancer treatment (Wen et al., 2020).

4.2 Oral controlled release

Since the last decade, electrospinning has been classified as a potential method of drug delivery systems (DDSs) (Gao et al., 2017). The drug can be controlled-release from fibers into the desired location by using a pH-responsive polymer which changes its physicochemical properties in response to the pH variation (Li, Liu, et al., 2018a). A variety of sensitive polymers as well as electrospinning techniques, such as core–shell electrospinning, can be used to control the kinetics of drugs released from the nanofibers (Sofi et al., 2020). Eudragit polymers are widely used as active pharmaceutical ingredients in drug capsules and tablets with controlled release properties. In a study conducted by Han et al., 2017, core-sheath fibers using different Eudragit materials were successfully produced, and their controlled multi-pH responses have been demonstrated. All core − sheath Eudragit fibers show no noticeable release at pH 5, while they are completely dissolved at pH 7 is illustrated in Fig. 4 (Han & Steckl, 2017).

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Fig. 4

Core-sheath Eudragit fibers show no noticeable release at pH 5, while they are completely dissolved at pH.

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A few scientists have applied the method to exploit the pH response using different formulations, for example, Eudragit L100 has been used in the healthcare industry to pass through the digestive tract by oral administration (Illangakoon et al., 2015). In the study conducted by Illangakoon et al. (2015), a pH-responsive polymer, Eudragit L100 was designed and it only dissolved at pH values above 6.0. Therefore, the delayed-release formulations used in the pharmaceutical sector is useful so that drugs can be absorbed into the intestinal tract.

A study has been conducted to prepare effective and low-cost dual or multi-responsive DDSs in a simple manner using the new knowledge on multi-jet electrospinning (Li, Liu, et al., 2018a). Three types of polymers have been used to develop the fibers, which comprise PNVCL with ethyl cellulose (EC) while the third polymer is pH-sensitive, Eudragit L100-based fibers. All these three polymers have been blended with KET drug as a hybrid fiber mat. The hybrid fiber mat's drug release kinetic profiles showed a higher kinetic release at pH 7.4 than at 4.5 (Fig. 5). The lowest level of KET release was observed at 37 °C and pH 4.5, only 15% after 60 h.

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Fig. 5

In vitro KET release profiles from the hybrid electrospun fiber mats of Eudragit L100 and PNVCL/EC (Li et al., 2018) (Adapted from ref 38. Copyright 2018 Colloids and Surfaces B: Biointerfaces).

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In comparison, the hybrid mats showed the highest amount of release at the fastest rate at 25 °C and pH 7.4 compared to the individual fiber polymer. A further study was performed using KET but it was combined with non-steroidal anti-inflammatory drug, ibuprofen, crosslinked in PCL-based double hydroxide (LDH) nanoparticles (Gao et al., 2017). At pH 7.4, the LDH-drug particles released about 80% of both drugs, which were ibuprofen and KET after two hours. Then, at least 60% of drugs were released from the PCL-drug fibers after four hours, and it stagnated after ten hours.

Besides that, the pH-responsive nanofibrous mats were prepared using co-axial electrospinning to control the antibiotic release (Son et al., 2015). Various ratios of Eudragit EPO (EPO) and Eudragit L100 (L100) were injected by using co-axial nozzles to the fibrous meshes. The EPO and L100 generated electrostatic interactions and different release profiles of tetracycline were expected to be produced. The Eudragit nanofibrous mats containing 40%, 50%, and 70% (w/w) EPO were labelled as EPO40, EPO50, and EPO70. The tetracycline was quickly extracted from mesh at pH 6.0 even though it has delayed its release levels at pH 2.0. The tetracycline was extracted more easily from the mesh at higher EPO concentrations at both pH levels. The electrostatic reactions between EPO and L100 are projected to create specific tetracycline release profiles.

As a consequence, higher concentrations of encapsulated drugs were extracted from mesh at neutral pH, effectively preventing the development of bacteria. Another study using modified co-axial electrospinning involved a new type of structural nanocomposite (SC), which was loaded with diclofenac sodium (DS). At the same time, the shellac was coated with composite polyvinylpyrrolidone (PVP)–DS core (Yang et al., 2018). The drug release kinetics in a neutral media occurred in 10 min after it was placed into the media; while all the DS cores was released, at the first two hours only 7.1% ± 2.8% was released.

Moreover, Eudragit S100 (ES100) as the pH-dependent polymer has been used to develop fibers using tri-axial electrospinning process with pure ethanol as the outer solvent, and an unspinnable lecithin diclofenac sodium (PL–DS) core solution is fabricated into nanofibers (Yang et al., 2016). Although the tri-axial electrospinning or multifluid electrospinning is still new compared to the standard method of single-fluid electrospinning or double-fluid co-axial electrospinning, the polymer nanocomposites have been produced for oral colon-targeted drug delivery (Yu et al., 2020). The drug release kinetic profiles for the fiber mats showed that the highest drug release occurred when the pH rose to neutral. After two hours in acid, 2.8% DS was released in the dissolution media while in the neutral dissolution media, which resembled a colonic environment, a total of 79.1% nanofibers was released over 22 h. Another study conducted with a similar electrospinning method involved paracetamol as an active ingredient incorporated in complex sheath-separate-core nanofibers which comprise of standard shell and two separate cores (Chang et al., 2020). The nanofibers contained three different types of Eudragit co-polymers: Eudragit® E100, Eudragit® L100-55 and Eudragit® S100. Those three have different pH-dependent solubilities. The release percentages at the stomach, small intestine, and colon with pH 2.0, 6.0 and 7.4, respectively, were 24.4%, 46.7%, and 28.6%, indicating that the highest contents released in the three targeted places were at the small intestine at pH 6.0.

A study conducted by Akhgari et al. (2017) reported combined pH-dependent and time-dependent polymers, which were Eudragit S100 and Eudragit RS100, respectively for drug delivery to the colon. Due to its possible cure for colon cancer, an active ingredient, indomethacin, was used as a drug. In addition to that, as indomethacin's pK_a is 4.5, the solubility is predicted to be lower in acidic conditions. At pH 6.4, the release of drugs in all of the buffer medium formulations was higher than the acidic media might be partly due to the improved pH solubility of indomethacin 6.4. Nevertheless, at pH 7.4, the dissolution of ES was the highest, the release of the drug was somewhat proportionate to the amount of ES in the formulation, and the higher the ES ratio compared to ERS, the higher the release of the drugs (Akhgari et al., 2017b).

Furthermore, a study conducted by Da Costa et al. (2015), an enteric polymer of Eudragit L-100 has been incorporated with additives block co-polymers, PE-b-PEO, loaded with nifedipine drug. At pH 6.8, the release of the drug was prolonged after the introduction of PE-b-PEO into the electrospun fibers. Other studies that aimed to control the release of budesonide, which was a low water-soluble glucocorticosteroid, used enteric polymer to locally treat inflammatory bowel diseases (Bruni et al., 2015). The drug release kinetics showed at pH 1, budesonide was released but the highest was at pH 7.2. The results were due to the presence of the hydrophilic polymer, and low amorphization of the drug in the fibers, preventing the dissolution of budesonide in the acid environment. Therefore, the system is believed to improve the local efficacy of the drug and is a more effective approach for enteric drug targeting.

4.3 Wound healing

Nanofabrication drug delivery has a higher potential in wound healing process due to its lengthy retaining periods at the wound site owing to the high volume ratios, large surface area, persistent diameter, and porous, thin and flexible structure (Giram et al., 2018; Stocco et al., 2018). The above characteristics of an electrospun nanofiber will allow better removal of exudates at wound area, and transportation of nutrients, oxygen supply and water. There are two types of wounds: acute wound and chronic wound. Acute wound heals faster whereas chronic wound takes a longer time to resolve and thus, they are prone to bacterial infections (Gizaw et al., 2018). However, with the advancement of technology, various types of bioactive molecules, such as drugs, including graphene, KET and ciprofloxacin (CIP), and biological molecules, such as collagen, vitamins, nucleic acids and human umbilical vein endothelial cells, can be loaded into the nanofibers (Ambekar & Kandasubramanian, 2019). Furthermore, the nanofibers can be theoretically integrated into several features in wound dressings to address various forms in wounds, positions of wounds, and circumstances of wounds. Ultimately, it is to boost consistency, providing a higher rate of wound healing.

In a study conducted by Giram et al. (2018) on chronic wound healing, antimicrobial electrospun non-woven Eudragit L-100 nanofibrous mats were fabricated for fast-dissolving DDSs (Giram et al., 2018). The nanofibrous mats were loaded with an active ingredient of moxifloxacin hydrochloride at various pH and evaluated for their antibacterial activities against both Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria. The Eudragit nanofibers exhibited slower-release at pH 1.2 and burst release at higher pH, which was pH 6.8, around 30 s. The qualitative antimicrobial assay showed positive antibacterial activities against both strains. Another study using polymers with selective pH dissolution was conducted using ES100 polymeric solutions loaded with a bactericidal and fungicidal drug, nitrofurazone (Rivero et al., 2020). The co-axial electrospinning process resulted in a relatively gradual release of drug when the pH was higher than 7 and it was effective against Gram-negative (E. coli) bacteria.

Furthermore, a new dual nano-carrier system bio-based nanofibrous mat was developed, containing the standard local anaesthetic benzocaine (BZC) for pain killer with bromocresol green (BCG) (Kurečič et al., 2018). The needleless electrospinning process injected BZC and BCG into cellulose acetate (CA)-based nanofibers. Kinetic tests showed that the amount of BZC produced was higher at pH 9.0 relative to a lower pH of 3.7, with a variation of 50%. The simultaneous activity of active pain-relieving of BZC and pH-indicating agent properties will allow easier implementation in wound management, where treatment of infected and painful wounds is highly generally desired. Besides that, a study was conducted to fabricate Janus wound dressing by a side-by-side electrospinning process whereby CIP and silver nanoparticles were loaded (Yang et al., 2020). The fibers were composed of PVP and EC polymer mats. At pH 7.0, the CIP was released more than 80% in the first 30 s, showing its potential as good antibacterial agents that yield ameliorative effects during a critical wound healing time.

4.4 Intravaginal drug delivery

Drug delivery via the vaginal mucosa using drug-loaded electrospun nanofibers is a novel strategy that can be beneficial in cases where local drug delivery is required supported by their versatility, high loading ability, high mucoadhesive strength, typical softness, targeted drug delivery in the vagina, reduced toxicity to other organs, and lack of sharp corners that suit lesions with easy to use. (Tuğcu-Demiröz et al., 2020). The development of work, especially in treating HIV infection using nanofibers, has resulted in a patent published on Vaginal Matrices: Nanofibers for Contraception and Prevention of HIV Infection in 2016 (Woodrow et al., 2016). Thus, in this section, we will discuss a few innovative applications for vagina local drug delivery.

A study by Sharma et al. (2016) developed electrospinning nanofibers using PVA for the localization of fluconazole with mucoadhesive polymeric nanofibers to treat microbial vaginal candidiasis infections. Excellent antimicrobial activities against Candida albicans were observed based on the findings from the drug-loaded polymeric nanofibers. At pH 4.2, the drug release kinetics indicated a sustained release of fluconazole for 6 h. There was a rapid burst of around 35.13% of the medication in the first 2 h at initiation, and after 6 h, it was accompanied by a progressive yet continuous release of up to 97.8% of the medication. The large surface area of the nanofibers affected the immediate and sustained release of the drugs. However, the drug was still present in the core of the nanofibers because of the diffusion and erosion mechanisms; thus, a slower release of the drugs is still progressing.

In another study conducted by Zong et al., 2015, incorporating cisplatin drug in the nanofibers of poly (ethylene oxide)/polylactide recently achieved for the treatment of cervical cancer. A murine cervical cancer model was used to assess the nanofiber method for mucoadhesion and in-vivo vaginal retention. In-vivo drug release findings showed that the drug accumulated more in the cervical region, as opposed to intravenous cisplatin injections, which spread the drug mostly to peripheral organs like the kidneys and liver or the bloodstream. When compared to the intravenous injection of cisplatin, the nanofiber mats significantly reduced the size of the excised cervical tumors.

Furthermore, recent studies have been efficiently used nanofiber platforms to simultaneously deliver drugs to treat Bacterial Vaginosis (BV), where PVP nanofiber formulations were loaded with metronidazole (MET) as a model drug (Tuğcu-Demiröz et al., 2020). In vitro drug release test showed that all the MET released from nanofibers in the buffer at pH 4.5 within 5 min in the dissolution medium. This result was expected due to the hydrophilicity of the polymer and the high surface area of the nanofibers