Introduction
During the past several decades, polymers have acted as a backbone supporting the rapid development of drug delivery.1–3 Numerous dosage forms are fabricated through the integration of an active ingredient with one or more polymeric excipients.4–7 These polymeric matrices serve to modify the drug molecules' release behavior and/or absorption for improved therapeutic efficacy, regardless of the administration route.8–10 This approach represents the mainstream of the modern pharmaceutical industry. In the current nano era, this trend has extended into the nanoscale domain; numerous polymer-based nano drug delivery systems (DDSs) have been extensively reported in the literature through bottom-up and top-down nanofabrication approaches.11–14 However, very few polymer-based nano drug delivery systems can be fabricated on a large scale for potential commercialization.15–18 The large-scale production of nano DDSs—particularly those with special and complex structural characteristics—in a feasible and simple manner poses one of the most significant and challenging issues for interdisciplinary researchers.
Electrospinning, a typical electrohydrodynamic atomization method as electrospraying,19–23 takes advantage of the facile interactions between the electrostatic energy and the working fluids.24–27 One of the most recognized advantages is that it is able to create nanofibrous products and also nano DDSs on a large scale through simply increasing the parallel spinnerets.28–30 Meanwhile, after over two decades of efforts all over the world, over 40 commercial products of nano DDSs are available online.31,32 It seems that the expected values of electrospinning for industrial productions of nano products have been realized gradually. However, almost all the commercial products are based on electrospun monolithic polymeric nanofibers, and most of them are produced by the free-surface electrospinning. Up to now, there are no reports about the commercial products based on complex structures.
Among the three directions of nano science and nano engineering (small sizes down to picotechnology, complex nanostructures and nano devices, nano patterns and nano alignments),33 complex nano structures represent the most important one, and many nano techniques are just named after the nanostructures created, such as coaxial electrospinning, so named because of its resultant core-sheath nanostructures, and side-by-side electrospinning owing to the Janus nano products.34–39
Initially, electrospinning was implemented using a metal needle as the spinneret, i.e., the working fluid was guided into the electric field through the capillary metal needle.40–43 Later, free-surface electrospinning was developed to meet the strong demand for large-scale production, which can be initiated by applying a high voltage to the working fluid.44–46 Although bulk production is straightforward, it is difficult for this technique to create nanofibers with complex inner structural characteristics, as in needle-based electrospinning. Most recently, Wang, Guo, et al. integrated needle-based and free-surface electrospinning to develop a novel third type of electrospinning technique, i.e., needle-in-hole electrospinning.47–49 This novel technique combines the advantages of both the needle-based process (enabling the creation of complex nanostructures using nozzle geometries as macro templates) and the free-surface process (facilitating large-scale fabrication). Based on this technique, we investigated the batch production of a Janus film for treating pharyngitis using a sequential hole electrospinning process characterized by a newly developed hole spinneret with two inlets and multiple orifices as outlets.
Materials and method
Materials
Polyvinylpyrrolidone (PVP K90, Mw = 1 300 000 Da) was purchased from Sigma-Aldrich, Shanghai Co., Ltd (Shanghai, China). Borneol was provided by Guilin Bi-sheng Pharmaceutical Co., Ltd (Guilin, China). Sucralose (with a purity of 89%), shellac and acetaminophen (APAP, with a purity of 98%) were bought from Shanghai Macklin Biochemical Co., Ltd (Shanghai, China).
Artificial saliva was provided by Shaanxi Yapai Biotechnology Co., Ltd (Xi'an, China), whose details are included in Section 1 of the SI. Anhydrous ethanol and methanol (analytical grade) were obtained from Shanghai Chemical Reagents Co., Ltd (Shanghai, China). Water was double-distilled just before use.
Sequential hole electrospinning for batch production of Janus films
Homemade electrospinning apparatus
Based on the most recent report on hole electrospinning,47 this study modified the combined spinneret to introduce another inlet for the fluid tank for sequential hole electrospinning. Details of its design and fabrication are discussed later. Using this homemade spinneret—the key element in an electrospinning apparatus—the new sequential hole electrospinning system was assembled into a traditional needle-based laboratory setup, which included a power supply (ZGF 2000/60 kV/2 mA, Wuhan Huatian High Power Co.
Ltd, Wuhan, China) to supply the applied voltage, two syringe pumps (KDS 100 and KDS 200, Cole-Parmer®, Vernon Hills, USA), and a homemade collector prepared from cardboard wrapped in aluminium foil. Other accessories for manipulating and recording the electrospinning process included a Huawei P60 smartphone (Shenzhen, China), a Canon G7X camera (Tokyo, Japan), and an LED light (MJSDT001QW, Shenzhen Lehuifeng Digital Co., Ltd, Shenzhen).
Working fluid preparation and electrospinnability
Two working fluids were prepared for the sequential batch electrospinning, which are included in Table 1. Both solutions were poured into the 20 mL syringes and were connected with the inlets of the spinneret.
Some pre-experiments about the electrospinnability of the two working fluids are included in Section 2 of the SI.
Physic-chemical characterizations
Morphologies and the uniformity of nanofibers
The surface of fibers on the top layer and bottom layer were observed using a scanning electron microscope (SEM, QuantaFEG450, FEI Corporation, USA). Elemental analysis of the fibers were evaluated using energy dispersive spectrometer (EDAX EDS Element, AMETEK, USA). The diameter of the fibers was estimated by ImageJ software (National Institutes of Health, USA) on 100 points.
A strip was cut from the collected Janus fibrous films. The strip was immersed in liquid nitrogen for over 20 min, and was then manually broken before Au coating and observation.
Physical state and compatibility
The physical states of the raw materials (PVP, shellac, sucralose, APAP, and borneol) and the electrospun top and bottom layers were evaluated by conventional powder X-ray diffraction (PXRD) in reflection mode (Bragg–Brentano geometry). XRD patterns were collected on a Bruker D8 Advance diffractometer (Bruker, Karlsruhe, Germany) using Cu Kα radiation (λ = 1.5406 Å) at 40 kV and 40 mA, over a 2θ range of 5–60° at a scanning rate of 2° min−1.
Fourier transform infrared spectroscopy (FTIR) was used to investigate the compatibility of the components within the electrospun Janus films using the potassium bromide pellet method, and the infrared spectra were recorded on an IRTracer-100 Fourier transform infrared spectrometer (Shimadzu, Kyoto, Japan). During testing, the scan number was set to 8, the wavenumber range was 500–4000 cm−1, and the resolution was 2 cm−1.
Wetting properties
A simple method was established for assessing the wetting properties of electrospun Janus films. Circular patches were cut from the collected Janus films. The Janus patch was placed on wet paper to observe the gradual wetting process, which was recorded using a Canon camera.
In vitro functional evaluation
Quantitative measurements
A calibration curve was developed using a UV-vis spectrophotometer (UV-2102PC, Unico Instrument Co. Ltd, Shanghai, China) for the quantitative determination of APAP. The absorbance of sample solutions was measured at 258 nm (λmax), and APAP concentrations were calculated from the calibration equation.
Encapsulation efficiency
A section of the Janus fibrous film was dissolved in ethanol. An aliquot of the solution was dripped into distilled water to release the APAP. The aqueous solution was filtered through a 0.22 µm micro-filter membrane (Lab Instrument Co., Ltd, Tianjin, China) and subsequently diluted appropriately prior to UV-vis measurements.
The determined contents were used to calculate the drug encapsulation efficiency (EE%) according to eqn (1):1EE% = (Wd/Wt) × 100%where Wd is the measured mass of APAP in the Janus fibrous films, and Wt is the theoretical mass of APAP added to the working fluids.
In vitro dissolution tests using artificial tongue
The in vitro dissolution tests were carried out in a simulated oral environment. An artificial tongue (Simulated electric tongue, https://jd.com/ Self-operated Official Store, Shanghai, China) was placed in 200 mL of the artificial saliva. The cellulose paper covering the tongue surface was used to mimic the lingual mucosa.
The Janus fibrous films were cut into rectangles and placed on the root of the artificial tongue. Through the vibration of the artificial tongue, the dynamic oral environment was established.
At predefined time intervals, 2.0 mL of solution was withdrawn and replaced with 2.0 mL of artificial saliva. The absorbance was measured at λmax = 258 nm using a UV-vis spectrophotometer. All experiments were performed in triplicate.
The cumulative drug release percentage (P%) was calculated according to eqn (2):2where V0 is the volume of dissolution medium (200 mL), V is the volume of the extracted sample (2 mL), Q0 is the theoretical drug amount in each sample (mg), Cn is the drug concentration measured in the nth aliquot (mg L−1), and Ci is the drug concentration measured in the ith aliquot (mg L−1).
Statistical analysis
All the quantitative measurements in this study were repeated at least 3 times with the data expressed as mean ± standard deviation. Comparisons were performed using one-way analysis of variance (ANOVA) followed by Tukey's test, with p < 0.05 considered as statistical significance.
Results and discussion
Reasonable design of the batch production spinneret for sequential treatment of different kind of polymeric composites
Among the four elements comprising an electrospinning apparatus, the spinneret or spin head is the most important element for two reasons: (1) the resultant structures are determined by the nozzle of the spinneret, e.g., concentric nozzle for the core-sheath structure and eccentric nozzle for the Janus structure;50–53 (2) it is the convergent point of the working fluids and electrostatic energy to initiate the whole electrospinning process.54–57 Thus, the reasonable design of the batch production spinneret is the key to implementing the sequential treatment of different kinds of polymeric composites and creating Janus nanofibrous films.
As shown in Fig. 1, the combined spinneret consists of several components. Fig.
1a presents a diagram of the whole spinneret and its inner structure. The starting elements for preparing the spinneret include a syringe, four copper wires, a traditional needle, and epoxy resin (Fig. 1b).
Four copper wires with a diameter of 0.3 mm (Fig. 1c) were bundled together at one end for fixation (Fig. 1a).
The other ends were inserted into the bottom four holes. This arrangement is useful not only for energy transfer, but also for overcoming surface tension to initiate the Taylor cone.47 The stainless steel tube connected to plastic Inlet 1 has an exposed section for energy conversion via an alligator clip. The other end of the stainless steel tube was connected to the four copper wires, ensuring smooth electrostatic energy conversion at each hole.
The hole diameter could be manipulated using a traditional stainless steel capillary; here it is 0.76 mm (Fig. 1d). The whole spinneret has a length of 10.963 mm (Fig.
1e) and a height of 6.033 mm (Fig. 1f). The total weight of the spinneret is 8.7026 g.
The four holes at the bottom of the spinneret (Fig. 1g) are shown in enlarged images in Fig. 1h1–h4.
Fig. 1i shows the connection of the spinneret to two syringes for sequential treatments.
The advantages of this spinneret include but are not limited to the following: (1) low cost, light weight, and small size, facilitating the organization of the electrospinning apparatus; (2) the arrangement of two inlets with four holes facilitates batch production; (3) more reasonable from the standpoint of the electrohydrodynamic atomization process due to almost complete isolation of the metal sections in the spinneret from the ambient environment, preventing electrostatic energy loss to the environment; (4) the number of holes can be further increased as much as possible, but the pumps for driving the working fluids can still be limited to one or two depending on the number of working fluids, greatly saving space and resulting in a compact arrangement of the elements, which also raises the concern of how to achieve even dispersion to each hole. Just as integrated circuits outperform ordinary circuits in size, speed, energy efficiency, stability, and cost, the integrated electrospinning process47–49 offers similar advantages over conventional needle-based electrospinning.
The sequential electrospinning processes for creating the Janus films containing bottom adhesive layer and top fast dissolution layer
Layer-by-layer deposition is frequently exploited for collecting multiple-layer nanofibrous films.58–63 Bi-layer and tri-layer sandwich fibrous films are the most common organized macro structures in the literature. Macro bi-layer films, in which each layer possesses distinct properties and functional performances, are often termed Janus films.58 The other involves micro side-by-side components within an electrospun nanofiber, which can only be created using side-by-side electrospinning or conjugated electrospinning. The former can be facilely prepared by depositing nanofibers in a layer-by-layer manner using any electrospinning process.
In this investigation, a batch production concept was integrated into the layer-by-layer deposition process for creating Janus films. A schematic of the Janus nanofibrous film design and its three steps for potential therapeutic applications is presented in Fig. 2.
Step 1 involves preparing the top layer containing PVP, sucralose, and APAP (Fig. 2a). Step 2 involves fabricating the bottom layer composed of shellac, sucralose, and APAP (Fig.
2b). The patches can simply be cut from the collected Janus nanofibrous films for administration (Fig. 2c).
After topical administration on the base of the tongue, the bottom layer containing shellac can be adhered to the tongue. The sucralose molecules can contact taste receptor cells for better patient compliance. The APAP molecules can be released in a step-by-step manner through the sequential dissolution of the top-layer PVP matrix and the bottom-layer shellac matrix.
Compared with the previous hole electrospinning,47 this process not only introduced innovations to the spinneret (an additional fluid inlet and a visible window for monitoring the depletion of working fluids), but also incorporated new modifications to the working process. Here, a simple sequential treatment of two separate working fluids was employed to create Janus nanofibrous films. In the future, the two inlets can be simultaneously manipulated for the in situ mixing of polymeric solutions, as well as of polymeric solutions with solutions of functional small molecules.
Thus, this new process can serve as a versatile platform for establishing novel process–structure–performance relationships and for developing a wide variety of functional nanomaterials for applications in drug delivery and biomedical devices.
Observation details about the preparations of double layers of the Janus films are included in Fig. 3. Fig.
3a shows the homemade electrospinning apparatus, which consists of a spinneret, a collector, a power supply, and two syringe pumps. Lights, a camera, and a humidity/temperature meter are auxiliary devices for monitoring the working process (electrospinning processes for the preparations of top and bottom layers can be shown in SI Video I and II, respectively). An up-right inset shows the collected nanofibrous films after about 5 min.
Fig. 3a2 is an optical image of the working process for creating the top PVP layer. Only four “white” regions are discernible when using a Huawei smartphone (Pro60).
However, when a Canon G7X camera (Yoko, Japan) is used, the typical electrospinning process can be clearly discerned at each hole. As indicated in Fig. 3a3–a6, they have similar lengths of straight fluid jets and similar bending and whipping unstable regions.
Upon further enlargement of the images, Taylor cones from the four holes can be discerned in Fig. 3a7–a10, respectively. Different from needle-based electrospinning, in which the angle for initiating the electrospinning process must exceed 46°,64 the angle here is very small, with the fluid almost ejected parallel to the bottom of the combined spinneret.
After the PVP working fluid was exhausted, the shellac working fluid was pumped into the syringe tank and through the holes. An overall image of the preparation of the bottom layer of the Janus films is shown in Fig. 3b1.
Fig. 3b2 shows the working process for creating the bottom shellac layer. The four regions could still be discerned, although the color was very light.
Using the Canon G7X camera, the typical electrospinning processes were observed from each hole, as indicated in Fig. 3b3–b6. Still, these spinning processes had similar lengths of straight fluid jets and similar bending and whipping unstable regions.
However, the lengths of the straight fluid jets were shorter than those of the PVP solutions from the same holes. Meanwhile, the Taylor cones from the 4 holes could be discerned in Fig. 3b7–b10.
In comparison, these Taylor cones were significantly larger than those of the PVP solutions from the same holes. Additionally, due to the strong adhesive properties, the shellac nanofibers clung to the PVP syringe tank, and the fibers could be removed manually periodically for a better, continuous, and robust preparation process.
SEM images for the Janus nanofibrous films
There are plenty of reports about the electrospinning of PVP, which has good electrospinnability for those with a higher molecular weight such as PVP K30, K60, and K90.65–67 Reports about the electrospinning of shellac are relatively scarce. As the only plant-based resin, shellac also has fine electrospinnability in mixed solvents. In this investigation, they are exploited as the main top and bottom polymeric matrices for loading the drug and the sweetener.
SEM images of the electrospun top layer PVP nanofibers and bottom shellac nanofibers in the Janus films are included in Fig. 4 (the images under optical microscope of top and bottom layer fibers are included in Section 3 of the SI, respectively). As indicated from Fig.
4a–d, the SEM images of PVP/sucralose/APAP nanofibers in the top layer from the regions beneath the four holes all exhibit a linear morphology with few discernible beads or spindles. The diameter and diameter distributions are included in Fig. 4e–h.
Fig. 4i–l are the SEM images of shellac/sucralose/APAP nanofibers in the bottom layer from the regions beneath the four holes. Apparently, these fibers also had linear morphology without discernible spindles or beads among them.
Their corresponding diameter and diameter distributions are shown in Fig. 4m–p. Although these shellac fibers had a larger diameter than the top layer PVP nanofibers, they exhibited similar uniformity in diameter.
The SEM images of the cross-sections of the Janus films are shown in Fig. 4q, with an enlarged image of the bottom layer fibers in Fig. 4s and top layer nanofibers in Fig.
4t. The elements of C, N, O and Cl contained in the top PVP layer and bottom shellac layer are shown in Fig. 4u and v, respectively (nanofibers collected under the 4th hole).
It is the shellac that the bottom layer had a smaller content of N but had a larger content of O. The measured element contents on the nanofibers collected from the four holes have no significant difference, and also similar with those results measured on the nanofibers from the single-fluid electrospinning processes. These data are included in the Section 4 of the SI.
Compatibility and physical state of the multiple components within the electrospun Janus nanofibrous films
Both APAP and borneol are poorly water-soluble active ingredients; an amorphous state is useful for improving their dissolution and achieving controlled release profiles. As indicated in Fig. 5a, borneol exists as optical sheet-like crystals (inset) and exhibits a very strong Bragg peak at around 15°.
In Fig. 5b, both sucralose and APAP appear as colourful crystalline particles under polarized light in the optical microscope, and both show strong Bragg peaks in their XRD patterns. Shellac, the only natural resin, is a brown flake-like substance, while PVP is a popular soluble polymeric excipient (Fig.
5c). They exhibit similar halos in their patterns, suggesting that they are amorphous substances. When these raw materials were incorporated into the bottom layer, top layer, and the whole Janus films, all of them lost their previous crystalline physical state, as indicated by the presence of only halos in the XRD patterns of these nanofibrous mats in Fig.
5d.
It should be noted that the contents of borneol and sucralose in the solid nanofibers were theoretically set at 3% (w/w) and 2% (w/w), respectively. XRD has poor detection sensitivity for contents below 5%; in other words, there may still be small amounts of crystals present, but they cannot be accurately detected.68,69 Nevertheless, electrospinning is a very rapid “drying” process, in which the homogeneous state of the components in the working solution can be transferred to the solid nanofibers in one step, often within a time scale of tens of milliseconds. Provided that favorable secondary interactions exist among the components, the amorphous or molecularly dispersed state can be stably and completely preserved in the medicated nanofibers.
The compatibility of the ingredients in the electrospun nanofibrous composites is important for their stability. To evaluate this aspect, the FTIR spectra of raw borneol (Fig. 6a), raw APAP and sucralose powders (Fig.
6b), and raw polymeric matrices of PVP and shellac (Fig. 6c) were measured. The FTIR spectra of the separate top layer, bottom layer, and the whole Janus films are included in Fig.
6d. In the spectra of the Janus films, the peak at 2931 cm−1 originates from a combined effect of C–H stretching of the alkyl chain in different molecules. The peak at 3422 cm−1 corresponds to the terminal hydroxyl group (–OH).
Compared with 3451 cm−1 of PVP and 3437 cm−1 of shellac, the red shifts are obvious, which should be attributed to the abundant hydrogen bondings among the various molecules. The peak of 1663 cm−1 at the spectra of the Janus film is a compound one corresponds to various carbonyl groups (–C <svg xmlns="http://www.w3.org/2000/svg" version="1.0" width="13.200000pt" height="16.000000pt" viewBox="0 0 13.200000 16.000000" preserveAspectRatio="xMidYMid meet"><metadata> Created by potrace 1.16, written by Peter Selinger 2001-2019 </metadata><g transform="translate(1.000000,15.000000) scale(0.017500,-0.017500)" fill="currentColor" stroke="none"><path d="M0 440 l0 -40 320 0 320 0 0 40 0 40 -320 0 -320 0 0 -40z M0 280 l0 -40 320 0 320 0 0 40 0 40 -320 0 -320 0 0 -40z"/></g></svg> O) of different molecules.
The following observations can be derived from the comparisons between the FTIR spectra of the composite nanofibrous films and the raw active ingredients: (1) the sharp peaks in the spectra of borneol, APAP, and sucralose disappeared from the composite fibers' FTIR spectra; (2) the top layer, the bottom layer, and the Janus films have similar FTIR curves, which are similar to the spectra of PVP; (3) no new peaks resulting from functional groups were observed. These observations suggest that the raw APAP, borneol, and sucralose molecules were homogeneously distributed within the polymeric matrices. This is likely due to the extremely fast drying process of electrospinning, as well as the potential secondary interactions between these molecules and the polymeric carriers, such as hydrogen bonds, electrostatic interactions, and hydrophobic interactions.
These favorable secondary interactions can be deduced from their molecular formulas in Fig. 6e. In particular, the OH groups in APAP, sucralose, and borneol molecules can form hydrogen bonds with the CO groups in PVP and shellac molecules.
Furthermore, PVP and shellac molecules are also highly compatible in the bottom layer due to these secondary interactions.
Wettability performance and drug release profiles
The collected nanofibrous films can be cut into various shapes to meet patient preferences for potential commercial products. Circular, square, and rectangular patches can be readily prepared, as shown in Fig. 7a.
For administration of the medicated patch, fast hydration is important for topical drug delivery at the base of the tongue. PVP molecules are not only readily soluble in water but also highly hygroscopic. Thus, the PVP in the top layer, together with that added to the bottom layer, should jointly provide fast and even film hydration (a typical process is shown in SI Video III).
As shown in Fig. 7b, progressive wetting of the top PVP layer of a circular patch was evident when placed on wet paper. Based on estimation of the white area, linear wetting kinetics was observed, as shown in Fig.
7c. The white surface (S, mm2) has a linear relationship with time (T, s) of S = 4.1949 × T − 3.7750 with a correlation coefficient R of 0.9713.
In the Janus nanofibrous films, sucralose and borneol molecules do not contain conjugated or chromogenic functional groups. Borneol is a saturated monocyclic monoterpene alcohol. Therefore, neither exhibits characteristic absorption in the ultraviolet region (200–400 nm).
Thus, UV-vis spectroscopy was employed to measure APAP concentrations in the dissolved saliva. APAP is a typical poorly water-soluble drug, which has a maximum absorbance at λmax = 258 nm. The scanning curves of APAP standard solutions with concentrations from 1 to 50 µg mL−1 and a scan range from 200 to 300 nm are included in Fig.
8a. Based on the absorbances at 258 nm, the standard equation between absorbance (A) and concentration (C, µg mL−1) was regressed as A = 0.2014 + 0.0208C (R2 = 0.9998) (Fig. 8b).
The in vitro dissolution tests were conducted using an artificial tongue in 200 mL artificial saliva; the fast wetting and subsequent dissolution profiles are included in Fig. 8c. Three circular patches cut from the collected Janus fibrous films with a weight of 14.7 ± 3.1 mg were used to determine the EE%, which had an average value of 96.4 ± 2.8%.
This high EE% value suggests that there is almost no drug loss during the batch sequential electrospinning process.
Three rectangular patches were cut and selected for the in vitro dissolution tests, which had weights of 54.7 mg, 52.8 mg, and 57.3 mg. The drug content in the separate top layer, the separate bottom layer, and the whole Janus films was all 10% (w/w). For the same electrospinning time period, the 10% (w/w) drug of the Janus films had a portion of 33.33% (w/w) in the top PVP layer and the other 66.67% (w/w) in the bottom shellac layer.
In the first hour of the in vitro dissolution tests, the general drug release content was (47.3 ± 7.1)% (Fig. 8d), suggesting that about (47.3–33.3%) = 14.0% of the APAP was also released from the bottom shellac layers. However, the release contents can be readily manipulated by tailoring the electrospinning time periods of the top and bottom layers.
After the first-hour pulsatile release, the APAP entered a sustained release phase. Based on the Peppas equation, the regressed equation for the relationship between the accumulative release content (Q) and the release time period (t) was log Q = 1.4167 + 0.2383 log t (R = 0.9979) (Fig. 8e).
The exponent n was 0.2383, smaller than 0.45, indicating a typical Fickian diffusion mechanism for the loaded APAP molecules from the bottom composite matrices of shellac and PVP,70 a typical in vitro dissolution test is shown in SI Video IV.
Mechanisms of the Janus nanofibrous films for synergistic therapy
For the conversion of raw materials, the resulting structures are critical to their function.71–74 As for the applications of the resulting products, their functional performance is the gold standard for evaluation. Thus, the process–structure–performance relationship comprises the internal support axis for developing novel functional materials, including those for “effective, safe, and convenient” drug delivery.
Fig. 9 shows a schematic illustration of the structure–performance relationship mechanisms for the synergistic therapy of pharyngitis based on the Janus films developed in this study. The fibrous patches are designed for topical administration to the base of the tongue.
Spanning from the macroscale to the nanoscale, and further to the molecular scale, a series of structural characteristics underpin the desired functional performances. First, the Janus films have two distinct macro layers that provide complementary performances, which can be combined to achieve a synergistic action in the treatment, namely the biphasic release of APAP. Not only are these various APAP release profiles combined, but other functions are also simultaneously integrated, including the bioadhesive performance of the bottom shellac layer and the fast and sustained release of sucralose and borneol to enhance patient compliance.
Furthermore, borneol contributes to therapeutic effects such as clearing heat, detoxifying, relieving pain, alleviating throat swelling, and promoting local blood circulation to accelerate inflammation resolution.
Because of the high solubility of the carrier matrix (i.e., PVP), the top-layer nanofibrous composites are able to facilitate the rapid release of loaded APAP, sucralose, and borneol through a typical erosion mechanism. Meanwhile, water absorption from saliva, swelling, and interactions between shellac molecules and the tongue surface enable the bottom-layer fibrous composites to adhere stably to the base of the tongue, thereby allowing the sustained release of APAP, borneol, and sucralose.
Secondly, the microstructures of the electrospun fibrous mats play a role in promoting both the initial pulsatile release and the subsequent sustained release, primarily through a Fickian diffusion mechanism due to the insoluble shellac matrix. The electrospun fibrous mats possess high porosity and small fiber diameters, which facilitate the penetration and transport of both water and active ingredient molecules.
Thirdly, at the molecular scale, all active ingredients—APAP, borneol, and sucralose—are homogeneously distributed within the polymeric matrices (i.e., PVP for the top layer and shellac/PVP for the bottom layer). This composite structural characteristic is favorable for predictable and controllable drug release. In summary, the biphasic release performance of APAP from the Janus structures is supported by molecular, micro-, and macro-scale elements, which are integrated in a systematic and compatible manner.
Perspectives along the present investigation
The developments of pharmaceutics require continuous support from modern materials science and engineering.75–78 In this study, the developed sequential batch electrospinning technique was successfully demonstrated to be capable of creating Janus films with a series of micro- and molecular-scale structural elements in a simple, facile, and straightforward manner for drug delivery applications. Along this direction, several topics deserve further investigation, including:
(1) A series of specific parameters related to batch production, such as the number of holes and the uniform distribution of fluids as well as electrostatic energy; the matching of applied voltage with the overall fluid flow rate; the appropriate diameter of the holes and the wire-to-hole ratio;
(2) The batch production of nanoproducts with core-sheath nanostructures79–83 and other complex internal configurations, such as bi-chamber Janus,84 tri-chamber Janus, core-sheath structures, and their combinations. Although these complex nanostructures are highly promising for developing multifunctional nanomaterials and so-called all-in-one functional materials, no commercial products have yet been realized;
(3) Theoretical issues associated with hole electrospinning, as a free-surface electrospinning process within a limited region, which should help clarify the theory of needle-based electrospinning, such as the influence of capillary forces on the working process and the quality of the resultant nanofibers.
(4) Potential commercial applications of nano products, particularly those with complex nanostructures, pose one of the most difficult and most important challenges in almost all the applied scientific fields. This proof-of-concept demonstrations can be combined with ideas in many other fields such as active food packagings, medical devices, and friendly environment85–87 for creating new possibilities.
(5) Moving forward, the Janus fibrous films developed herein should undergo safety evaluations, stability tests, animal experiments, and clinical trials.
It should be noted that most reported Janus nanofibrous films are essentially macroscale bi-layer structures, in which each layer consists of a distinct set of nanofibers. Only a small fraction comprise nanofibers with intrinsic side-by-side Janus nanostructures.84 The reported integrated electrospinning processes readily enable the fabrication of all three architectures—inner Janus nanofibers, macroscale bi-layer Janus films, and hierarchical combinations thereof in which the nanofibers retain their inner Janus nanostructures.
Conclusions
A brand-new sequential batch electrospinning technique was successfully developed. The homemade electrospinning apparatus was characterized by a special integrated spinneret, which comprised two fluid inlets and four fluid outlets. Janus nanofibrous films were directly fabricated in a straightforward manner by sequential pouring of the top layer working fluids and bottom layer co-dissolved solutions.
The Janus nanofibrous films, consisting of shellac/PVP/sucralose/borneol/APAP as the bottom layer and PVP/sucralose/borneol/APAP as the top layer, were able to provide typical biphasic release profiles of APAP, which showed potential for topical delivery (base-of-tongue) to treat pharyngitis. Different from traditional needle-based electrospinning and free surface electrospinning, here, the hole electrospinning exhibits a new concept for large-scale production of nanofibrous devices with special and complex structural characteristics, in a feasible and simple manner. In the future, a simple increase in the number of bottom holes can further increase the yield by hundreds of times.
Author contributions
Xiaoming Yu: data curation, formal analysis, investigation, validation, visualization, methodology, software, writing – original draft. Yuxuan Xu: investigation, validation, methodology. Bo Wang: methodology, software, writing – review & editing.
Deng-Guang Yu: conceptualization, supervision, methodology, project administration, writing – review & editing, funding acquisition. Ming Zhang: conceptualization, supervision, project administration. Yuanjie Zhu: conceptualization, project administration, writing – review & editing.
All authors participated in discussions and manuscript preparations.
Conflicts of interest
The authors declare no conflicts of interest.
Supplementary Material