Versatility of electrospun Janus wound dressings

ABSTRACT

Electrospun nanofibers produced through single-fluid blending processes have successfully demonstrated their potential as highly effective wound dressings. However, electrospun Janus nanofibers, in which various chambers can be designed to load different active pharmaceutical ingredients into different polymeric matrices, are further exhibiting their versatility for promoting wound healing. This commentary declares that wound dressings always need multiple functional performances to promote wound healing. Janus nanofibers have their unique advantages, with different parts interacting with their environments, thereby providing a versatile platform for developing novel wound dressings. Two recent examples, each with a different preparation strategy for developing novel wound dressings, are discussed, and the promising future of Janus nanofibers in wound dressing applications is highlighted.

1. Multiple functional performances of ideal wound dressings

As the biggest organ of human body, skin is responsible for preventing external pathogens [1]. This important role makes it susceptible to damage from a variety of causes, such as surgical operations, burns, external mechanical forces, and ulcers resulting from certain chronic diseases [2–6]. Skin wounds represent one of the most significant burdens on patients and healthcare systems worldwide [7–9]. Therefore, new types of wound dressings that are able to shorten the treatment process and promote skin repair are always highly desired.

In general, wound dressing is a type of biomedical product used to protect against external factors during skin regeneration [10–12]. It typically contains active ingredients that can promote the wound healing effect. Ideally, wound dressings can promote angiogenesis and tissue regeneration, provide analgesia, and have anti-inflammatory effects through the sustained release of drug molecules [13,14]. On the other hand, they possess excellent properties for preventing microbial infection, absorbing excess exudate, and allowing gas exchange [15,16].

In the commercial markets, wound dressings take the formats of sponge, film, foam, hydrogel, powder, and also nanofibrous membrane. During the past several decades, new excipients and novel technical methods have been continuously introduced into this applied field for potential new clinical products [10,17–19]. Among them, medicated nanofibers fabricated using electrospinning are projecting their potential value due to some unique properties, such as high porosity, large surface area, big surface-to-volume ratio, large drug loading capacity, and an amorphous drug presentation state [20,21]. The nanofibrous films have a structure and biological function similar to the natural extracellular matrix (ECM), which is crucial for creating an ideal microenvironment conducive to cell adhesion, proliferation, migration, and differentiation [22]. To date, in line with the rapid developments of nanoscience and nanoengineering, nanomedicine is permeating all types of wound dressings. Particularly, medicated multi-chamber Janus nanostructures represent one of the most promising approaches for developing high-performance wound dressings [23].

2. Side-by-side electrospinning and Janus nanostructures

Electrospinning, a technique akin to electrospraying, leverages the facile interactions between working fluids and electrostatic energy [24,25]. Initially a textile method alongside wet spinning or dry spinning, electrospinning was revitalized with the advent of nanotechnology [26,27]. Through a top-down process, electrospinning can directly create polymeric nanofibers. Initially, the nanoscale diameters of these nanofibers were explored to ensure a range of functional applications. Later, coaxial electrospinning emerged as one of the most significant breakthroughs due to its ability to create core-shell nanostructures simply and robustly [28–30].

Although bi-fluid coaxial, tri-fluid coaxial, and quad-fluid coaxial electrospinning have been successively and continuously reported in the literature for generating bi-chamber core-shell nanofibers, tri-chamber, and quad-chamber nanofibers, respectively [31–34], bi-fluid side-by-side electrospinning and the related bi-chamber Janus nanofibers have received very limited attention [35]. Figure 1(a,b) show the diagrams of a traditional single-fluid blending electrospinning setup and a bi-fluid side-by-side eccentric electrospinning device, respectively. It is evident that the four fundamental components of these setups are similar, as indicated by 1, 2, 3, and 4 for the power supply, syringe pump, fiber collector, and spinneret, respectively. Similarly, there is no significant difference between a coaxial electrospinning system and a side-by-side electrospinning system.

Figure 1.

The working processes of a traditional single-fluid blending electrospinning (a), and a bi-fluid side-by-side electrospinning via an eccentric spinneret (b). The number 1, 2, 3, 4 represent the four fundamental part of an electrospinning system, i.e., power supply, syringe pump, fiber collector, and spinneret.

Both bi-chamber core-shell and Janus structures are among the most fundamental types of objects. The bi-chamber core-shell structure features a core section that is surrounded by a shell section, while the Janus structure consists of two distinct sections connected together. The functional materials based on these two fundamental structures are similarly vast. This can be easily judged by searching items in Web of Science. When using “Janus” or “core-sheath” as the “Topic,” the respective numbers are 49,577 and 69,319 (Figure 2(a)). However, when searching with “Janus fiber” or “core-sheath fiber” as the “Topic,” the respective numbers are 977 and 22,832. The ratio of Janus fiber to Janus is only 1.97%, significantly smaller than the ratio of 32.94% for core-sheath fiber to core-sheath. Similarly, for structure preparation methods, the respective numbers for side-by-side electrospinning and coaxial electrospinning are 158 and 2714 (Figure 2(b)).

Figure 2.

The current state, history and perspective of side-by-side electrospinning and Janus nanofibers: (a) A comparison Janus and core-shell fibers; (b) A comparison of side-by-side electrospinning and coaxial electrospinning; (c) A comparison of side-by-side electrospinning using a traditional parallel capillaries spinneret and an eccentric spinneret. Figure images reproduced with permission from [36], copyright 2015 Elsevier and [37], copyright 2020 the Authors; (d) A series of novel spinnerets with structural exports for duplicating tri-chamber nanofibers through electrospinning.

The real reason for the huge gap between the two bi-fluid electrospinning processes and their bi-chamber structures is revealed in the rightmost section of Figure 2(b). When two parallel metal capillaries are exploited for side-by-side electrospinning, the same electrical charges on the two working fluids, along with the small contact point (as indicated by “A” in Figure 2(b)), are likely to cause the working fluids to separate, resulting in a failure to create integrated Janus nanofibers. A real digital photo of this situation is provided in the two upper-left insets of Figure 2(c), with one side marked with methylene blue [36]. In sharp contrast, when an eccentric spinneret is exploited for implementing side-by-side electrospinning, a full compound Taylor cone and the homogeneous light blue color of the collector are evident in the two upper-right insets of Figure 2(c), indicating a successful process and the formation of an integrated Janus nanostructure [37]. From left to right at the bottom of Figure 2(c), diagrams of the spinneret and Taylor cone, the charge distribution on the nozzle, a real digital image, and possible Janus nanofibrous structures are displayed.

Compared with the traditional two parallel metal capillaries as a spinneret, the new eccentric spinneret has its unique factors to support the successful side-by-side electrospinning process and the creation of integrated Janus nanostructures [38]. These factors include a round charge surface area, an arch fluid contact area, and a slight projection of the round capillary over the crescent capillary. The advantages of the eccentric spinneret are evident in the following aspects [37–39]: 1) A round electrical charge surface is conducive to preventing separation and conserving energy; 2) A larger fluid contact area between the two working fluids, as indicated by “B” in the second bottom inset of Figure 2(c); 3) The slight projection of the round capillary is useful for preventing the possible encapsulation of one fluid by the other. If the two working fluids are compatible, the possibility of separation is minimal during the working process, which in turn ensures an integrated Janus nanostructure. Based on this breakthrough, many possibilities for both multi-fluid side-by-side electrospinning processes and side-by-side nanofibers have been unlocked. The corresponding tri-chamber structures are diagrammed in Figure 2(d), including tri-chamber Janus nanostructures, Janus nanostructures with one core-sheath side, core-sheath fibers with Janus cores, and core-sheath nanofibers with Janus sheaths. These Janus nanofibers will gradually demonstrate their potential for developing a series of innovative medicated nanofibers and related wound dressings with enhanced healing effects.

3. The advantages of electrospun Janus nanofibers for supporting their versatility as novel wound dressings

Compared with traditional homogeneous nanofibers produced by single-fluid blending electrospinning and core-sheath nanostructures from coaxial electrospinning, Janus nanostructures from side-by-side electrospinning possess unique properties and a range of advantages that support their diverse applications in promoting effective wound healing. These advantages can be summarized as follows:

1. The advantages and characteristics similar to the electrospun monolithic nanofibrous mats include: i) unique physical properties (small diameter, huge porosity, 3D web structures, large surface areas, and structural characteristics similar to the extracellular matrix); ii) adjustable functional performance through the polymeric matrices (such as pH sensitivity, mechanical properties, and hydrophilicity); iii) high drug encapsulation efficiency; iv) a robust and simple working process, i.e., a straightforward and single-step “top-down” nano fabrication process.

2. Their special advantages over nano products prepared by traditional blending electrospinning include: i) the powerful ability that results from the multi-chamber structure, which allows different types of active ingredients to be co-loaded into their separate chambers, each with its own controlled release profile for a synergistic wound healing effect; ii) the integration of different polymer matrices in different compartments can be a powerful tool for tailoring the apparent properties of the fibrous mats, such as mechanical properties, bioadhesive performance, and hydrophilicity; iii) only one of the multiple fluids needs to be electrospinnable, which endows the capability to convert a wide variety of unspinnable fluids into structural nanofibers.

3. The special advantages of Janus nanostructures over core-sheath nano products prepared by coaxial electrospinning include: i) all chambers can contact the surrounding environment, making them more effective at creating a suitable microenvironment for wound sites; ii) a greater variety of tri-chamber subcategories to support the development of novel functional materials with specific structure-performance relationships; and iii) the separate sides provide a powerful tool for developing additional functional properties beyond drug loading and controlled release, such as nanofiber alignment, bioadhesion, and mechanical properties.

Zhang et al. recently reported a type of tri-chamber eccentric Janus nanofibers (TEJNs), fabricated using a trifluid side-by-side electrospinning process (Figure 3(a)). The TEJNs demonstrated both antibacterial and antioxidant properties, hinting at their potential for various biomedical applications, including wound dressings [38]. Two polysaccharide polymers, chitosan (CS) and ethylcellulose (EC), were explored as matrices for different chambers. The TEJNs featured a unique structure with an outer CS chamber, a middle EC chamber loaded with curcumin (Cur), and an inner EC chamber loaded with vitamin E (VE). The multiple-fluid side-by-side electrospinning processes were robustly and continuously implemented using a homemade spinneret. In vitro dissolution tests showed that the TEJNs could provide a sustained release of 90% of the loaded Cur and VE for 34.30 h and 24.86 h, respectively. Antibacterial and antioxidant experiments indicated that the TEJNs offered enhanced effects compared to traditional homogeneous electrospun nanofibers. While popular core-sheath and tri-layer core-sheath nanomaterials can load multiple active ingredients in different compartments, these compartments have a strictly inner-outer spatial relationship, which can negatively influence the potential synergistic action due to a delayed release of inner ingredients. In contrast, Janus, and especially tri-chamber Janus nanomaterials, allow each chamber to contact the environment, potentially providing the most favorable release formats for synergistic actions during wound healing. These synergistic actions include: 1) the combined antibacterial effects of the outer chamber CS through contact mechanisms and the release of Cur from the middle chamber; and 2) the combined antioxidant effects of Cur from the middle chamber and VE from the inner chamber. The superior performance of TEJNs is attributed to a combination of factors, including their unique tri-chamber structure, the specific shape of the chambers, the distribution and spatial positioning of drugs within the nanofibers, and the rational selection and pairing of drugs with polymeric matrices.

1. (4) There are abundant organizational methods using Janus nanofibers as building blocks to fabricate even more complex Janus structures: i) layer-by-layer organization of different medicated nanofibers [39]; ii) combination of side-by-side electrospinning with other techniques, such as electrospraying and casting, to create novel configurations for an effective wound healing process [40,41].

Figure 3.

Two typical examples for fabricating potential wound dressings from the electrospun Janus nanofibers: (a) A kind of tri-chamber eccentric nanofibers with synergistic antioxidant and antibacterial performances. Figure images reproduced with permission from [38], copyright 2024 Elsevier; (b) A tri-layer hybrid film composed of both Janus nanofibers and monolithic nanofibers from the double sides for promoting wound healing. The outer layer is composed of highly hydrophobic polycaprolactone (PCL), the inner layer is composed of highly hydrophilic gelatin, and the middle layer is Janus nanofibers mixed with ciprofloxacin (CIP) and zinc oxide nanoparticles (n-ZnO), redrawn from [39].

In literature, there are abundant reports about Janus films and particles for wound dressing applications [42–45]. However, almost all of the so-called Janus films are essentially a type of double-layer film. Most of them are two-layer films, with each layer consisting of electrospun monolithic nanofibers with various components and compositions, and some films are composed of one layer of electrospun monolithic medicated nanofibers, while the other layer is a casting film or just electrosprayed micro-/nano-particles. Although these Janus films have been demonstrated to be useful for treating targeted wound areas, they are essentially “Janus” on a macro scale, and often require multiple steps with various working fluids and operational conditions. Therefore, the fabrication processes are time-consuming, and the properties and quality control of Janus films raise significant concerns due to the integration of two different working processes.

The layer-by-layer collection strategy can also be combined with side-by-side electrospinning to elevate the ability of electrospinning in generating novel nanofibrous films. Xu et al. reported a type of tri-layer hierarchical structural nanofibrous dressing for accelerating wound healing (Figure 3(b)) [39]. The top layer, consisting of hydrophobic polymer polycaprolactone (PCL), resists the adhesion of external microorganisms. The bottom layer, composed of hydrophilic polymer gelatin, furnishes a moist environment for the wound healing. The intermediate layer is composed of hydrophilic Janus nanofibers fabricated through the eccentric side-by-side electrospinning technique. PCL and gelatin serve as polymer matrices, loaded with zinc oxide nanoparticles (n-ZnO) and ciprofloxacin (CIP), respectively. The experimental results indicate that the dressing shows fine surface wettability, strong mechanical performances, and fast drug release profile. The presence of biologically active ingredients endows antibacterial activity against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). Ultimately, the experimental results of wound treatment in mice exhibit promotion of angiogenesis, accelerated collagen deposition, and complete wound healing within 14 days. Overall, this hierarchical structural dressing holds strong potential for accelerating wound healing. Nanostructures always play their important roles in developing a wide variety of functional nanomaterials [46–49]. Among them, side-by-side electrospinning and its various multi-chamber Janus nanostructures can be expected to hold more promises for new wound dressings with higher therapeutic effects.

Several typical multi-chamber Janus nanostructures are depicted in Figure 4. Figure 4(a) presents a TEM image of a type of bi-layer Janus nanofibers designed for biphasic drug controlled release [50]. Figure 4(b) showcases as SEM image of a special tri-section chimeric Janus structure, which contains “A,” “B” and “C” three sections and is intended for the rapid dissolution of a poorly water-soluble drug helicid [51]. Figure 4(c) displays a SEM image of a tri-layer eccentric Janus nanofiber, which contains T1, T2, and T3 chambers and is aimed for the anti-adhesion of tendons [35]. Figure 4(d) illustrates an SEM image of a Janus nanofiber with a core section on one side and a coordination side, reported to be useful for combined anticancer therapies [52]. These multi-chamber Janus nanostructures hold great promise as a powerful platform for tailoring and organizing various active ingredients to achieve a synergistic effect in promoting rapid wound healing.

Figure 4.

Images of four typical multi-chamber Janus nanostructures: (a) A TEM image about a bi-chamber Janus nanofiber, reprinted with permission from [50]. Copyright 2017 American Chemical Society; (b) An SEM image of a tri-section chimeric Janus nanofiber [51]. Copyright 2022 Springer Nature; (c) An SEM image of a tri-layer eccentric Janus nanofiber. Reproduced with permission from [35]. Copyright 2024 Elsevier; and (d) A TEM image about a tri-section Janus nanofiber with one side containing a core section. Reproduced from [52], published under a CC-BY 4.0 license.

4. Conclusions

The popularity of electrospun medicated nanofibers, prepared from single-fluid blending electrospinning and coaxial electrospinning, has obviously shown a bright future for electrospun Janus nanofibers as wound dressings. Based on the approach of creating Janus nanofibers with integrated side-by-side nanostructures using an eccentric spinneret, a series of tri-chamber nanostructures, characterized by the presence of inner side-by-side chambers, can be similarly developed through tri-fluid side-by-side electrospinning, using a structural spinneret as the template. The advantage of Janus nanostructures is that they have multiple chambers to encapsulate various ingredients while keeping several chambers in contact with the environment, which is impossible for other nanostructures. These Janus multi-chamber structures are versatile for meeting the multifunctional demands of all types of wound dressings. In addition to the diversity of structures with various organizations of the inner chambers, the electrospun nanofibers from both the blending process and the side-by-side process can be organized into Janus films or tri-layer films, further enriching the development approaches for Janus structure-based wound dressings.

5. Future perspectives

To rapidly promote the real applications of Janus fiber-based wound dressings, several key issues need urgent resolution. First is the large-scale production of Janus structural nanofibers. Although the production of nanofibers from blending processes has been widely reported, the creation of nanofibers with complex structures remains a laboratory endeavor. Combining side-by-side electrospinning with other techniques, such as casting films, electrospraying, artificial intelligence, and bioprinting [53–55], has the potential to accelerate the commercialization process. Traditional free surface needleless electrospinning, used for producing monolithic nanofibers, cannot be used to create Janus nanofibers. Second is the advancement of wound dressings toward clinical applications. Most current studies, whether based on inner Janus nanostructures or double-layer Janus films, are still at the proof-of-concept stage. Third is the electrohydrodynamic mechanism, which remains unclear even for single-fluid blending processes. The interactions between electrostatic energy and various working fluids, their behavior under identical electrical fields, and the guiding effect of the spinneret’s nozzle template are all intriguing aspects that merit further investigation. Several pioneering studies on these topics can be found in literature [38,56].

Funding Statement

The paper was financially supported by the Medical-Engineering Cross Project between USST and 411 hospital, the Shanghai Industrial Collaboration Project [HCXBCY-2023-042 & XTCX-KJ-2023-44], and the Funding from China RongTong Medical Healthcare Group Co.Ltd. to Haisong Yang [No. 20240709411].

Article highlights

• Points out the versatility of electrospun Janus nanofibers for wound healing.

• New types of wound dressings should have multiple functional performances.

• There is a big gap for developing wound dressings from electrospun Janus nanofibers.

• The eccentric spinneret is useful for implementing side-by-side electrospinning.

• There are eight different kinds of tri-chamber Janus nanofibers.

• Electrospun Janus fibers have their special merits for wound healing applications.

• Janus nanofibers support the co-contact of each chamber with the environment.

• Bi-layer electrospun nanofibers can be viewed as a Janus film.

• Point out the further investigation directions of electrospun Janus wound dressings.

Credit author statement

Conceptualization: D.-G.Y. and H.Y.; Data curation: D.-G.Y., W.H. and C.H.; Methodology: W.H., C.H. and H.L.; Project administration: D.-G.Y. and H.Y.; Resources: D.-G.Y. and H.L.; Software: W.H., C.H. and H.L.; Funding acquisition: D.-G.Y. and H.Y.; Supervision: D.-G.Y. and H.Y.; Validation: D.-G.Y.; Writing – original draft: D.-G.Y. and W.H.; Writing – review & editing: H.Y. and D.-G.Y.

Disclosure statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.