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- Springer Journals
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- Copyright © The Author(s) 2022
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- 2524-7921
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- 2524-793X
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- 10.1007/s42765-022-00198-9
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Abstract
Versatile strategies have been developed to construct electrospun fiber-based drug delivery systems for tissue regeneration and cancer therapy. We first introduce the construction of electrospun fiber scaffolds and their various structures, as well as various commonly used types of drugs. Then, we discuss some representative strategies for controlling drug delivery by electrospun fibers, with specific emphasis on the design of endogenous and external stimuli-responsive drug delivery sys- tems. Afterwards, we summarize the recent progress on controlling drug delivery with electrospun fiber scaffolds for tissue engineering, including soft tissue engineering (such as skin, nerve, and cardiac repair) and hard tissue engineering (such as bone, cartilage, and musculoskeletal systems), as well as for cancer therapy. Furthermore, we provide future development directions and challenges facing the use of electrospun fibers for controlled drug delivery, aiming to provide insights and perspectives for the development of smart drug delivery platforms and improve clinical therapeutic effects in tissue regen- eration and cancer therapy. Keywords Electrospinning · Electrospun fibers · Drug delivery · Stimuli-responsive · Tissue engineering · Cancer therapy Introduction self-repair can cause the occurrence of many diseases [2]. In these cases, the assistance of biologically active substances Living systems are based around complex and precise or drugs is necessary to inhibit or eliminate the internal and regulatory rules that modulate the on-demand release or external factors that are unfavorable to health, effectively alteration of important biologically active substances in treating diseases and promoting regeneration of damaged a spatiotemporally controlled manner to maintain normal tissues [3]. As a key component of drug delivery systems metabolic balance [1]. However, the limited capability (DDSs), drugs play pivotal roles and are responsible for of many human tissues to perform self-regulation and/or achieving satisfactory therapeutic effects [4 , 5]. However, most drugs are administered systemically, require frequent administration and are characterized by short-term effective- Longfei Li and Ruinan Hao have contributed equally to this work. ness, potentially leading to adverse cytotoxic side effects and * Jiajia Xue the development of drug resistance. In addition, drug con- jiajiaxue@mail.buct.edu.cn centration and therapeutic effects at targeted tissues cannot be guaranteed [6]. Meanwhile, the tissue regeneration and State Key Laboratory of Organic-Inorganic Composites, cancer treatment involve complex physiological processes Beijing University of Chemical Technology, Beijing 100029, People’s Republic of China [7], so it is difficult for a single type of drug to achieve an ideal therapeutic effect; rather, effective treatment usually Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, requires multiple types of drugs to be released in a coordi- People’s Republic of China nated and periodically controlled manner. Trauma Center, Peking University People’s Hospital, With the rapid development of nanotechnology, various Beijing 100730, People’s Republic of China DDSs have been developed to address problems such as Department of Orthopaedics, Peking Union Medical burst and discontinuous drug release, unsatisfactory drug College Hospital, Chinese Academy of Medical Sciences, loading efficiency, and low drug stability and utilization Beijing 100730, People’s Republic of China Vol.:(0123456789) 1 3 1376 Advanced Fiber Materials (2022) 4:1375–1413 efficiency in vivo [8 –10]. Compared with DDSs based on drug doses with spatiotemporal control have received liposomes, micelles, nanoparticles and hydrogels, electro- great attention [28, 29]. It is well known that responsive spun fibers have attracted increasing attention as promising DDSs can exploit intrinsic endogenous stimuli in living drug carriers [11]. DDSs based on electrospun fibers have systems to develop new strategies for drug delivery with been studied and explored due to the maneuverability of electrospun fiber scaffolds based on factors such as drug the electrospinning process and the subsequent customiz- sensitivity to pH [30], reactive oxygen species (ROS) able design of the fiber-based scaffolds [12, 13]. Electro- [31], enzymes [32], and glucose [33]. Likewise, external spun fiber scaffolds have characteristics that include simple stimuli such as temperature [34], light [35], electricity preparation, high material universality, and favorable surface [36], magnetic fields [37], and ultrasound [38] have also chemical properties for drug adsorption [14, 15]. In addition, been used to modulate cellular behaviors, inducing tissue the high porosity and large specific surface area of elec- regeneration, and to remotely control drug delivery [39]. trospun fiber scaffolds make them beneficial to increasing Based on this, stimuli-responsive electrospun platforms drug-loading efficiency and the response speed of stimuli- can serve as precise on-demand drug release repositories delivered drugs [16]. The extracellular matrix (ECM)-like to mimic the function of living systems as much as pos- morphology of electrospun fibers inherently guides cellular sible and develop new tissue regeneration methods via drug uptake [1]. These advantages allow multifunctional the design of fiber structural features, thereby expanding electrospun fiber scaffolds to support customizable drug the application of electrospun fibers for drug delivery in delivery platforms that can achieve the sustained and pro- the fields of tissue regeneration and disease treatment. grammed release of multiple drugs for tissue regeneration Herein, we summarize the recent progress on con- and cancer therapy. trolling drug delivery from electrospun fiber scaffolds In principle, almost all polymers and many additional for tissue engineering, including soft tissue engineering functional components can be integrated into the electrospun (such as skin, nerve, cardiac, blood vessels) and hard tis- fiber platform [13, 17]. As for drug delivery, a variety of sue engineering (such as bone, cartilage, musculoskel- technologies derived from electrospinning, including coaxial etal, dental), as well as for cancer therapy. Meanwhile, electrospinning [18], multiaxial electrospinning [19], elec- emerging strategies for combining drugs with electrospun trospraying [20], etc., have been developed to prepare drug- fibers and the resultant mechanism of drug delivery are loaded electrospun fiber platforms. In addition, electrospin - discussed, and the effects of endogenous and external ning can be used to fabricate porous micro- and nanofibers, stimuli on drug release are emphasized (Fig. 1). Typically, as well as various types of hierarchically controlled fibrous “drugs” refer not only to traditional small-molecule drugs structures, ranging from 1 to 3D fibrous scaffolds. A grow - but also to bioactive components with specific therapeu- ing number of customized electrospun fiber scaffolds have tic and regenerative functions, which can be divided into been used for drug delivery to facilitate tissue regeneration small molecular drugs and bioactive substances (e.g., and cancer therapy. By modifying loading strategies, drugs growth factors, protein polypeptides, gene nucleic acids, can be released in a fast, sustained, heterogeneous or con- and liposomes), as well as nanoparticles with therapeu- trolled manner by being combined with polymers, adsorbing tic effects. Finally, the future directions of electrospun on the fiber surface, or indirectly encapsulating onto electro - fibers for controlled drug delivery in tissue regeneration spun fibers [21, 22]. Similarly, multifunctional electrospun and cancer therapy are prospected, providing insights and fiber scaffolds that allow the sequential release of multiple perspectives for the development of smart drug release drugs or in a spatiotemporally controllable manner, can be and highlighting the challenges to accelerate clinical created to meet a variety of in vivo needs [23, 24]. translation. Critically, a combination of strategies is needed for tis- sue engineering and cancer therapy, including the devel- opment of multifunctional scaffolds to provide biomi- Construction of Electrospun Fibers for Drug metic topographical cues and mechanical support, as well Delivery as the simultaneous delivery of small molecule drugs, growth factors, and other biochemical signals [25–27]. In The setup of electrospinning consists of a high-voltage addition to serving as a drug carrier, electrospun fibers power supply, a syringe pump, a spinneret, and a conduc- can also be engineered to manipulate cell morphology and tive collector. Firstly, the solution is extruded from the spin- migration, neurite elongation, and stem cell differentia- neret and forms a hanging droplet due to surface tension. tion by controlling their structure and array. Given that When the high voltage power supply is applied, electrostatic the realization of multiple functions in the body requires repulsion among the same charges formed on the droplet high levels of temporal and spatial precision, electro- surface turns it into a Taylor cone, from which a charged jet spun fiber scaffolds that enable the precise delivery of is ejected. Because of the behavior of bending instability, the 1 3 Advanced Fiber Materials (2022) 4:1375–1413 1377 jet undergoes a whipping motion after initially extending in it has been found that the presence of beads changes the sur- a straight line. The jet will get slimmer and solidify quickly face roughness of the fiber, and this high surface roughness when the diameter of jet is optimal under the action of the can have some beneficial effects on cell differentiation [45]. electric field, then finally deposit on the surface of the con- The fabrication of fiber by multi-fluid control technology ductive collector [17]. To meet various applications, differ - is a new method in recent years [46]. A porous or grooved ent electrospun fiber sizes and morphologies can be obtained structure can be formed by electrospinning and stretching by changing the spinning process and parameters such as two incompatible polymers, then removing one of the com- the voltage, solution composition, and collector design [40]. ponents with a specific solvent [47] (Fig. 2c, d). Compared Meanwhile, satisfactory fiber structures can also be obtained with the original fibers, both of these structures possess by post-treatment procedures, such as weaving [41], twisting increased surface roughness and area, which are beneficial [42], foaming [43] and others. In this section, electrospun cell adhesion [48]. In addition, the grooved surface can pro- fibers are divided into three categories as follows: 1D pris- vide topographic cues to promote the directional migration tine fiber (an individual fiber with different morphologies of cells. Meanwhile, some additional properties can be inte- and structures), 2D hybrid fiber (in which material is loaded grated into the hollow lumen of core–shell structures [46] on the lumen/surface of an individual fiber), and 3D fiber and multi-channel structures [49] to meet the unique condi- architecture (arrangement and combination of fibers in 3D tions for the regeneration of different tissues (Fig. 2e, f). space). Distinct from pristine fibers, 2D hybrid fibers can com - The morphology and structure of 1D pristine fibers bine nanoparticles, cells, and bioactive factors to provide are the most basic units, and the most common and eas- some specific effects. For example, embedding bioactive ily obtained morphology is the fiber with a smooth surface factors in fibers can promote cell migration, proliferation, (Fig. 2a), however, at the same time, its simpleness makes and differentiation [50] (Fig. 2g). Packing cells in fibers can it unsuitable for many applications. Many emerging struc- not only maintain high cellular activity and the ability to tures, such as beaded, grooved, multi-channel, core–shell, secrete immune molecules but can also provide a suitable and porous structures, have been designed and constructed, environment for tissue regeneration [51] (Fig. 2h). In addi- with various advantages described. Contrary to previous per- tion, embedding nanoparticles, such as iron oxide nanoparti- ception, beaded fibers tend to be produced due to a decrease cles [52], graphene and organic materials [53] in fibers, can in surface tension or an uneven distribution of solution con- increase the intensity of external signals, thereby enhanc- centration (Fig. 2b) [44], which is considered to be a struc- ing stimulation to promote tissue repair (Fig. 2i). Attaching tural defect that needs to be avoided and removed. However, specific substances to the fiber surface by post-treatment or Fig. 1 Schematic illustration showing electrospun nanofiber scaffolds for controlling drug delivery and their biomedical applications in tissue regeneration and cancer therapy 1 3 1378 Advanced Fiber Materials (2022) 4:1375–1413 in-situ growth is also a common method for broadening the with excellent photocatalysis and antibacterial properties applications of electrospun fibers [54– 56] (Fig. 2j–l). For [56]. example, the introduction of polydopamine (PDA) coatings Compared with the 2D hybrid fibers, the growth, mor - to electrospun nanofiber membrane could provide nuclea- phology, differentiation, and function of cells in 3D scaf- tion sites and active centers for zinc oxide (ZnO) nano-seeds folds are closer to those found in in vivo microenvironments. to form nanorod structures, endowing nanofiber membrane Using the previously described pristine fibers or hybrid fib- ers, 3D scaffolds with different structures can be fabricated, Fig. 2 The versatile structure of electrospun fibers. a Solid fiber. [55]; Copyright 2021, Elsevier Limited. l Nanorod-grown fiber. Reproduced with permission from Ref. [200]; Copyright 2020, Reproduced with permission from Ref. [56]; Copyright 2018, Else- Wiley–VCH Limited. b Beaded fiber. Reproduced with permission vier Limited. m Radially aligned fiber array. Reproduced with per - from Ref. [44]; Copyright 2008, Wiley–VCH Limited. c Porous fiber. mission from Ref. [57]; Copyright 2010, American Chemical Society Reproduced with permission from Ref. [47]; Copyright 2008, Wiley– Limited. n Bionic patterned fiber array. Reproduced with permission VCH Limited. d Grooved fiber. Reproduced with permission from from Ref. [41]. Copyright 2020, Wiley–VCH Limited. o Complex Ref. [48]; Copyright 2020, Wiley–VCH Limited. e Core-sheath fiber. pattern fiber array. Reproduced with permission from Ref. [58]; Cop- Reproduced with permission from Ref. [46]; Copyright 2010, Ameri- yright 2011, Wiley–VCH Limited. p Fiber mat with grooved surface. can Chemical Society Limited. f Multi-channel fiber. Reproduced Reproduced with permission from Ref. [59]; Copyright 2021, Ameri- with permission from Ref. [49]; Copyright 2007, American Chemi- can Association for the Advancement of Science Limited. q Tubu- cal Society Limited. g Fiber loaded with bioactive molecules. Repro- lar conduit. Reproduced with permission from Ref. [60]; Copyright duced with permission from Ref. [50]; Copyright 2014, Wiley–VCH 2017, Wiley–VCH Limited. r Multi-tubular conduit. Reproduced Limited. h Cell-encapsulated fiber. Reproduced with permission from with permission from Ref. [61]; Copyright 2018, Wiley–VCH Lim- Ref. [51]; Copyright 2020, Elsevier Limited. i Nanoparticles-embed- ited. s 3D porous fiber scaffold. Reproduced with permission from ded fiber. Reproduced with permission from Ref. [53]; Copyright Ref. [62]; Copyright 2019, American Chemical Society Limited. t 2015, Elsevier Limited. j Nanoparticles anchored fiber. Reproduced Multifilament electrospun fiber yarns. Reproduced with permission with permission from Ref. [54]; Copyright 2020, Elsevier Limited. from Ref. [42]; Copyright 2018, Elsevier Limited (k) Nanosheet-grown fiber. Reproduced with permission from Ref. 1 3 Advanced Fiber Materials (2022) 4:1375–1413 1379 typically by changing the collector, or by post-processing molecular drugs, such as ciprofloxacin [67, 68], doxorubicin procedures such as crimping, weaving, molding, and others. (DOX) [69], and ibuprofen [70], (ii) bioactive substances, By using different collectors, such as rollers and conductive such as peptides [71], proteins [72], nucleic acids [73], and rings [57], fibers arranged in an orderly 3D direction can be liposomes [74], and (iii) nanoparticles with therapeutic effi- prepared (Fig. 2m), and the collector substrate pattern can cacy, such as Ag nanoparticles [75], mesoporous silica nano- be changed to fabricate various patterned scaffolds (Fig. 2n, particles (MSNs) [76], nano-enzymes [77, 78], and bioglass o), making these scaffolds conducive to the development of [79, 80]. cells in vivo [41, 58]. In addition, post-treatment methods Small molecular drugs are typically signal transduction can be used to change the surface morphology of scaffolds. inhibitors that can treat diseases by blocking correspond- For example, molding and photoetching can form grooves ing signaling pathways [81–83]. Small molecular drugs on the surface, providing topographical cues for cell migra- are mainly chemically synthesized or derived from natural tion (Fig. 2p) [59]. Another simple method, rolling-up, is extracts, and their molecular weights are usually less than often used to fabricate conduits from fiber membrane to con- 1,000 [84]. They have a wide range of applications due to nect defective nerves and build a bridge conducive to nerve their low cost, ease of storage and transport, high tissue regeneration (Fig. 2q) [60]. To improve the ability of bion- permeability and minimal immunogenicity [85]. Although ics to simulate physiological cues, several small tubes were small molecular drugs have excellent therapeutic effects, sequentially embedded in a larger tube to simulate the multi- most have poor pharmacokinetics and are easily metabo- fascicle structure of normal nerves, effectively avoiding mis- lized into other substances in the body [86]. Therefore, it is aligned axons growth (Fig. 2r) [61]. Foaming technology is essential to effectively deliver small molecular drugs using a another important method to fabricate 3D scaffolds com- suitable platform. Loading small molecular drugs into b fi ers posed of fibers. Scaffolds with radial arrangement structure can significantly overcome the above challenges by improv - can be fabricated through customizable control technology, ing water solubility and stability, increasing drug concentra- which can effectively promote the migration of cells from tions at disease sites, and reducing side effects. the periphery to the center (Fig. 2s) [62]. Moreover, this 3D Compared with small molecular drugs, bioactive sub- structure provides larger porosity and pore size, broaden- stances have relatively larger molecular weights, more ing the applications of electrospun fiber scaffolds in tissue complex structures, and better water solubility. The immo- engineering [62, 63]. Yarn can be made of electrospun fibers bilization or encapsulation of these bioactive substances by weaving and twisting, leading to better permeability and onto the surface and into the interior of fibers can over - drafting behavior (Fig. 2t), as well as increased suitability come limitations associated with systemic administration for tissue suturing [42]. or local injection. Proteins and growth factors are involved Electrospun fiber scaffolds have wide application pros- in many physiological processes in the human body. For pects in tissue regeneration and cancer therapy due to their example, bone morphogenetic protein-2 (BMP-2) and insu- porosity, high loading capability, adjustable mechanical lin-like growth factor-1 [72, 87] have the ability to promote properties, and excellent biocompatibility [64]. The inte- bone tissue repair, while vascular endothelial growth fac- gration of emerging 3D printing technology can support tor (VEGF) [88], epidermal growth factor (EGF) [89], and the design of more scaffolds with different structures and nerve growth factor (NGF) [90] can promote skin and nerve patterns, which can play unique roles in specific tissue tissue repair. Unlike macromolecule proteins, peptides are regeneration processes [65]. Furthermore, advanced 4D not specifically absorbed by the reticuloendothelial system electrospun fiber scaffolds can be developed by incorporat- or liver, leading to fewer toxic side effects and more mature ing shape memory or stimuli-responsive properties for bio- peptide synthesis technology. Therefore, many types of pep- medical applications [66]. Accordingly, the optimization of tides are widely used in tissue engineering repair, including electrospun fiber scaffold-based DDSs has attracted increas- ε-polylysine peptides with antibacterial properties [91] and ing attention. Therefore, it is believed that a wide variety of peptides for angiogenesis [71], as well as many other types electrospun fibers will be developed to support better and of anti-bacterial peptides. For the delivery of nucleic acids, multifunctional drug delivery platforms. the key outstanding issue is protecting nucleic acid activity from the surrounding environment [92–95]; currently, com- monly used nucleic acids primarily include plasmid DNA, Drug Delivery for Tissue Engineering microRNA, and small interfering RNA, among others [96]. and Cancer Therapy Most bioactive molecules are easily damaged by the exter- nal environment due to their chemical instability, relatively In recent years, the loading of functional therapeutic agents short half-lives, and vulnerability, so it is often difficult to into electrospun fibers has attracted research attention. effectively encapsulate bioactive molecules in nanofibers Functional therapeutic agents can be classified into (i) small with conventional electrospinning technology. Therefore, 1 3 1380 Advanced Fiber Materials (2022) 4:1375–1413 it is particularly important to develop new technologies to Specifically, a number of drugs or functional nanoparticles enable the effective encapsulation and delivery of bioactive with chemical stability and organic solvent resistance can be molecules by nanofibers. mixed with polymers to form a homogeneous electrospin- In addition to the above-mentioned drugs, a number of ning solution. Then, micro- or nanofibers loaded with one functional nanoparticles have the ability to promote tissue or multiple drugs can be fabricated by electrospinning [70, repair and cancer treatments. For example, Ag nanoparti- 103]. Due to the random distribution of drugs on the fiber cles have excellent antibacterial effects [75], and manganese surface and inside the fibers, the release process is generally dioxide nanoparticles can effectively scavenge excess hydro- characterized by an initial burst release and subsequent slow gen peroxide in the body [91]. Similarly, metal–organic release [104]. Since most fibers have high specific surface framework materials, such as magnesium organic frame- area and large porosity, the drug is often completely released works, can effectively scavenge ROS, slow down the inflam- from the fibers within a few hours or days, incompatible matory response, and promote angiogenesis [97]. Compared with long-term administration at the tissue. In these cases, with small molecular drugs and bioactive substances, these polymers that can form electrostatic adsorption interac- therapeutic nanoparticles have more stable chemical prop- tions with the drugs can be used to delay drug release. It erties and are easier to load into electrospun fibers. More is difficult to induce interactions between some chemical importantly, they can also act as drug carriers to facilitate the drugs or biologically active molecules and polymers, so new controlled release of drugs from electrospun fibers [76, 98]. technologies are urgently needed to prolong release time. One solution is to load chemical drugs and bioactive mol- ecules into a secondary carrier, after which the drug-loaded Manipulation of Electrospun Fibers electrospun fibers can be prepared by blending electrospin- to Control Drug Delivery ning. These secondary carriers can be nanoparticles [105, 106], micelles [107], vesicles [108], microspheres and other Strategies for Encapsulating Drugs in Electrospun forms. For example, drug-loaded halloysite clay nanotubes Fibers were doped into polycaprolactone (PCL)/gelatin nanofibers, achieving sustained drug release over 20 days, which was Due to their ECM-like structure, high specific surface area, greatly extended compared to directly loading the drugs in high porosity, high drug loading capability, and controlled pristine electrospun fibers [109]. drug delivery function, electrospun fiber-based scaffolds Chemically unstable and easily inactivated bioactive have outstanding advantages for the delivery of functional factors, such as growth factors, proteins and nucleic acids, therapeutic agents [99–102]. Functional therapeutic agents function only when they are able to enter cells. Therefore, it can be loaded into electrospun fibers by blending electro - is important to avoid contact between bioactive factors and spinning, second carrier electrospinning, emulsion electro- organic solvents, as well as to deliver bioactive molecules spinning, coaxial electrospinning, electrospraying, physi- successfully to the cellular interior without inactivation cal adsorption, and covalent immobilization. In selecting [110, 111]. The above-mentioned problems can be solved the fiber matrix for drug loading to achieve a typical drug using emulsion electrospinning technology [112]. In emul- release profile, the interaction between the drug and the fiber sion electrospinning, there is no direct contact between the scaffolds should be considered. The composition, molecu- molecules and the dissolved organic matter, as the bioac- lar weight, hydrophilicity, and degradation rate of the fiber tive substances are partitioned into the aqueous phase, thus polymer matrix all affect the drug release behavior. In addi- greatly enhancing molecular activity. The loading of drugs tion, the relative molecular mass, crystallinity and solubility into the fiber interior by emulsion electrospinning effectively of the drug, and other properties of the drug also affect the mitigates the explosive release of drugs at early stages. In release behavior. In addition to hydrogen bonds and electro- addition, emulsion electrospinning enables the simultaneous static interactions, covalent bonds can also be used to link loading of multiple drugs. Furthermore, emulsion electro- the drug with the fibers. Evaluations of the bioactivities of spinning can realize the simultaneous loading of multiple both the drug-loaded scaffolds and the released drug are drugs and alleviate the problem of explosive drug release necessary. Typically, the activities of both the drug-loaded in early stages [113]. For instance, emulsion electrospin- scaffolds and the drug can be evaluated by co-culturing with ning was applied to fabricate nanofibers loaded with hydro- cells or bacteria to observe the influence of the scaffolds phobic 10-hydroxycamptothecin (HCPT) in the sheath on the adhesion, growth, migration and differentiation of layer and with hydrophilic tea polyphenols in the core layer cells or the growth of bacteria, depending on the applica- [114]. In the initial 4 days, the release of HCPT reached tion direction. about 61.5%, while the release of tea polyphenols was only Blend electrospinning is the most straightforward about 20.4%. Although emulsion electrospinning has sig- technique for loading drugs into nanofibers (Fig. 3a). nificant advantages, it still has some problems, including 1 3 Advanced Fiber Materials (2022) 4:1375–1413 1381 Fig. 3 Schematic illustration showing the different fabrication meth- b coaxial electrospinning, c electrospinning combined with electro- ods of drug-loaded electrospun fibers, including a blend electro- spraying, and d post-processing by physical adsorption and covalent spinning, second carrier electrospinning, emulsion electrospinning, immobilization poor solution stability and low drug-loading efficiency. In electrospinning can reduce the explosive early-stage release this case, microsol-electrospinning technology can be used of drugs, realize the simultaneous loading of hydrophilic to achieve efficient loading and slow release of hydrophilic and hydrophobic drugs, and avoid the biological toxicity drugs or easily deactivated biomolecules [115, 116]. For caused by late crosslinking of hydrophilic polymers [18, example, when microsol-electrospinning was used to load 119]. Since coaxial electrospinning can be used to prepare VEGF in electrospun nanofibers, only 36.8% of VEGF was core-sheath electrospun fibers, it is feasible to load different released in the initial two days, followed by sustained release drugs or bioactive molecules into the core and sheath layers, over 4 weeks [117]. respectively. The drug in the core layer needs to pass through Similar to emulsion electrospinning, coaxial electro- the sheath layer to be released, slowing its release rate com- spinning can successfully be used to encapsulate bioactive pared to that of the sheath layer [102]. As an example, an molecules with unstable chemical properties into electro- in vitro release study showed that the amount of doxoru- spun fibers (Fig. 3b) [118]. For coaxial electrospinning, bicin hydrochloride released from the sheath of nanofibers a core layer spinning solution composed of biomolecules reached 62.2% in the first 200 hours, while the amount of and a sheath layer spinning solution composed of polymers matrix metalloproteinase-2 released from the core layer was form two separate jets from the coaxial needle to fabricate only about 50% through 960 hours [120]. To further delay core-sheath nanofibers. Compared with commonly used the rate of drug release, the drugs can also be encapsulated electrospinning methods, coaxial nanofibers are prepared into a secondary carrier before preparation of the nanofiber in a way that minimizes interactions between the organic membrane by coaxial electrospinning [121]. polymer solution and the water-based biomolecules, main- Electrospray technology can integrate nanoparticles taining the biological activity of unstable biomolecules. loaded with bioactive molecules or drugs into and/or onto Meanwhile, compared with blend electrospinning, coaxial fibers (Fig. 3c) [122]. For electrospraying, it allows the 1 3 1382 Advanced Fiber Materials (2022) 4:1375–1413 deposition of particles loaded with bioactive molecules or sequential electrospinning was used to prepare a three-layer drugs on the fibers. It can not only encapsulate drugs with nanofiber scaffold in which the inner and middle layers were bioactive molecules, microspheres, and micelles to protect loaded with microRNA-126 and microRNA-145, respec- their activity and prolong drug release but can also allow the tively, leading to the sequential release of microRNA-126 design of on-demand DDSs responsive to external stimuli. followed by microRNA-145 [131]. Compared with the passive release of drugs from other elec- trospun fibers, fibers that enable spatiotemporally controlled Stimuli‑Responsive Drug Delivery Systems drug release can be prepared by integrating electrospinning and electrospraying technologies. For example, collagen par- Electrospun fiber platforms incorporating stimuli-response ticles loaded with neurotrophin-3 (NT-3) can be sandwiched are emerging as a major driving force in the development of between two nanofiber layers using electrospray technology, smart drug delivery [132]. Just like many important func- realizing the sustained and controllable release of NT-3 tions in the human body are achieved in a site-specific and [123]. In addition, the combination of masked electrospray time-controlled manner, the responses to intrinsic endog- technology and electrospinning can achieve a gradient distri- enous and external stimuli provide more possibilities for the bution of biomacromolecular particles on fibers [124]. development of new drug delivery strategies [29, 39]. To this In addition to the above methods, a number of drugs can end, it can be realized to signic fi antly improve the selectivity also be loaded onto fibers by physical adsorption (Fig. 3d) and targeting of drugs, deliver appropriate drug concentra- [125, 126]. Especially for certain biomolecules, physical tions to the target site at a specific time, effectively reduce adsorption is not only the simplest way to load biomolecules side effects, and meet the requirements of tissue regeneration into fibers but can also effectively maintain the activity of and cancer treatment. Herein, typical endogenous and exter- the biomaterials. Although this method of drug loading is nal stimuli are summarized, and their potential to deliver relatively simple, the drugs cannot be released in a sustained precise amounts of drugs in a spatiotemporally controllable manner [127]. In particular, drugs and bioactive molecules manner is also described. that do not make electrostatic interactions with nanofib- ers are difficult to load by this method [15]. For example, Endogenous Stimuli‑Responsive Drug Delivery Systems recombinant human BMP-2 was adsorbed on the surface of poly(D,L-lactide-co-glycolide)/hydroxylapatite composite Differences in pH, enzyme expression, ROS levels, and glu- nanofibers by the physical adsorption method [128]. The cose content in pathological environments compared to nor- in vitro BMP-2 release profile showed that 75% of BMP-2 mal physiology can provide some ideas for the development was released within the first 5 days. In addition, layer-by- of smart drug delivery platforms. Indeed, various types of layer self-assembly (LBL) is another common physical nanofiber delivery systems responsive to endogenous stimuli adsorption method for drug loading onto fibers based on have been developed based on microenvironmental changes the alternating adsorption of polyelectrolytes on the matrix in cells or tissues [68, 133]. through electrostatic interactions, hydrogen bonds or other By selecting the appropriate type of polymer and post- interactions. For example, positively charged chitosan and processing method, electrospun fibers can be endowed with negatively charged type I collagen can be assembled onto pH-responsive drug release characteristics [134, 135]. pH- electrospun silk fibroin fiber membrane by LBL technology sensitive polymeric nanofibers change their own volume in for scar-free wound repair [129]. response to external pH changes, enabling intelligent and In addition to physical absorption, drugs or biomacro- responsive drug delivery [136]. Some nanofiber membranes molecules that can react with functional groups on the fiber contain chemical groups that are sensitive to hydrogen and surface can be bound to nanofibers by covalent immobiliza - hydroxide ions, enabling the controlled release of drugs by tion [125, 129]. Such drugs and biomacromolecules can also changing intermolecular forces of the polymers when exter- be released in vivo by endogenous stimuli. For example, a nal pH changes. For instance, under acidic conditions, the polypeptide containing a carboxyl group reacted with the amino and acetyl amino groups of chitosan undergo a pro- amino group on the surface of chitosan hydrogel nanofibers tonation reaction to form an amine cation [137]. Swelling to form an amide bond; thus, the polypeptide was success- of the nanofiber membrane is increased due to mutual repul- fully loaded onto the nanofibers [71]. sion between ammonia cations and hydrogen ions. Thus, the At present, the development of a multi-functional elec- interaction forces between allicin and chitosan or polyvinyl trospinning platform is conducive to the delivery of multi- alcohol (PVA) are weakened, accelerating the release of alli- ple drugs. Sequential electrospinning is a technique used to cin from the fibrous membrane into the surrounding environ- construct multilayer nanofibers, and a variety of drugs can ment (Fig. 4a). However, in alkaline environments, inter- be loaded into the different nanofiber layers, so as to con- actions between hydroxide ions, chitosan and PVA are not trol the release rates of different drugs [130]. For example, obvious, reducing the degree of fiber membrane swelling. 1 3 Advanced Fiber Materials (2022) 4:1375–1413 1383 Fig. 4 Endogenous stimuli-responsive drug delivery fiber systems. triggered release of IBU from the prodrug, and the release curve of a Schematic illustration and SEM image showing the microstructure IBU from the different types of scaffolds in the presence or absence of CS/PVA/GO/Alli fiber mat, and the release of Alli from the fiber of enzyme. Reproduced with permission from Ref. [143]; Copyright mat at different pH values. Reproduced with permission from Ref. 2015, Elsevier Limited. d Schematic illustration showing that the [137]; Copyright 2020, Elsevier Limited. b Schematic illustration thioketal linkers in polyurethane containing thioketal (PUTK) can be showing the pH-responsive release of liposomes from the surface of cleaved in response to ROS, and the cumulatively released percent- a nanofiber, and the release curves of liposomes from the electrospun age of MP in vitro from the electrospun fiber patch in PBS solution fiber mat at different pH values. Reproduced with permission from (pH = 7.4) and 1 mM H O solution at 37 °C, respectively. Repro- 2 2 Ref. [138]; Copyright 2020, Springer Nature Limited. c Schematic duced with permission from Ref. [31]; Copyright 2020, Elsevier Lim- illustration showing the degradation-triggered release of esterase- ited sensitive prodrug from electrospun fiber mat followed by the enzyme- In addition to fiber swelling, pH-responsive drug release can responsive drug release. For example, electrospun PVA be triggered by external pH change through chemical bond nanofibers were loaded with a reduction-responsive Pt (IV) breakage. For example, IL-4-loaded liposomes containing prodrug micelle and dichloroacetate [139]. Simulation of the aldehyde groups were grafted onto the surface of fibers cancer cell state with s acetate buffer solution and sodium containing amino groups via Schiff base reactions (Fig. 4b) ascorbate better triggered the release of Pt (II), and levels of [138]. In acidic environments, these chemical bonds were cleaved Pt rapidly accumulated to 50% within 24 h. broken due to hydrolysis reactions, and the liposomes were Enzymes play important roles in different biological pro- released from the nanofibers. The in vitro release profile cesses and usually have high specificity, with various species showed that the release rate of liposomes was significantly of enzymes distributed across different tissues at specific faster at pH = 5.8 than at either pH = 7.4 or pH = 6.6. concentrations. Therefore, in response to abnormal concen- In addition to the above methods for preparing pH- trations of enzymes, enzyme-responsive DDSs provide a responsive nanofibers, a number of pH-responsive nano- way to increase selectivity and sensitivity [140]. In inflam- materials, such as liposomes, micelles and others, can also matory locations and tumor tissues, some specific enzymes be encapsulated into nanofibers to realize controllable and are significantly different from those in normal tissues, 1 3 1384 Advanced Fiber Materials (2022) 4:1375–1413 so it is feasible to exploit this feature to enable enzyme- Temperature controls almost all physical, chemical, and responsive controlled drug release [141, 142]. For exam- biological reactions, in addition to being critical regula- ple, an esterase-sensitive prodrug was loaded in electrospun tory parameter for the human body. Temperature-respon- nanofibers to realize enzyme-triggered release of ibuprofen, sive materials can enable the controlled release of drugs an anti-inflammatory drug [143]. As shown in Fig. 4c, in by modulating the critical solution temperature (LCST) of the presence of lipase, nanofibers loaded with prodrug-of- thermosensitive polymers through volumetric phase tran- ibuprofen exhibited enzyme-triggered drug release, and sitions. As shown in Fig. 5a, a mixture of PCL and tem- the cumulative release of ibuprofen reached 100% within perature stimuli-responsive nanogel was used to form the 14 weeks; in contrast, only a small amount of drug was outer shell [151]. The nanogel was composed of temper- released in the absence of the lipase enzyme. ature-responsive poly(N-isopropylacrylamide) copolymer- ROS can regulate intracellular biological behaviors as ized with acrylic acid, which could shrink or expand with signaling molecules [144, 145]. However, excessive ROS ambient temperature changes. Therefore, the existence or production usually causes severe oxidative damage to cells disappearance of nanochannels between the nanogel and and tissues. At present, due to the high concentrations PCL could be controlled by varying the temperature. In this of ROS in pathological environments, a variety of ROS- case, the drug-encapsulating shell acted as a valve to control responsive DDSs have been developed [146, 147]. As shown ordered drug release. Three-cycle low-to-high temperature in Fig. 4d, ROS-responsive nanofibers can be prepared by transition images of drug release demonstrated better tem- electrospinning a biodegradable elastomer containing thiok- perature-responsive drug release properties when nanogels etone [31]. Nanofibers loaded with glucocorticoid methyl- were encapsulated in the shell compared to when nanogels prednisolone (MP) were incubated in 1 mM H O solution were omitted. 2 2 for 2 weeks, and the release of MP was significantly higher Considering the advantages of long-range and stronger than that of any other groups. penetration, near-infrared (NIR) light has been increas- Since hyperglycemia patients have excess blood glucose ingly adopted as a light source in drug release-assisted in their plasma, a glucose-responsive DDS can be estab- tissue regeneration [152]. By introducing photothermal lished based on a gradient in blood glucose levels [148]. agents, electrospun fibers can be endowed with excellent At present, many researchers have realized the release of photothermal properties, enabling the effecting delivery of insulin triggered by hyperglycemia and have applied glucose nutrients and drugs [52]. Gold-based nanorods (GNRs) can oxidase to reduce the pH or oxygen content in hypergly- also generate heat through the plasmonic resonance effect cemic regions through an enzymatic reaction, thereby pro- under NIR irradiation. As shown in Fig. 5b, GNRs-loaded moting insulin release [149, 150]. These glucose-responsive poly(N-isopropylacrylamide) (PNIPAM) composite nanofib- nanofibers are mostly used for monitoring blood glucose. ers were used to allow the controlled release of drugs by NIR By encapsulating glucose oxidase or glucose dehydrogenase irradiation [153]. The heat generated by the GNRs ensured into nanofiber scaffolds, blood glucose levels can be quickly the shrinkage of thermally responsive PNIPAM nanofibers and sensitively monitored [28]. Obviously, a system respon- to allow for the drug release, and this on-demand DDS could sive only to an individual type of endogenous stimulus is be regulated by the NIR power density. This convenient, unable to meet current needs. Therefore, to deliver thera- remote-controllable, non-invasive approach provides new peutic agents to the right place at the right time in physi- ideas for the on-demand delivery of required doses of drugs. ologically relevant doses, it is particularly critical to develop Magnetic fields, electric fields, and ultrasound are also endogenous stimuli-responsive nanofiber scaffolds that can research foci due to their relevance to corresponding stimuli respond synergistically to multiple signals. and ease of operation. For magnetic fields, superparamag- netic iron oxide nanoparticles (IONPs) have been applied External Stimuli‑Responsive Drug Delivery Systems for osteogenic die ff rentiation and axon extension [ 154, 155]. The hyperthermia caused by IONPs under magnetic field External stimuli, such as heat, light, electricity, magnetic is also beneficial for reducing drug transmission loss and fields, and ultrasound, have attracted much attention due enhancing targeted delivery [37]. In one study, a nanofiber to their non-invasive nature, high tissue penetration depth, scaffold composed of temperature-responsive polymers, and spatiotemporal controllability [38]. All these strategies magnetic nanoparticles (MNPs), and an anticancer drug can be combined with electrospun drug-loaded scaffolds to (DOX) was designed (Fig. 5c) [156]. The MNPs generated enable stimuli response and synchronize drug release pro- heat under an alternating magnetic field (AMF), which dis- files under real physiological conditions by manipulating sociated the polymer network in the nanofibers and allowed the external environment, providing new avenues for tissue the release of DOX. By switching the “on–off” properties of regeneration and cancer therapy. the magnetic field, the drug could be delivered on demand. 1 3 Advanced Fiber Materials (2022) 4:1375–1413 1385 Fig. 5 External stimuli-responsive drug delivery fiber systems. a d Schematic illustration showing the electrical-responsive release Schematic illustration showing the mechanism of thermal switch- of DEX from PLGA nanofibers, and the cumulative mass release of controlled drug release system, and the release rate of drug upon DEX under the control of electrical stimulation. Reproduced with multiple cycles of low-to-high temperature transitions. Reproduced permission from Ref. [162]; Copyright 2006, Wiley–VCH Limited. with permission from Ref. [151]; Copyright 2015, Wiley–VCH Lim- e Schematic illustration showing the multimodal-responsive release ited. b Schematic illustration showing the thermal-responsive release of DEX from piezoelectric nanofibers by breaking the silica (SiO ) of fluorescein from nanofibers containing gold nanorods upon NIR capsules under the action of ultrasound, the images showing the situ- irradiation, and the release curves with NIR irradiation at different ation after 60 s of sonication. Reproduced with permission from Ref. power densities. Reproduced with permission from Ref. [153]; Copy- [32]; Copyright 2018, American Chemical Society Limited. f Sche- right 2021, Multidisciplinary Digital Publishing Institute Limited. c matic illustration of synergistic sono-photodynamic therapy for breast Schematic illustration showing the temperature-responsive release of cancer via 808 nm laser and 1 MHz ultrasound, as well as the live/ DOX, and the cumulatively released percentages of DOX with alter- dead staining images. Reproduced with permission from Ref. [166]; nating cycles of “ON–OFF” switching of AMF. Reproduced with Copyright 2020, American Chemical Society Limited permission from Ref. [156]; Copyright 2013, Wiley–VCH Limited. The generated heat and chemotherapeutic effects of the induced by the voltammetric response of PEDOT nanopar- released DOX rapidly induced cancer cell apoptosis. ticles [160]. A PPy-PVDF electrospun system was used as External electrical stimulation has also been used for a carrier to load growth factor complexed with streptavi- bone repair [157], nerve regeneration [158], and drug deliv- din, and the release curve of the growth factor showed an ery [159]. For example, electrical stimulation can modu- obvious electro-sensitive release behavior [161]. As shown late curcumin (CUR) delivery through volume changes in Fig. 5d, dexamethasone (DEX) was released from the 1 3 1386 Advanced Fiber Materials (2022) 4:1375–1413 PEDOT nanotubes by controlling the contraction or expan- Skin Tissue Engineering sion of PEDOT by electrical stimulation [162]. The blue curve represents the cumulative mass release of DEX from Skin regeneration and wound healing are dynamic and com- PEDOT-encapsulated poly (lactic-co-glycolic acid) (PLGA) plex processes that usually include four overlapping and nanofibers when 1 V electrical stimulation was applied at different periods: hemostasis, inflammation, proliferation, five specific times. and remodeling [167]. To promote wound repair, functional As for ultrasound, it usually provides a sustained thermal drug-loaded fibrous scaffolds can be prepared through elec- effect from continuous oscillation of microbubbles and a trospinning technology, which can effectively avoid wound mechanical effect upon rupture [163]. Ultrasound has been infection, shorten the inflammatory stage, promote tissue shown to trigger the release of drugs, as well as promote proliferation and remodeling, and prevent granulation tissue deep drug penetration with minimal thermal damage to sur- proliferation and scar formation. rounding tissues [164]. By encapsulating drugs into ultra- Bacterial infection is an inevitable and urgent prob- sound-sensitive microcapsules, scaffolds can be effectively lem during wound healing [168, 169]. Therefore, many combined for multimodal triggered release [32]. Figure 5e researchers have loaded antimicrobial agents or nanopar- shows that silica microcapsules in the fibers were destroyed, ticles into nanofibers by blending electrospinning technol - and TRITC-BSA was effectively released under the stimula- ogy to improve antibacterial function [170, 171]. For exam- tion of ultrasonic waves. This approach can be extended to ple, tetracycline hydrochloride has been loaded into poly both exogenous (NIR irradiation, electrical stimulation) and (ω-pentadecalactone-co-ε-caprolactone)/gelatin/chitosan endogenous (enzymatic treatment) stimuli to improve the nanofibers to achieve excellent antibacterial effects against precise delivery of multiple drugs. gram-positive and gram-negative bacteria [172]. However, Recently, attention has been drawn to the idea of applying given the increasing bacterial resistance and the burst release multiple stimuli synergistically to deliver drugs. For exam- of drugs, it remains a great challenge to achieve sustained ple, a smart hyperthermic nanofiber has been developed with and ec ffi ient antibacterial activity at the wound site using the the ability to simultaneously switch two-stage drug release aforementioned methods [173]. In addition to exploring and in response to AMF and heat [34]. In addition to their own synthesizing new types of alternative antimicrobial agents, effects on cell behavior and tissue regeneration, some related antimicrobial peptides have also been incorporated in fib- therapies, such as photothermal therapy, magnetothermal ers to achieve deep bactericidal effects [174]. For instance, therapy, electromagnetic thermotherapy, and sonodynamic a Janus-type antibacterial dressing loaded with antimicro- therapy, have also been derived from these strategies and bial peptides was prepared by combining electrospinning show to have synergistic effects with drugs [ 165]. As shown nanofiber membranes with dissolvable microneedle arrays in Fig. 5f, the synergistic sono-photodynamic therapy sig- [175]. This antibacterial dressing could penetrate bacterial nificantly promoted the generation of ROS and achieved a biofilms to effectively kill bacteria. To further enhance the 95.8% inactivation rate of breast cancer cells under 808 nm antibacterial effect of these materials, as well as to achieve NIR irradiation and 1 MHz ultrasound treatment [166]. the controlled release of drugs, some drug-loaded fiber plat- These potential integrative mechanisms should be incorpo- forms have been explored with respect to external stimuli rated into drug-loaded electrospun fiber scaffolds to facilitate [176]. The obtained nanocomposite fiber scaffolds exhib- the development of future nanomedicines and promote tissue ited excellent NIR light-triggered controlled drug release regeneration and cancer therapy. behavior. As shown in Fig. 6a, the dressing caused irrevers- ible damage to bacterial biofilms under NIR irradiation, thus effectively inhibiting infection by drug-resistant bacteria. Applications for Tissue Regeneration Hemostasis is a critical period in the wound healing and Cancer Therapy process. Although the body has an inherent hemostatic sys- tem, it cannot stop bleeding quickly [43]. Therefore, many Electrospun fibers for DDSs have been developed and hemostatic agents have been incorporated into hemostatic explored based on the diversity and simplicity of the prepa- dressings by electrospinning technology, and this approach ration methods for drug-loaded electrospun fiber scaffolds, has attracted wide attention. For example, an ultralight 3D as well as the design of fiber structures, the selection of gelatin sponge prepared by conjugate electrospinning tech- electrospinning parameters, post-treatment methods, and the nology was able to aggregate a large number of activated combination of various stimuli. These products have been platelets and accelerate the formation of platelet clots [177]. widely applied to tissue regeneration, including soft tissues An in vivo study showed that this gelatin nanofiber sponge (such as skin, nerve, cardiac, and blood vessels) and hard could rapidly induce stable blood clots in a rabbit ear model tissues (such as bone, cartilage, and musculoskeletal and of artery injury and was associated with reduced bleeding dental systems), as well as cancer therapy. compared to gelatin nanofiber membrane (Fig. 6b). 1 3 Advanced Fiber Materials (2022) 4:1375–1413 1387 Sustained inflammation also seriously postpones wound by neutrophils and macrophages, can also severely delay healing [178–180]. Especially in chronic wounds, high ROS wound healing [182]. It has been shown that anti-inflamma - levels often result in a failure of wound healing. Therefore, tory drugs released at a wound can effectively down-regulate removing excessive ROS can reduce oxidative stress to effec- expression of IL-6 and TNF-α [183]. At the same time, this tively promote collagen deposition and ECM remodeling approach can reduce inflammatory response at the wound, [181]. For example, poly (l -lactide-co-caprolactone)/gelatin promote fibroblast proliferation, and accelerate the recon- core-sheath nanofibers loaded with epigallocatechin-3-O- struction of granulation tissue. For example, PCL nanofib- gallate (EGCG) exhibited excellent ROS-scavenging abil- ers loaded with dimethyloxalylglycine can significantly ity, promoting skin regeneration and inhibiting subsequent promote angiogenesis and improve the re-epithelialization wound infection [180]. ratio [184]. Meanwhile, at the molecular level, this approach In addition to excessive ROS, high expression of various promoted wound healing by enhancing the expression of pro-inflammatory chemokines, such as interleukin-6 (IL-6) anti-inflammatory factors (IL-4) and reducing the expression and tumor necrosis factor-α (TNF-α), which are secreted of pro-inflammatory factors (IL-6) (Fig. 6c). Fig. 6 Drug delivery systems based on electrospun fiber scaffolds tochemical staining images of different groups of wound areas at for skin tissue engineering. a Illustration of dual stimuli-responsive 14 days. The black arrow indicates the blood vessel, the semi-black fibrous membranes for drug-resistant bacterial infection, and SEM arrow indicates the keratinous basal cells, and the dotted circle shows images of E. coli and MRSA incubated with or without NIR irradia- the epithelial spike. Reproduced with permission from Ref. [185]; tion. Scale bar = 5 μm. Reproduced with permission from Ref. [176]; Copyright 2019, American Chemical Society Limited. e Schematic Copyright 2022, Elsevier Limited. b Illustration and macroscopic diagram of the synthesis of careob-like 5-Fu@dMBG/PEO@PEEUU images of the different samples after in vivo hemostasis in an ear nanofibers (((F@B)/P)@PU) and the quantitative analysis of relative artery injury model and a liver trauma model of rabbits. Reproduced occupied area of collagen I at post-surgery. Reproduced with permis- with permission from Ref. [177]; Copyright 2021, Wiley–VCH Lim- sion from Ref. [189]; Copyright 2022, Elsevier Limited. f Schematic ited. c Schematic illustration of PCL nanofibers loaded with dimethy - of the fabrication of on-skin electronic devices and temperature- loxalylglycine can significantly promote angiogenesis and re-epithe- sensitive on-demand drug release, the release profiles of MOX, and lialization, and expression levels of IL-6 and IL-4 were detected in photographs of agar plates onto which S. aureus suspensions. Repro- macrophages cultured for 2 days. Reproduced with permission from duced with permission from Ref. [196]; Copyright 2019, Wiley–VCH Ref. [184]; Copyright 2017, American Chemical Society Limited. Limited d Schematic illustration of H&E, Masson’s and CD31 immunohis- 1 3 1388 Advanced Fiber Materials (2022) 4:1375–1413 Tissue regeneration and remodeling involve angiogenesis, For peripheral nerve repair, nerve guidance conduits granulation tissue formation and re-epithelialization [167]. (NGCs) constructed from electrospun fibers are considered During the process of wound healing, angiogenesis is ben- to be optimal nerve graft substitutes because of their excel- eficial for the continuous delivery of oxygen and nutrients lent biocompatibility, tunable mechanical properties, poros- to the wound. As shown in Fig. 6d, an oriented, aligned PCL ity, and capacity to provide guidance cues [64]. Unmodi- nanofiber membrane loaded with tazarotene promoted angi- fied fiber-based NGCs often fail to overcome the barriers of ogenesis and significantly accelerated wound healing and limited regenerative capacity and disordered axonal growth, re-epithelialization ratio [185]. In addition, various types of especially when used to repair thick nerves with large gaps growth factors, peptides, and RNA can be delivered from [198]. To this end, integrating NGCs with topographic cues electrospun nanofibers to promote angiogenesis [71, 74]. [48, 197] and biological signals [123, 124, 199, 200] is During the tissue regeneration stage, loading growth fac- often done to overcome these barriers. One current potential tors into nanofibers is an effective way to improve the wound strategy is to create nerve conduits based on topographical healing rate. For example, PCL/PEG core–shell nanofibers cues in combination with drugs, with different drug loading loaded with EGF and basic fibroblast growth factor can sig- modes controlling drug release [3, 16]. For example, drugs nificantly promote fibroblast proliferation and enhance col- physically attached to a scaffold usually have faster release lagen deposition and keratin synthesis [186]. rates, while drugs embedded in microspheres or fibers are If a wound is not treated properly, scar formation is very hindered by complex cross-linking networks [201, 202]. likely. Scar formation is primarily due to excessive inflam- Typically, gradient structures can provide chemotactic or mation, myofibroblast proliferation, and over-deposition of haptotactic cues for accelerating cell migration and neurite collagen [187]. Loading of nanofibers with scar inhibitors extension. As shown in Fig. 7a, a concentration gradient of can effectively inhibit the formation of scars. At present, active functional groups was first generated on nanofiber common scar inhibitors include TGF-β inhibitor [188], surface, after which an NGF density gradient was success- 5-fluorouracil [189], α-lactalbumin [190], 20(R)-ginsenoside fully constructed based on the amphiphilic nature of heparin, Rg3 [191], palmatine, and triamcinolone acetonide [192, ultimately promoting the directional outgrowth of neurites 193]. Typically, 5-fluorouracil (5-Fu)-loaded dendritic from DRG along the direction of increasing NGF concentra- mesoporous bioglass nanoparticles (dMBG) are loaded in tion [200]. In addition to the adsorption or immobilization of electrospun nanofibers by coaxial electrospinning, and the growth factor on the fiber surface, bioactive particles have obtained scaffolds can significantly promote wound healing also been deposited on fibers. Figure 7b shows the applica- and inhibit scar formation (Fig. 6e) [189]. tion of a masked electrospray method to construct a density Currently, another challenge for wound dressings is that gradient of biomacromolecular nanoparticles on the surface it is difficult to monitor the real-time state of wound repair of uniaxially aligned fibers by manipulating the deposition while simultaneously meeting the needs of wound healing period with a movable physical mask [124]. The aligned fib- treatment [194]. With the emerging development of bioel- ers could guide neurite extension along the fiber alignment, ectronics, many integrated electronic dressings have been while the density gradient of biological macromolecules fur- developed to integrate diagnosis, monitoring, and treat- ther promoted directional extension of neurites along the ment [195]. These techniques also allow the monitoring of direction of increasing particle density. wound status and on-demand controlled drug delivery based Another therapeutic approach is to combine external on changes in the wound microenvironment. As shown stimuli, such as light [203], electricity [204, 205], or mag- in Fig. 6f, a flexible and breathable thermal-responsive netic field [206], to regulate cell behavior and induce tissue nanofiber membrane can monitor the temperature of wound regeneration. Under the action of AMF, superparamagnetic tissue in real time and trigger the on-demand release of anti- iron oxide nanoparticles could be uniformly distributed in biotics from the fibers according to temperature changes fibers, and the fabricated hybrid fibers could respond to a [196]. magnetic field and promote neurite extension (Fig. 7c) [206]. In addition, as electrically active tissues, neurite extension Nerve Tissue Engineering can be promoted by applying electrical stimulation at an appropriate intensity. For example, electrically conductive Injuries to the nervous system, including both the periph- electrospun fibers can be loaded with NGF and combined eral nervous system and the central nervous system, often with electrical stimulation to further accelerate the exten- lead to nerve cell death and tissue destruction, resulting in sion of neurites from PC12 cells along the direction of the permanent loss of nerve function [197]. Although recent electrical field (Fig. 7d) [158]. developments are promising, it nevertheless remains a great For peripheral nerve repair, some researchers rely on challenge to treat nerve injuries using tissue engineering different drug release rates to design NGCs. As shown in scaffolds. Fig. 7e, core-sheath fibers loaded with two growth factors 1 3 Advanced Fiber Materials (2022) 4:1375–1413 1389 were prepared by coaxial electrospinning [207]. The fast decompose these proteoglycans and break down this barrier release of VEGF from the sheath layer promotes the migra- [214]. Thus, protease- and neurotrophic factor-based fiber tion, proliferation, and differentiation of endothelial cells, scaffolds can build renewable bridges in spinal cord defects. while the slow release of NGF promotes long-term axonal In summary, electrospun fiber scaffolds for the repair of spi- elongation. With the release of VEGF, intraneural vascu- nal cord injury require a combination of multiple optimiza- larization, an important prerequisite for nerve regeneration tion factors to regulate the microenvironment and promote [208], could be achieved. More importantly, the generated nerve regeneration [218]. blood vessels could provide guidance for cell migration and Brain tissue is a complex nerve tissue, and common brain transport oxygen and nutrients to axons and Schwann cells diseases include traumatic brain injury [219, 220], stroke [60, 209], which is particularly significant for the repair of [221] and others. In the repair of brain injury, it is also thick nerve defects. Polymer microspheres [210] and inor- important to promote endogenous cells to migrate toward the ganic nanoparticles [211] can also serve as carriers of neu- damaged area and differentiate into neurons to rebuild the rotrophic factors and be incorporated with electrospun fibers damaged nervous system [216]. Neurotrophic factors play an to regulate conduit delivery behavior. important role in the protection and migration of nerve cells. Furthermore, hydrogels can encapsulate a variety of However, they cannot be delivered to injured sites because bioactive substances, and their degradability can be var- of their lack of permeability through the blood–brain bar- ied by regulating the degree of cross-linking [2, 212]. In rier (BBB) [222, 223]. Engineering bioactive electrospun addition, hydrogels can simulate the ECM of natural tissues fiber scaffolds can enable the treatment and repair of brain and generate a 3D microenvironment conducive to nerve diseases. Monosialotetrahexosylganglioside (LysoGM1) is tissue regeneration [213]. Therefore, the development of one kind of drug that can protect neurons and promote nerve electrospun fiber-hydrogel drug loading systems has signifi- regeneration [224]. By chemically grafting LysoGM1 onto cant potential. Multiple small conduits can be sequentially fiber scaffolds, its biological activity can be maintained, and embedded within a larger conduit to simulate the multi- the diffusion effect could be weakened to some extent [220]. bundle structure of human nerves, effectively reducing side As shown in Fig. 7g, the scaffold could continuously deliver effects associated with disordered axon growth [61]; further - drugs to the injured area in a traumatic brain injury model, more, this type of NGC can be combined with drug loaded- contributing to a reduction in the number of astrocytes and hydrogels to additionally promote nerve repair. Distinct good regeneration of nerve tissue. Meanwhile, neurodegen- properties can be introduced into each lumen to optimize erative diseases, including Alzheimer's disease [225] and conduit performance, so this highly bionic structure will be Parkinson's disease [226], are common mental disorders ideal for nerve tissue regeneration. caused mainly by the decreased ability of neurons and glial Distinct from peripheral nerves, neurons of the central cells to secrete nutritional factors. Therefore, the ability of nervous system (CNS) can hardly regenerate axons due to electrospun fibers to deliver nutritional factors to brain tis- the harsh microenvironment after CNS injury [138, 214]; sue is highlighted again, and the release profile of factors is therefore, remodeling the microenvironment can support more suitable than that associated with current clinical drug CNS regeneration [215]. Furthermore, more endogenous administration methods; thus, the frequency of drug admin- cells should be promoted to migrate, infiltrate into the dam - istration could be reduced [227]. Of note, electrospun fibers aged area and differentiate into neurons to rebuild the dam- also play an important role in detecting diseases, including aged neural circuit network [216]. The main approach is to potential diagnosis of neurodegenerative diseases through a release anti-inflammatory drugs to reduce inflammation and variety of physiological indicators [228, 229]. For instance, regulate the acidic microenvironment. MP, a strong anti- coupling dopamine receptors to electrospun fibers can ena- inflammatory drug, can be loaded on the electrospun fiber ble the detection of neurodegenerative disorders with high scaffold with polysialic acid to promote axonal regeneration sensitivity and rapid responsiveness [229]. [217]. As shown in Fig. 7f, MP can effectively inhibit inflam- Great progress has been achieved in applying drug-loaded matory reactions and glial cell proliferation while ensuring electrospun fiber scaffolds to promote nerve regeneration, axon growth. In contrast to direct release, anti-inflammatory but some side effects remain due to fast drug diffusion, drugs can be loaded in liposomes and grafted onto scaffolds resulting in high local drug concentrations. In addition, by chemical bonds that can be broken in response to the short drug half-lives also present a major challenge for acidic pH of the inflammatory environment [138], thereby nerve repair [209]. Therefore, the long-term maintenance reducing the risk to benign areas. In addition, proteoglycans of drug activity in vivo and precise response to microen- in the ECM of neurons condense around neurons to prevent vironmental changes at various stages remain the key foci the influence of harmful substances. However, proteoglycan of follow-up research. Moreover, axonal myelin formation condensation becomes a physical barrier to nerve recovery is another key factor in functional recovery, and ways to after spinal cord injury, so the addition of proteases could regulate the phenotype of Schwann cells should be included 1 3 1390 Advanced Fiber Materials (2022) 4:1375–1413 Fig. 7 Drug delivery systems based on electrospun fiber scaffolds with electrical stimulation, and the chart showing the promoting for nerve tissue regeneration. a Schematic illustration showing the effect of electrical stimulation on neurite growth. Scale bar = 50 μm. construction of concentration gradient of NGF on aligned fibers by Reproduced with permission from Ref. [158]; Copyright 2014, The amino and heparin functionalization, and fluorescence micrographs Royal Society of Chemistry Limited. e Schematic illustration of showing the extension of neurites from DRGs on the uniform and simultaneous loading of NGF and VEGF in the scaffold, the chart gradient scaffolds. Scale bar = 500 μm. Reproduced with permission showing the different diffusion rate of different growth factors, and from Ref. [200]; Copyright 2020, Wiley–VCH Limited. b Schematic both of SFI value and Tissue section staining images showing the illustration showing the generation of density gradient of biomolecu- scaffold with NGF and VEGF has a good ability to promote repair. lar nanoparticles on the surface of uniaxially aligned electrospun fib- Scale bar = 25 μm. Reproduced with permission from Ref. [207]; ers using masked electrospray method, and fluorescence micrographs Copyright 2018, Elsevier Limited. f Schematic illustration of scaffold showing the extension of neurites from DRGs on the uniform and loaded with MP and polysialic acid (PSA) implanted in the model of gradient scaffolds. The neurites were stained with Tuj1 (green). Scale spinal cord injury in mice, and both of BBB score and Tissue sec- bar = 500 μm. Reproduced with permission from Ref. [124]; Copy- tion staining images showing the scaffold has the abilities to inhibit right 2020, Wiley–VCH Limited. c Schematic of external stimula- inflammation and promote spinal regeneration. Scale bar = 100 μm. tion device, SEM images showing the morphology of pristine fibers Reproduced with permission from Ref. [217]; Copyright 2018, and SPION-grafted fibers, and fluorescence micrographs showing the Elsevier Limited. g Schematic illustration of scaffold containing extension of neurites from DRGs on the blank and SPION-grafted LysoGM1 implanted in traumatic brain injury model, and the scaffold scaffolds. The neurites were stained with neurofilament (green). Scale have abilities to promote cell migration and differentiation. Tissue bar = 500 μm. Reproduced with permission from Ref. [206]; Copy- section staining image also present the enhancement of nerve regen- right 2021, Elsevier Limited. d Fluorescence micrographs showing eration. Scale bar = 500 μm. Reproduced with permission from Ref. the extension of neurites from PC12 cells on the scaffolds without/ [220]; Copyright 2020, American Chemical Society Limited 1 3 Advanced Fiber Materials (2022) 4:1375–1413 1391 in future scaffold design [230]. In addition, scaffold neuro- pharmacological functional groups with biodegradable PCL imaging will have great potential in future applications, as [241]. To further reduce cardiac fibrosis, an alternative strat- it is indisputable that non-invasive imaging helps monitor egy induces fibrotic cardiomyocytes into new cardiomyo- nerve regeneration and enables real-time adjustments based cytes. In particular, functionalized nanofibers can effectively on individual regeneration differences. support the proliferation and adhesion of cardiomyocytes to promote the self-repair of cardiac tissue. For example, Cardiac Tissue Engineering PLGA nanofibers covalently coupled with two adhesion pep- tides, YIGSR and RGD, could promote the adhesion and Due to the limited regenerative capacity of cardiac tissue, it proliferation of cardiomyocytes [242]. is dic ffi ult for ischemic myocardial tissue to repair itself after Functionalized nanofibers also support the adhesion and myocardial infarction (MI) [231]. Although heart transplan- proliferation of other cells that can differentiate into cardio- tation is the most effective way to restore cardiac function, myocytes. For example, a VEGF-coated nanofiber scaffold the shortage of donor organs and side effects after trans- can significantly promote the differentiation of human mes- plantation seriously limit its application [232]. Electrospun enchymal stem cells into cardiomyocytes [243]. In addition, nanofibers can mimic the natural ECM structure, provide as shown in Fig. 8b, a chitosan/serin protein-modified cel- temporary physical support for damaged heart tissue, and lulose nanofiber patch not only improved the survival rate limit ventricular dilatation and remodeling [233]. Therefore, of adipose tissue-derived mesenchymal stem cells but also it is possible to use nanofibers for cardiac tissue engineering reduced myocardial fibrosis and inhibited ventricular remod- because of their controllable fiber structure and capacity to eling after MI [244]. Beyond exogenous cell therapy, two improve the retention rate of bioactive substances. muscle-specific microRNAs can be delivered using nanofib- During the necrotic phase after MI, a large number of ers with different topologies, after which they reprogram cardiomyocytes necrotize while releasing excessive ROS cardiac fibroblasts into cardiomyocyte-like cells and reduce and other cellular contents into the surrounding micro- myocardial fibrosis [245]. environment [234, 235]. As a result, many immune cells After MI, the electrical microenvironment usually under- are recruited to the damaged cardiac tissue. After MI, this goes pathological changes, such as abnormal contraction, inflammatory environment disrupts cell homeostasis, lead- disruption of the conductive network, and irregular propaga- ing to more severe oxidative damage. Therefore, to avoid tion of electrical signals, which severely limit repair of the the occurrence of inflammation, scavenging of excessive damaged myocardium [246]. Usually, various conductive ROS can effectively inhibit pathological remodeling of the agents can be added to improve the electrical microenviron- left ventricle. For example, MP-loaded polyurethane fiber ment in the MI area [247]. However, it is difficult to achieve patches can release anti-inflammatory drugs to remove real electrical anisotropy matching the natural myocardium excess ROS [147]. As shown in Fig. 8a, fiber patches con- by simply loading conductive materials or adjusting the taining MP could significantly promote cardiac functional orientation of the fiber structure. In one study, a reduced repair and angiogenesis while reducing fibrosis and cardiac graphene oxide functional silk fibroin nanofiber patch was remodeling. In addition to the local delivery of anti-inflam- developed with a similar anisotropic conductivity to natural matory drugs by nanofibers to reduce inflammation, many myocardium to improve the electrical microenvironment of anti-inflammatory nanoparticles can be loaded into nanofib- infarcted myocardium (Fig. 8c) [248]. In addition to improv- ers to effectively remove excessive ROS and relieve inflam- ing the electrical microenvironment of the myocardium, it mation. For example, a cerium oxide nanoparticles-loaded is particularly important for the myocardium to beat syn- PCL/gelatin nanob fi er scao ff ld can signic fi antly reduce ROS chronously and rhythmically [249]. Although it has been levels in the MI area and inhibit cardiomyocyte hypertrophy verified that spontaneous cardiomyocyte contraction can be [236]. observed when cardiomyocytes are cultured on fibers, it is After MI, the hypoxic state is highly susceptible to oxida- also essential that they beat synchronously with the natural tive stress and irreversible cardiomyocyte death, so the res- myocardium. The mechanical properties, arrangement struc- toration of oxygen supply is extremely important [237–239]. ture, chemical composition and electrical conductivity of Therefore, a bilayer cardiac patch loaded with calcium per- fibers significantly affect the beating of cardiomyocytes on oxide and adipose stem cell exosomes was fabricated to fibers [250]. When cultured on parallelly aligned conductive enable continuous oxygen supply, alleviate oxidative stress, polyaniline/PLGA nanofibers, all cardiomyocytes within a and promote angiogenesis [240]. In addition to reducing single cluster were found to beat synchronously [251]. inflammation, an ideal cardiac patch also needs to provide Congenital heart disease is a congenital disease distinct adequate blood supply to the left ventricle. To this end, a from MI [252], and autologous cardiomyocyte therapy is cardiac patch was prepared by covalently combining nitrate the main treatment method. Due to the low retention rate of injected cells, one promising solution for the treatment of 1 3 1392 Advanced Fiber Materials (2022) 4:1375–1413 Fig. 8 Drug delivery systems based on electrospun fiber scaffolds domly arranged layer, randomly oriented layer and oriented layer, for cardiac tissue engineering. a Schematic illustration showing the the thickness between different layers, and the conductive anisotropy application of a methylprednisolone (MP)-loaded PUTK fiber patch that can be transmitted through the patch through implantation were to suppress inflammation, and Masson and Sirius red staining shows used to reconstruct the anisotropic electrical microenvironment of the pathological examination of the hearts. Reproduced with permis- the infarcted myocardium. Reproduced with permission from Ref. sion from Ref. [31]; Copyright 2020, Elsevier Limited. b Schematic [248]; Copyright 2022, Elsevier Limited. d Schematic illustration of illustration showing the application of chitosan/silk fibroin-modified using computational methods to design patient-specific electrospun nanofiber patch seeded with mesenchymal stem cells for prevent- fiber-based cardiac patches for pediatric heart failure, representative images of patches attached to the RV in tissue sections collected after ing heart remodeling post-MI in rats. Reproduced with permission 4 weeks following implantation, and quantification of vessel density from Ref. [244]; Copyright 2018, Elsevier Limited. c Schematic and and myocyte hypertrophy. Scar bar = 200 μm. Reproduced with per- cross-sectional SEM images illustrating the structure of the rGO/ mission from Ref. [256]; Copyright 2022, Elsevier Limited silk fibroin scaffolds, from the bottom to the top, consisting of a ran- congenital heart disease is the delivery of c-Kit cardiac pro- achieving synchronized contraction and electrical anisotropy genitor cells via nanofiber scaffolds [253, 254]. For example, that matches the natural myocardium remain major chal- nanofibers coated with gelatin and/or fibronectin effectively lenges. Electrically active biomaterials can combine elec- enhance the metabolism of c-Kit + cardiac progenitor cells trical stimulation with scaffolds to promote cardiac tissue [255]. However, the quality of c-Kit progenitor cells dif- regeneration and maintain synchronized beating contractions fers significantly across patients. To solve these problems, of heart tissue. Continuous delivery of different bioactive a computational modeling approach has been used to deter- factors at typical time points is also important to improve mine the repair mechanisms of cardiac-derived c-Kit cells repair efficacy. In situ measurement of delivered drug con- and understand how these mechanisms can be used to design centrations during the delivery period remains difficult. In biomaterials to improve cardiac patch performance [256]. addition, real-time monitoring of the regeneration process As shown in Fig. 8d, a nanofiber patch for pediatric heart is important. The integration of imaging techniques can fur- failure patients was designed and prepared by computational ther address both issues and has important implications for methods and was confirmed to effectively achieve antifibro- the exploration of physiological processes in cardiac tissue sis and angiogenesis. regeneration, as well as the study of the regulatory behaviors DDSs based on electrospun nanofiber scaffolds can be of materials in vivo. engineered with anti-inflammatory capabilities to promote myocardial cell adhesion and proliferation and achieve car- Bone Tissue Engineering diac phenotype and function for cardiac tissue engineering. To enable versatility and achieve these functions simul- As a typical hard tissue, bone tissue exhibits a complex and taneously and comprehensively, multiple regulatory sig- highly stratified structure with high density and involves nals need to be integrated on a single platform. Moreover, various growth factors and endogenous signals [257]. Bone 1 3 Advanced Fiber Materials (2022) 4:1375–1413 1393 tissue engineering also involves many aspects, including formation process by promoting angiogenesis and bone cal- osteogenic differentiation, angiogenesis, bone healing, and cification [106]. Coaxial electrospinning can also provide the treatment of bone-related diseases [258]. Electrospun a similar dual-delivery system to modulate the osteogen- fiber scaffolds provide a structure that simulates the bone esis–osteoclastogenesis balance. In particular, the rapid environment and have drug-delivery advantages (for small release of substance P enhanced the migration and osteo- molecule drugs and growth factors, etc.), which are expected genic differentiation of BMSCs, while the sustained release to solve problems related to limited donor sites for autolo- of ALN reduced bone resorption [266]. Of note, delivery gous transplantation and to provide a promising avenue for systems programmed to match the spatiotemporal specificity bone tissue engineering. of bone healing are increasingly being developed. To promote bone tissue regeneration, the primary task is The ability of exogenous stimuli to regulate cells is gradu- to enhance osteogenic activity. To this end, researchers have ally being appreciated. Most commonly, bioelectrical sig- investigated a series of electrospun fibers combined with the nals in native bone serve as key factors in regulating bone delivery of bioactive substances that promote osteogenesis growth, structural reconstruction, and healing [36]. Some [259–261]. For example, a layered micro/nanofiber biomi- studies have confirmed that electrical stimulation treatment metic periosteum with sustainable release of VEGF has been promotes the adhesion, growth, and proliferation of osteo- developed (Fig. 9a) [117]. VEGF was encapsulated in hyalu- blasts, as well as significantly enhancing calcium and phos- ronan (HA)-poly(l -lactide) acid (PLLA) core-sheath fibers phorus deposition [267, 268]. Similarly, the heat generated and released in a sustained manner to promote angiogenesis, by NIR not only penetrates the tissue but also regulates the and collagen self-assembly on the fibers greatly mimicked expression of heat shock proteins (HSPs) and enhances the the microenvironment necessary for intramembranous osteo- expression of osteogenesis-related proteins [269]. By incor- genesis. The 3D reconstruction images of the defect at 4 and porating MoS , an osteogenesis promoter and photothermal 8 weeks post-surgery showed that the repair ee ff ct of the mat agent, into electrospun fibers, the obtained scaffold exhibits was the most satisfactory, suggesting a synergistic effect of stronger cell growth and osteogenic ability in combination hierarchical structure and VEGF in promoting osteogenesis. with photothermal therapy [270]. Under NIR-triggered mild In view of the complexity of the bone repair process, co- photothermal treatment for 30 or 60 s, the expression lev- delivery or sequential delivery of multiple drugs is generally els of OPN and OCN, osteogenesis-related genes, were up- required, so it is particularly important to design electrospun regulated in BMSCs after 7 and 14 days of culture, and the fiber scaffolds that can carry multiple drugs and allow their ability to accelerate osteogenesis and bone healing was also release in a controlled manner [262]. Coaxial electrospin- demonstrated in vivo in a rat tibial defect model (Fig. 9d). In ning and LBL provide good methods for this. For exam- addition to the introduction of stimulatory components, the ple, a nanofiber mat made of core-sheath fibers with PVA design of 3D-structured fiber scaffolds can also better simu- as the core and SF/PCL as the shell was prepared, BMP-2 late the bone environment. For example, a radial 3D scaffold introduced into the core, and connective tissue growth factor obtained by NaBH foaming not only provides topographical (CTGF) was bound to the surface of the nanofibers through clues and a good bone repair environment but also allows the LBL technology (Fig. 9b) [263]. Fluorescent labeling in vivo loading of various growth factors to promote the bone heal- showed the sustained release of BMP-2 over 30 days, while ing process [63]. In the future, it remains a key challenge to CTGF rapidly dropped to minimum levels within 6 days, incorporate stimulation into 3D electrospun fiber scaffolds indicative of an early, transient release. In vivo studies to develop 4D bone tissue scaffolds. showed that areas of alkaline phosphatase (ALP) positive One of the main causes of bone defects is bone tumors, so tissues and angiogenesis were both significantly increased the design of bone tissue scaffolds requires the consideration compared with a single BMP-2 release system. Similarly, of bone repair and prevention of bone tumor recurrence. For the combination of DEX and BMP-2 also had a synergistic example, DOX was intercalated into lamellar hydroxyapatite effect on ALP expression and osteogenesis [264]. and dissolved in PLGA for electrospinning, after which the The regulation of the activity balance between osteo- surface of the electrospun fibers was further coated with blasts and osteoclasts is another important factor to be PDA to obtain a PDA@DH/PLGA scaffold. The PDA coat- considered in bone repair [265]. As shown in Fig. 9c, the ing prolonged the drug release (Fig. 9e) [271]. More impor- scaffold could achieve the simultaneous dual delivery of tantly, the PDA@DH/PLGA scaffold significantly inhibited alendronate (ALN) and silicate to further adjust the balance tumor cells growth initially, then subsequently improved between bone resorption and bone formation, thus acceler- osteoblast proliferation and promoted the repair of bone ating bone repair. ALN encapsulated in MSN was released defects caused by tumor resection in vivo. The development from nanofibers and inhibited the bone resorption process of electrospun drug-loaded fiber scaffolds for bone tumor by preventing the expression of GTP-related proteins, while treatment is still worthy of further investigation, while the silicate released upon MSN hydrolysis accelerated the bone extensive ability to incorporate drugs into electrospun fibers 1 3 1394 Advanced Fiber Materials (2022) 4:1375–1413 Fig. 9 Drug delivery systems based on electrospun fiber scaffolds for the balance between bone resorption and bone formation. Reproduced bone tissue engineering. a Schematic illustration showing the con- with permission from Ref. [106]; Copyright 2019, The Royal Society struction of a nanofiber-based biomimetic periosteum for periosteum of Chemistry Limited. d Schematic illustration showing PCL/MoS and bone regeneration and 3D reconstructed images of the regener- nanofibrous mat with photothermal property, the relative expressions ated bone after implantation for 4 and 8 weeks, respectively, in a rat of OCN, OPN, and HSPs genes with or without NIR irradiation, as calvarial critical size defect model. Reproduced with permission from well as photos of the rat tibias with implants and H&E staining of the Ref. [117]; Copyright 2020, Elsevier Limited. b Spatiotemporally tissues after implanting with PCL/1%MoS electrospun mat for 4 and controlled release of BMP-2 and CTGF for bone repair by combining 8 weeks with or without NIR irradiation, respectively. Reproduced coaxial electrospinning and LBL technology, and in vivo tracing of with permission from Ref. [270]; Copyright 2021, Wiley–VCH Lim- fluorescent dye-labeled BMP-2 and CTGF, as well as ALP-positive ited. e Schematic illustrations showing a dual function nanofibrous tissue areas in a model of ectopic osteogenesis. Reproduced with per- scaffold for tumor suppression and bone repair by loading DOX and mission from Ref. [263]; Copyright 2019, American Chemical Soci- modifying PDA, as well as the release route of DOX from the scaf- ety Limited. c Schematic illustration showing design of nanofiber for fold. Reproduced with permission from Ref. [271]; Copyright 2021, simultaneously dual delivery of ALN and silicate, as well as tuning American Chemical Society Limited provides a good alternative for bone tumor treatment and explored for application to cartilage regeneration. To avoid postoperative repair. rapid drug clearance and ensure controlled release [273], electrospun fibers are widely applied due to their customiz- Cartilage Tissue Engineering able structures and selectable properties with regards to drug binding, enabling these scaffolds to mimic the different mor - Articular cartilage, which is primarily composed of chon- phologies of cartilage ECM and control drug delivery [274]. drocytes and ECM, is responsible for reducing interface In general, PLLA [275–277] and PLGA [278, 279] are friction and assisting in bearing loads. Due to its low level rarely used due to their potential to cause inflammation dur - of regeneration and limited self-healing capacity [272], the ing degradation, while PCL [280–282] and polyhydroxybu- clinical pressures of cartilage-related diseases have been tyrate [283] can be applied after modification or blending. increased with population aging. Thus, there is an urgent Methylsulfonylmethane, a typical drug to inhibit inflamma- need to develop new biomaterial scaffolds to treat cartilage tion and promote chondrocytes differentiation [284, 285], damage, and various drugs and growth factors have been was loaded on PLGA fiber mats to accelerate cartilage 1 3 Advanced Fiber Materials (2022) 4:1375–1413 1395 Fig. 10 Drug delivery systems based on electrospun fiber scaffolds [295]; Copyright 2021, Elsevier Limited. d Schematic illustration for cartilage tissue engineering. a Schematic of kartogenin-loaded of the structure of the biomimicking multilayer scaffold loaded with monoaxial and coaxial nanofibers, and comparison of their release FGF-2, BMP-2, as well as some other components promotes deep profile. Reproduced with permission from Ref. [289]; Copyright cartilage defect from regenerating, and results of micro-CT examina- 2020, Elsevier Limited. b The gross view and H&E staining images tion at different time points. Reproduced with permission from Ref. of regenerated cartilage after implanting the cECM-loaded PCL [296]; Copyright 2018, Elsevier Limited. e PCL nanomembranes membrane into mice. Reproduced with permission from Ref. [292]; realized sustained release of lignin, thus suppress inflammation fac- Copyright 2020, Elsevier Limited. c Gas-foamed chondroitin sulfate tors, scavenge ROS, restrain osteoarthritis from deteriorating by sup- crosslinked PLCL/SF-based three-dimensional scaffold enhances car - pressing expression of IL-1β, MMP13 and Keap1, at the same time tilage regeneration, with gross view at 12 weeks and stain results of upregulate the expression of ATG4 to adjust autophagy. Reproduced COL-II revealing its effects. Reproduced with permission from Ref. with permission from Ref. [301]; Copyright 2020, Elsevier Limited regeneration [279]. However, the release curve reached sta- of glycosaminoglycan deposited on the coaxial fibers were bility within 24 h after the initial burst release, indicating a lower than those found on monoaxial ones, but they were deficiency in sustained release. Candidate drugs [278] and modestly higher at 21 days, implying the advantages of long- effective natural plant components [286] have faced similar lasting sustained release. For the same purpose, nanoparti- problems. To this end, the design of fiber structures and in- cles loaded with small molecular drugs [290] and growth depth exploration of drug combinations remain under way. factors [277] have been combined with electrospun fiber For example, Kartogenin [287, 288], has been shown to pro- scaffolds to maintain bioactivity and enable long-term con- mote cartilage defect repair, was loaded into coaxial fibers trollable delivery. Multidrug delivery systems have also been [289]. As shown in Fig. 10a, the existence of the PCL sheath developed to recruit endogenous cells and promote cartilage successfully alleviated burst release and lengthened the drug regeneration [291]. Cartilage-derived extracellular matrix release process to more than 20 days. At 14 days, levels (cECM), which contains various growth factors and natural 1 3 1396 Advanced Fiber Materials (2022) 4:1375–1413 components, possesses an imaginably unique potential. In enhance regeneration capacity [301]. With the deepening one study, cECM was mixed with PCL for electrospinning, of research on injectable hydrogels, it is becoming pos- and the as-obtained scaffold was seeded with chondrocytes sible to disperse electrospun fibers in hydrogels to form and implanted into nude mice [292]. Figure 10b shows the injectable DDSs, which is an excellent potential approach. repair effects, as well as H&E staining at different times, indicating that cECM has a positive effect on regenerated Other Tissue Engineering cartilage after 24 weeks, and more interestingly, the Young’s modulus of the regenerated cartilage reached approximately In addition to the above-mentioned applications, drug-loaded native auricular levels. electrospun fiber scaffolds have also been developed for the It is well known that larger pores are favorable to cell engineering of vascular, dental and musculoskeletal tissues, infiltration and proliferation [293]. Nevertheless, 2D mem- among others. The high specific surface area and porosity of branes are relatively dense and unsuitable for deep defects. electrospun fiber scaffold ensure excellent gas exchange and As a result, studies aiming at developing 2D membranes nutrient transport properties, making it to become a good to 3D scaffolds have arisen. For instance, 3D structures choice for artificial vascular grafts [302]. Considering the fabricated using NaBH exhibit large pores that facilitate structure of natural blood vessels, tubular morphologies with cell attachment and proliferation [294]. Chondroitin sulfate multilayered vessel walls have attracted much attention due (CS), a common component extracted from cartilage, can to their mimicry. As shown in Fig. 11a, a conduit composed be grafted to the matrix by chemical modification to further of a tri-layer electrospun fiber (R-126/R-145/PCL) was pre- enhance the effects of 3D scaffolds [295]. The lowest levels pared by encapsulating microRNA-126 and microRNA-145 of inflammatory cytokines and the highest glycosaminogly - in the inner and middle layers of poly(ethylene glycol)-b- can content were detected in 3D scaffolds crosslinked with poly(l -lactide-co-ε-caprolactone) fibers, respectively, in CS in vitro, and the optimal repair effects were confirmed combination with an outer layer of PCL fibers [131]. The by the results of morphological analysis and immunohisto- fiber mat enables the fast release of microRNA-126 and slow chemical staining, as shown in Fig. 10c. With respect to deep release of microRNA-145. Tri-layered electrospun grafts can osteochondral defects, multilayer scaffolds can be developed promote the growth and intracellular nitric oxide production to meet variable needs. A four-layer hydrogel-fiber compos- of vascular endothelial cells, modulate the phenotype of vas- ite was fabricated in which a fibrous membrane was used as cular smooth muscle cells, and suppress calcification. More a barrier to limit cell migration [296], and BMP-2 loaded importantly, color doppler ultrasound imaging demonstrated coaxial fibers were incorporated to promote subchondral prominent vascular patency in the fiber graft. Although the bone formation. Micro-CT images in Fig. 10d reveals that functions of electrospun fiber-based vascular scaffold are the boundaries between the defect and surrounding tissues continuously optimized, thrombosis and intimal hyperplasia almost disappeared at 12 weeks, with the exception of the still inevitably occurred [303]. The addition of a variety of blank group. In addition, electrospun b fi ers can be combined bioactive substances can be beneficial to accelerating the with freeze-drying [284, 297, 298] and 3D printing [299, replacement of autologous blood vessels and improving the 300] approaches to develop multi-dimensional scaffolds that treatment of cardiovascular diseases [304]. promote cartilage regeneration. As described above for bone tissue, a combination of Injured cartilage gradually leads to osteoarthritis, with electrospun fibers and osteogenic factors can also be used inflammation serving as the main culprit. As a durable to guide dental bone regeneration [305–307]. In this case, antioxidant, lignin can efficiently alleviate excessive oxi- it is necessary to consider the impact of the oral environ- dative stress. In one study, modified lignin was mixed ment [308]. Guided bone regeneration membranes with with PCL for electrospinning to prevent the development dual functions of anti-infection and osteogenesis have been of osteoarthritis. As shown in Fig. 10e, non-significant extensively studied [309–312]. In particular, in addition to differences were found among the groups without H O the good antibacterial properties of metronidazole, some 2 2 stimulation, while PCL-lignin50 increased the expres- inorganic particles can exhibit good anti-infective effects sion of inflammatory factors (MMP13 and IL-1β) after [313]. For example, ZnO can endow PCL fiber membrane H O treatment, thereby effectively preventing hydrogen with good osteo-conductivity and antibacterial properties 2 2 peroxide-induced chondrocyte inflammation. Moreover, (Fig. 11b) [314]. The number of Colony forming units lignin can upregulate the relative expression of allied of Pseudomonas gingivalis on the membrane surface was enzyme under the influence of H O , and higher expres- reduced, and micro-CT analysis of the rat maxilla con- 2 2 sion of ATG4 indicated that lignin can also prevent chon- firmed the effectiveness of ZnO-loaded PCL fibers in drocytes from experiencing excessive oxidative stress by periodontitis-related bone regeneration. This drug-loaded activating autophagy. Their work also demonstrated that electrospun fiber membrane can also be applied as an low intensity pulsed ultrasound (LIPUS) may further oral drug delivery patch for the treatment of oral diseases 1 3 Advanced Fiber Materials (2022) 4:1375–1413 1397 [315], this approach not only maintains good oral adhe- doped in electrospun fibers to deliver therapeutic ions for sion but also provides continuous and controllable drug tendon repair. For example, inspired by the structure of delivery capabilities to kill bacteria and eliminate inflam- cowpea, lithium was loaded in MSNs and doped in electro- mation [316–318]. spun poly(ester urethane) urea (PEUU) nanofibers (Li @ Tendon is an important part of musculoskeletal tis- MSNS/PEUU), allowing the slow release of Li to inhibit sues, and tendon grafts and tendon sutures used in surgical rotator cuff fat penetration and promote tendon and bone treatment cannot satisfy requirements relating to flexibil- healing (Fig. 11c) [321]. Western blotting results showed ity, anti-adhesion, and permanent remodeling [319]. To that Gsk3β was inhibited, while Wnt5a and β-catenin address these problems, electrospun drug-loaded scaffolds were up-regulated under the influence of Li ions. At the can serve as a potential alternative for the treatment and proximal tendon-bone junction, the osteogenic effects of regeneration of injured tendon tissue. In one study, thy-the Li -containing fiber patch were significantly higher mosin β4 (Tβ4)-loaded oriented fibers not only mimicked than those of the fiber patch without Li ions. Micro-CT the ultrastructure of natural tendon tissue but also showed analysis showed that the bone mineral density (BMD) and 28-day sustained release that promoted the migration and bone volume fraction (bone volume/total volume, BV/TV) proliferation of human adipose-derived mesenchymal of the group using Li @MSNS/PEUU nanofiber patch stem cells and supported tendon differentiation [320]. In were significantly higher than those in other groups after addition to direct drug delivery, nanoparticles can also be implanted for 2 and 8 weeks, respectively. Fig. 11 Drug delivery systems based on electrospun fiber scaffolds bi-stranded nanofibers prepared by electrospinning in the repair of for other tissue engineering. a Illustration of three-layered vascular chronic rotator cuff tears, the effect of lithium ion on the expression grafts prepared by successive three-step electrospinning to encapsu- of osteogenesis and adipogenic-related proteins in vitro was indicated late miR-126 and miR-145 in the inner and middle layers of fibers, by western blotting, and the repair effect of each group was shown respectively, as well as its multiple efficacies, including of patency by micro-CT image after implantation for 2 weeks and 8 weeks. testing after in vivo implantation for 4 weeks. Arrows indicate blood Reproduced with permission from Ref. [321]; Copyright 2020, Else- flow (yellow) and suture sites (blue). Reproduced with permission vier Limited. d Schematic diagram of the preparation of HCPT and from Ref. [131]; Copyright 2020, American Chemical Society Lim- diclofenac sodium (DS) composite membrane and the synergistic ited. b Depiction of periodontal defect in rats with fibrous membrane anti-adhesion combined with physical isolation and drug treatment, implantation, P. gingivalis colony forming units (CFUs) on mem- as well as H&E and Masson’s trichome staining of repair sites after brane surface and micro-CT analysis of rat maxilla after implantation 14 days. Reproduced with permission from Ref. [324]; Copyright for 6 weeks. Reproduced with permission from Ref. [314]; Copy- 2018, American Chemical Society Limited right 2018, Wiley–VCH Limited. c Schematic illustration of pea-like 1 3 1398 Advanced Fiber Materials (2022) 4:1375–1413 Tissue anti-adhesion is another research hotspot, espe- use of multiple chemotherapeutic drugs to improve the cially with respect to tendon tissues. By loading engineered therapeutic effects of chemotherapy. Meanwhile, combi- growth factors and related small molecular drugs into elec- nation chemotherapy can induce apoptosis of tumor cells trospun fibers, not only can the purpose of controlled release through different signaling pathways, exerting a synergis- be achieved, but also the formation of adhesion can also be tic effect in killing tumor cells [333]. For example, plu- inhibited [322, 323]. As shown in Fig. 11d, the synergistic ronic F127-modified nanofibers loaded with camptothecin prevention of peritoneal adhesions can be enabled by loading and CUR could achieve the simultaneous and sustained HCPT and diclofenac sodium (DS) into the sheath and core release of the two drugs [334]. Camptothecin can convert of nanofibers, respectively, to exert anti-fibrin proliferative topoisomerase I into a cytotoxic agent by inhibiting the and anti-inflammatory effects [324]. Histological staining movement of replication forks, leading to tumor death, confirmed that collagenous tissue was compartmentalized while CUR inhibits tumor cell growth by inhibiting the kB in the group loaded with HCPT and DS, with little adhesion and Wnt signaling pathways [335, 336]. The use of com- formation. Although electrospun drug-loaded scaffolds have bination chemotherapy can effectively inhibit the growth widespread applications in tissue engineering, it is worth- of colon cancer cells by inhibiting different signal path- while to continue to develop new DDSs based on electro- ways in tumor cells. Drug delivery platforms loaded with spun fiber scaffolds to broaden tissue regeneration strategies. multiple drugs can facilitate different therapeutic effects and avoid drug toxicity and side effects associated with Cancer Therapy prolonged overuse of a single drug. For instance, hierar- chical nanofibers loaded with DOX and matrix metallopro- Surgical resection of the tumor in combination with sys- teinases-2 were fabricated through coaxial electrospinning temic chemotherapy is one of the most common strategies [120]. With this approach, the rapid release of DOX from for cancer treatment [325–327]. However, as a result of its the fibrous nuclear layer could kill remaining tumor cells, systemic administration and poorly targeted delivery, con- while the loading of matrix metalloproteinase-2 inhibi- ventional chemotherapy often causes serious side effects to tor disulfiram in the fibrous shell could effectively inhibit other normal tissues [328, 329]. Therefore, it is urgent to tumor erosion and prevent metastasis. In addition, the develop a new anticancer drug delivery platform to solve the time-programmed release of multiple drugs is the most above problems. Electrospun fibers can allow the local deliv - critical factor in combination chemotherapy. For exam- ery of anticancer drugs, so they have been widely applied in ple, as shown in Fig. 12b, DOX formed periodic chambers tumor therapy [12]. In a recent study, CUR was incorporated inside the fibers, while the double walls of the fibers were into MSNs and embedded into PLGA nanofibers by blending made of polylactic acid and PCL containing the angiogen- electrospinning [76]. The nanofibers had an excellent ability esis inhibitor apatinib. In vivo experiments showed that a to scavenge tumor cells. In addition to the passive release good synergistic effect was obtained by transplanting the of anti-cancer drugs from drug-loaded nanofibers, many fiber into subcutaneous tissue near the tumor site in mice researchers have designed pH-responsive fibers to deliver [337]. anti-cancer drugs based on the acidic tumor microenviron- Although chemotherapy has great advantages in cancer ment [12]. For instance, DOX-loaded MSNs were doped treatment, the tolerance of tumors to chemotherapy drugs into nanofibers, and CaCO was used as an “inorganic cap” highlights the urgency of integrating these approaches with to control the opening of the MSN hole inlet [330]. In the other types of technologies. The delivery of photothermal acidic tumor microenvironment, CaC O reacted with hydro- agents or photosensitizers by nanofibers can effectively kill gen ions to generate carbon dioxide, promoting the release tumor cells [338–340]. As illustrated in Fig. 12c, the efficacy of DOX from MSNs. This type of intelligent-response drug of nanofiber scaffolds loaded with albumin-chloro-6-manga- delivery can be further endowed with targeting capacities to nese dioxide nanoparticles (ACM) for tumor treatment was enhance the utilization efficacy of chemotherapeutic drugs. evaluated using an in situ rabbit model of esophageal cancer Hydrophobic DOX was first encapsulated in folic acid-cou- [341]. In the presence of endogenous hydrogen peroxide, a pled PCL self-assembled micelles, after which core–shell nanofiber scaffold implanted into the area of tissue damage nanofibers loaded with the micelles were prepared by coax- could produce oxygen and alleviate tumor hypoxia. At the ial electrospinning (Fig. 12a) [331]. Compared with repeated same time, ACM nanoparticles gradually diffused out from intravenous injection, the delivery of targeted micelles can the scaffold to the tumor, resulting in effective photodynamic greatly reduce the dose, administration frequency, and side therapy for cancer treatment. effects of chemotherapy drugs. For tumors in the skin, bone and breast, surgical resec- Compared to chemotherapy with a single type of tion causes serious tissue defects. Therefore, the removal drug, multi-drug combination chemotherapy has obvious of remaining tumor cells needs to be accompanied by the advantages [332]. Combination chemotherapy allows the promotion of tissue regeneration [342]. Therefore, it is 1 3 Advanced Fiber Materials (2022) 4:1375–1413 1399 Fig. 12 Drug delivery systems based on electrospun fiber scaffolds TUNEL-stained slices of oesophageal cancer of each group. Black for cancer therapy. a Mechanism diagram of tumor clearance by the arrows indicate tracheas. Reproduced with permission from Ref. implantable DOX loaded active-targeting micelle-nanofiber platform [341]; Copyright 2019, Wiley–VCH Limited. d Schematic illustration and the micelles transfer from nanofiber matrix to tumor tissue, and of the application of Tra-CSO-PP scaffolds and representative pho- finally to tumor cells. Reproduced with permission from Ref. [331]; tographs of tumors and skin wounds on days 0, 4, 8, and 14. Repro- Copyright 2015, American Chemical Society Limited. b The release duced with permission from Ref. [343]; Copyright 2018, American of dual drugs from fibers and their synergistic treatment of tumor, Chemical Society Limited. e Schematic illustration of DOX@PLGA and CLSM image of cavity and fluorescence colocalization analy - fibrous rings for simultaneous tumor therapy and metastasis inhibi- sis. Reproduced with permission from Ref. [337]; Copyright 2020, tion, and T1-weighted MR images at different time points. Repro- Wiley–VCH Limited. c Schematic illustration of chemical relief of duced with permission from Ref. [346]; Copyright 2022, Elsevier the hypoxia environment with in situ release of ACM nanoparticles Limited for oesophageal cancer photodynamic therapy as well as Ki-67 and particularly important to functionalize nanofiber scaffolds modification of nanofibers, the targeted aptamer-modified to enable them to scavenge tumor cells and promote tissue nanofiber surface can be used to capture circulating tumor regeneration. In the study shown in Fig. 12d, drug-loaded cells. For example, coating anti-CD146 antibodies-to- copper silicate hollow microspheres were loaded into melanoma on the surface of PLGA nanofibers can enable nanofiber scaffolds, which exhibited excellent photothermal the capture of circulating melanoma cells [345]. As shown effects and the capability to trigger drug release under NIR in Fig. 12e, to achieve cancer treatment, tumor metastasis irradiation [343]. Upon NIR irradiation, the scaffold could inhibition, and magnetic resonance imaging, DOX-loaded both eliminate tumors and promote skin tissue healing. PLGA fiber mats were immersed in a salt solution to form Circulating tumor cells are cancer cells that are shed fibrous rings [ 346]. The fibrous rings were functionalized from the tumor and enter the circulatory system; therefore, with the chelating agent gadolinium and DNA aptamers via capturing circulating tumor cells is critical to delaying can- the ethylenediamine-mediated coupling reaction. Analysis cer metastasis [344]. However, it is quite difficult to cap- showed that the multifunctional fibrous rings could simul- ture tumor cells from circulating blood in vivo. Due to the taneously deliver tumor chemotherapy, enable magnetic advantages of high specific surface area and flexible surface 1 3 1400 Advanced Fiber Materials (2022) 4:1375–1413 Table 1 Representative types of drug-loaded electrospun fiber scaffolds for tissue engineering and cancer therapy Polymers Drugs Techniques Applications References PCL Tazarotene (TA) Blend electrospinning Skin tissue engineering [185] PLCL/gelatin Epigallocatechin-3-O-gallate Coaxial electrospinning Skin tissue engineering [180] (EGCG) PLA Curcumin (Cur) Physical adsorption Skin tissue engineering [176] PCL/PEG Epidermal growth factor (EGF); Coaxial electrospinning Skin tissue engineering [186] basic Fibroblast growth factor (bFGF) PEO/ PEEUU 5-Fluorouracil (5-Fu); dendritic Coaxial electrospinning Skin tissue engineering [189] Mesoporous bioglass nanoparticles (dMBG) PCL Collagen; Fibronectin Electrospray Nerve tissue engineering [124] PCL Methylprednisolone (MP); Blend electrospinning Nerve tissue engineering [217] Polysialic acid PLLA Nerve growth factor (NGF); Emulsion electrospinning; Physical Nerve tissue engineering [207] Vascular endothelial growth factor adsorption (VEGF) PVP/RLPO Levodopa (LD); Carbidopa (CD) Coaxial electrospinning Nerve tissue engineering [227] PUTK Methylprednisolone (MP) Blend electrospinning Cardiac tissue engineering [31] PCL/gelatin Cerium oxide nanoparticles (nCe) Blend electrospinning Cardiac tissue engineering [236] PCL/gelatin Vascular endothelial growth factor Blend electrospinning or Coaxial Cardiac tissue engineering [243] (VEGF) electrospinning PCE Bone morphogenetic protein-2 Blend electrospinning Bone tissue engineering [53] (BMP-2); Dexamethasone (DEX) PLGA/gelatin Substance P (SP); Alendronate Coaxial electrospinning Bone tissue engineering [266] (ALN) SF/PCL/PVA Bone morphogenetic protein 2 Coaxial electrospinning; Bone tissue engineering [263] (BMP-2); Connective tissue growth Physical adsorption factor (CTGF) PLGA Doxorubicin (DOX) Blend electrospinning Bone tissue engineering [271] PCL/gelatin Metronidazole (MNA) Blend electrospinning Bone tissue engineering [309] PLGA Methylsulfonylmethane (MSM) Blend electrospinning Cartilage tissue engineering [279] PGS/PCL Kartogenin (KGN) Coaxial electrospinning Cartilage tissue engineering [289] PCL/gelatin Chondrocyte Electrospray Cartilage tissue engineering [282] PLCL/SF Chondroitin sulfate (CS) Covalent immobilization Cartilage tissue engineering [295] PCL Kaempferol/Dexamethasone (KAE/ Second carrier electrospinning Cartilage tissue engineering [290] DEX) PCL MicroRNA-126; MicroRNA-145 Blend electrospinning Vascular tissue engineering [131] PCL Epigallocatechin gallate (EGCG); Covalent immobilization; Physical Vascular tissue engineering [303] Dexamethasone (DEX) adsorption PCL Zinc oxide (ZnO) nanoparticles Blend electrospinning Dental tissue engineering [314] PVP Lysozyme Blend electrospinning Oral tissue engineering [317] PLGA Thymosin beta-4 (Tβ4) Blend electrospinning Tendon tissue engineering [320] PCL Mechano-growth factor (MGF) Covalent immobilization Tendon tissue engineering [322] PEUU Lithium-containing mesoporous Blend electrospinning Musculoskeletal tissue engineering [321] silica (Li @MSNs) PLLA Mitomycin-C (MMC) Blend electrospinning Anti-adhesion [323] mPEG-b-PLGA 10-Hydroxycamptothecin (HCPT); Blend electrospinning Anti-adhesion [324] Diclofenac sodium (DS) mPEG-b-PLGA 10-Hydroxycamptothecin (HCPT); Emulsion electrospinning Cancer therapy [334] Hydrophilic tea polyphenols (TP) PCL Epigallocatechin-3-O-gallate Blend electrospinning Cancer therapy [327] (EGCG) 1 3 Advanced Fiber Materials (2022) 4:1375–1413 1401 Table 1 (continued) Polymers Drugs Techniques Applications References PLA; PGA Matrix metalloproteinases-2 (MMP- Coaxial electrospinning Cancer therapy [120] 2); Doxorubicin hydrochloride (DOX·HCl) PLGA Curcumin (CUR); Mesoporous silica Second carrier electrospinning Cancer therapy [76] nanoparticles (MSNs) PLGA Anti-CD146 antibodies Covalent immobilization Cancer therapy [345] resonance imaging, and anchor circulating tumor cells, ulti- magnetothermal therapy, sonodynamic therapy and multiple mately inhibiting the migration and erosion of tumor cells. therapies trigger by exogenous stimuli can achieve better therapeutic effects. Similarly, the introduction of unique imaging properties enables drug delivery to simultaneously Conclusions and Perspectives support long-term stable tracking and real-time monitoring, thereby greatly advancing the process of drug visualization Over the past decades, electrospun fibers have been increas- therapy [346, 349–351]. Furthermore, artificial intelligence ingly applied for controlled drug delivery in the fields of (AI) has also expanded the future of intelligent DDSs. Some tissue regeneration and cancer therapy. To meet the needs of strategies integrating electronic components into scaffolds target tissues, electrospinning provides customizable process have been recently proposed, and these techniques allow parameters, collection devices, and post-processing proce- remote monitoring of tissue function and intervention dures. Correspondingly, electrospun fiber scaffolds with through stimulation and controlled drug release [352, 353]. multiple structures, architectures, and dimensions, including We foresee that the integration of microelectronic devices aligned, core-sheath, porous, grooved, and gradient features, into electrospun drug-loaded scaffolds will provide a better have been fabricated to regulate cellular states and match the way to monitor patient health [354–356]. These additional anatomical structures of regenerating tissues. By combining advantages are likely to further optimize electrospun fibers- various therapeutic drugs, electrospun fiber-controlled drug controlled DDSs as ideal disease treatment platforms and delivery platforms with customizable characteristics have individually customizable therapeutic regimens. gradually broadened the potential applications of soft tissue Although the design of DDSs based on electrospun fiber engineering, hard tissue engineering and cancer treatment. scaffolds has reached a new stage, there is still a long way Thanks to the unremitting efforts of scientific researchers to go to translate into clinical and commercial applications. and developments in nanoscience, advances have been made The first consideration is the biosafety of drug-loaded elec- to the design of electrospun fiber structures, the in-depth trospun fiber scaffolds. All components should be stable and exploration of combinations of electrospun fibers and drugs, nontoxic, and the long-term immune and host responses and the combination of stimuli with controlled properties. after in vivo implantation should be well understood. It Herein, some representative examples of electrospun fibers is also a great challenge to match the degradation proper- loaded with functional therapeutic agents and their applica- ties of electrospun fiber scaffolds with tissue repair rates tions are listed in Table 1. It is believed that the electrospun in practical applications, which is expected to be solved fiber drug-loading platform can provide continued possi- by optimizing combinations of substrate materials, adding bilities for the development of new drug delivery strategies, other components or modifying the scaffolds. During these characterized by the valuable capacity to deliver precise processes, the implanted scaffold material can be adjusted amounts of drugs at specific locations and times in tissue by monitoring tissue repair through real-time imaging. In regeneration and cancer therapy. addition, the fate and pharmaceutic kinetics of drugs after For smart drug-loading platforms, electrospun fiber scaf- entering the body remain unclear. More detailed studies of folds are offering predictable potential. The emergence of fiber- and drug-induced inflammatory responses and healing technologies such as special collectors and gas foaming has mechanisms are also required. Furthermore, the design of enabled 3D electrospun fiber scaffolds to maintain their drug-loaded systems is currently based mostly on experi- original nano-morphology with larger porosity and pore mental trials and experience, so great advances could be size, broadening the applications of electrospun drug-loaded made by applying in-depth machine learning and AI to scaffolds in tissue engineering [347, 348]. In addition, by predict interactions between drugs and fibers and optimize introducing stimuli-responsive components, drugs can be drug selection, release behavior, and simulation of tissue precisely programmed for release in vivo. The combination degradation, among other factors, to direct system construc- of drugs with photothermal therapy, photodynamic therapy, tion. Finally, there is still a gap in the industrialization of 1 3 1402 Advanced Fiber Materials (2022) 4:1375–1413 7. Muzzio N, Moya S, Romero G. Multifunctional scaffolds and drug-loaded electrospun fiber scaffolds. 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Pharmaceutics technology, pharmacy, biomedicine, and clinical medicine 2019;11:6. to solve these challenges. 11. Luraghi A, Peri F, Moroni L. Electrospinning for drug delivery applications: a review. J Control Release 2021;334:463. Acknowledgements This work is supported by the National Natural 12. Zhao JW, Cui WG. Functional electrospun fibers for local therapy Science Foundation of China (Grant No. 52073014 and 82002049; to of cancer. Adv Fiber Mater 2020;2:229. J. Xue), Special Funds for Fundamental Scientific Research Expenses 13. Xue JJ, Xie JW, Liu WY, Xia YN. Electrospun nanofibers: of Central Universities (buctrc202020; to J. Xue), Key Program of New concepts, Materials, and applications. Acc Chem Res Beijing Natural Science Foundation (Grant No. Z200025; to J. Xue). 2017;50:1976. This work is also supported by the opening Foundation of State Key 14. Bhattarai RS, Bachu RD, Boddu SHS, Bhaduri S. 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Schilling K, El Khatib M, Plunkett S, Xue JJ, Xia YN, Vinogra- dov SA, Brown E, Zhang XP. Electrospun fiber mesh for high- resolution measurements of oxygen tension in cranial bone defect repair. ACS Appl Mater Interfaces 2019;11:33548. 1 3 Advanced Fiber Materials (2022) 4:1375–1413 1413 Prof. Liqun Zhang obtained his Prof. Jiajia Xue received her Ph.D. BSc (1990), MSc (1992), and in Materials Science and Engi- PhD (1995) degrees from Bei- neering from Beijing University jing University of Chemical of Chemical Technology in 2015 Technology. He has been a pro- with Prof. Liqun Zhang. She fessor in the College of Materials worked as a postdoctoral fellow Science and Engineering at Bei- in the Prof. Younan Xia's group jing University of Chemical at Georgia Institute of Technol- Technology since 1995. He ogy from 2015 to 2019. She is worked as a visiting scholar at now working as a professor at the University of Akron (1990– the Beijing University of Chemi- 2000) and then as a postdoctoral cal Technology. Her research fellow at Case Western Reserve interests include the fabrication University (2000–2001). His of nanomaterials and scaffolds research interests include rubber for tissue engineering and regen- science and engineering, poly- erative medicine. mer nanocomposites, bio-based and biomedical materials, polymer processing engineering, etc. 1 3
Journal
Advanced Fiber Materials – Springer Journals
Published: Dec 1, 2022
Keywords: Electrospinning; Electrospun fibers; Drug delivery; Stimuli-responsive; Tissue engineering; Cancer therapy