Accepted Manuscript

Electrospun starch nanofibers: Recent advances, challenges, and

strategies for potential pharmaceutical applications

Guodong Liu, Zhengbiao Gu, Yan Hong, Li Cheng, Caiming Li

PII: S0168-3659(17)30120-7
DOI: doi: 10.1016/j.jconrel.2017.03.016
Reference: COREL 8701
To appear in: Journal of Controlled Release
Received date: 20 December 2016
Revised date: 7 March 2017
Accepted date: 7 March 2017

Please cite this article as: Guodong Liu, Zhengbiao Gu, Yan Hong, Li Cheng, Caiming Li
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 ACCEPTED MANUSCRIPT

Electrospun starch nanofibers: Recent advances, challenges, and

strategies for potential pharmaceutical applications

abc
Zhengbiao Gu abc Yan Hong abc*
Guodong Liu Li Cheng abc Caiming Li abc

a The State Key Laboratory of Food Science and Technology, Jiangnan University, 1800 LiHu

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Avenue, Wuxi-214122, Jiangsu Province, P. R. China.

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b School of Food Science and Technology, Jiangnan University, 1800 LiHu Avenue,

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Wuxi-214122, Jiangsu Province, P. R. China

c Collaborative Innovation Center for Food Safety and Quality Control, Jiangnan University,
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1800 LiHu Avenue, Wuxi-214122, Jiangsu Province, P. R. China
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*Corresponding Author: Yan Hong

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Address: 1800 LiHu Avenue, Wuxi-214222, Jiangsu Province, P.R. China.

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Tel: +86-510-85329237
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Fax: +86-510-85329237

E-mail: hongyan@jiangnan.edu.cn
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Abbreviations: DS, degree of substitution; OS, oxidized starch; SA, starch acetate; CS, cationic

starch; hCS, homogenized cationic starch; FS, formy lated starch; HPS, hydroxypropyl starch; DMF,

dimethylformamide; DMSO, dimethyl sulfo xide; THF, tetrahydrofuran; MA, maleic anhydride;

PLGA, poly(lactide-co-glycolide); PVA , poly (vinyl alcohol); PE, po lyethylene; PLA, polylact ic acid;

PEO, poly(ethylene oxide); PMMA, poly(methyl methacrylate).

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Abstract

Electrospun starch nanofibers have high porosity, extremely high specific surface

area, and biocompatible, biodegradable, and bioabsorbable properties. As a result,

starch nanofibers have great potential in pharmaceutical applications, including drug

delivery, wound dressing, and tissue engineering. Here, we summarize and review

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the recent developments in the synthesis of electrospun starch fibers from common

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starch, modified starch, and hybrids with other polymers. Moreover, the challenges

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and strategies for the fabrication and application of starch fibers in pharmaceutical

applications are presented.

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Keywords : starch, electrospinning, nanofibers, drug delivery, tissue engineering,

wound dressing
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Contents
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1. Introduction ................................................................................................................... 4

2. Electrospinning .............................................................................................................. 6
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2.1 Principles of electrospinning....................................................................................... 6

2.2 Electrospinning parameters ........................................................................................ 8

2.2.1 Process parameters .............................................................................................. 9

2.2.2 Solution parameters........................................................................................... 10

2.2.3 Ambient conditions ........................................................................................... 12

3. Recent advances in the development of electrospun starch nanofibers ................................. 12

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3.1 Electrospinning of starch.......................................................................................... 13

3.2 Electrospinning of modified starches ......................................................................... 17

3.3 Starch electrospinning assisted by other polymers ....................................................... 22

3.3.1 Starch and polycaprolactone (PCL) ..................................................................... 24

3.3.2 Starch and poly(vinyl alcohol) (PVA) .................................................................. 25

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3.3.3 Starch and poly(ethylene oxide) (PEO) ................................................................ 26

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3.3.4 Starch and poly(lactide-co-glycolide) (PLGA) ...................................................... 26

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3.3.5 Starch and polylactic acid (PLA)......................................................................... 27

4. Pharmaceutical applications of starch-based nanofibers ..................................................... 27

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4.1. Drug delivery ........................................................................................................ 28
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4.2. Tissue engineering.................................................................................................. 30

4.3. Wound Dressing..................................................................................................... 31

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5. Challenges for electrospun starch nanofibers.................................................................... 31

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6. Strategies for pharmaceutical applications of electrospun starch nanofibers.......................... 33

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6.1 Starch modification and solvent selection ................................................................... 34

6.2 Functionalization of electrospun starch nanofibers....................................................... 36

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6.3 3D printing technologies for the fabrication of electrospun starch nanofibers on demand.. 38

7. Conclusions ................................................................................................................. 39

Acknowledgements .......................................................................................................... 40

References ...................................................................................................................... 40

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1. Introduction

Nanotechnology, which involves the manipulation of materials with nanoscale

dimensions, has been widely used in science and engineering owing to its unique

properties [1]. Nanomaterials have advanced and modernized almost every industry,

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including energy, electronics, agriculture, cosmetics, food, healthcare,

pharmaceutical, among others [2-5]. Among the various nanostructures that have

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been developed for practical applications, nanofibers are favored owing to their

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extremely high specific surface area, superior mechanical performance, high porosity,
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and ease of fabrication [6]. Furthermore, nanofibers can improve the bioavailability

and encapsulation efficiency of a drug, and control drug release behavior [7]. Based
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on the above advantages, nanofibers have been widely used in drug delivery, tissue

engineering, dental applications, wound dressing, and medical implants [6, 8].
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Over the past few decades, microfluidic fiber fabrication, electrospinning, rotary
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spinning, self-assembly, and wet spinning have been used to fabricate micro- and
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nano-scale fibers [9]. Among these fiber fabrication approaches, electrospinning is

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the most commonly used owing to its simplicity. Electrospinning is based on

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electrostatic interactions, and can be used to fabricate nanofibers with solid or

hollow interiors, and with flat or ribbon-shaped structures depending on the intended

application [1, 9]. Moreover, electrospinning can be used to continuously form

non-woven, long, nanoporous nanofibers in a diverse variety of compositions with

consistent diameter and other properties [1, 10-13].

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Electrospinning, an electrohydrodynamic processing technique, utilizes a high

voltage to stretch and elongate a viscoelastic jet derived from a polymer solution or

melt. Both synthetic polymers and natural biopolymers can be used to form micro-

or nano-scale fibers via electrospinning [1]. Compared to synthetic polymers, natural

biopolymers, such as animal-derived (chitosan, hyaluronic acid, alginic acid, heparan

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sulfate, chondroitin, collagen, gelatin, silk fibroin, fibrinogen, albumin, hemoglobin)

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or plant-derived (cellulose, starch, xylan, soy protein, aloe vera) proteins or

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carbohydrates, are biocompatible and biodegradable, which is critical for application

in drug release and tissue engineering [2, 14]. However, natural biopolymers are
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more difficult to fabricate than synthetic polymers owing to their complex chemical
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structures, poor solubility, and high surface tension. The applications of natural

biopolymers are limited by their poor mechanical properties, and rapid

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biodegradation [2, 6, 15]. These limitations of natural biopolymers can be overcome

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by using a hybrid system consisting of a blend of a natural biopolymer and a

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biocompatible synthetic polymer [16], or by using a post-spinning cross-linking

process with suitable cross- linkers which can interconnects the fibrous nanostructure
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with chemical bonds [2], such as genipin (to fibrinogen) [17], glutaraldehyde (to

gelatin) [18, 19].

Starch is the second largest source of biomass on Earth, after cellulose, and is

one of the most important renewable resources in sustainable societies [20]. Starch

and its derivatives have been widely used in the paper, textile, plastic, food, and

pharmaceutical industries owing to its various advantages, including it being a

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natural and renewable resource, its high abundance and low cost, and its

biodegradable and biocompatible properties [21-23]. Furthermore, various

techniques, including physical (e.g., pregelatinization), chemical (e.g., crosslinking,

esterification, etherification), and enzymatic (e.g., hydrolysis) modifications, can be

used to modify native starch to obtain specific properties, to meet the requirements

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of industrial applications [24-30].

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Based on current knowledge, starch has remarkable potential for the fabrication

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of nanofibers through electrospinning processes. An increasing number of research

papers and patents focus on starch-based nanofibers, and explore their applications
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in drug delivery, tissue engineering, and wound dressing. However, to the best of our
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knowledge, no review on this subject is currently available. This review presents the

recent advances in this field, and illustrates the challenges and strategies for
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synthesizing electrospun starch nanofibers, and applying them in the pharmaceutical

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industry. Upcoming research in this area is likely to open new avenues in the fields
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of drug delivery, tissue engineering, and wound dressing, and will facilitate further

development of the pharmaceutical industry.

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2. Electrospinning

2.1 Principles of electrospinning

Electrospinning is one of the most simple, versatile, and cost-effective techniques for

the fabrication of micro- and nano-scale fibers from an electrified liquid [31, 32].

The application of electrospun nanofibers in drug delivery, tissue engineering, and

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wound healing has gained widespread interest in the past few years, owing to the

various advantages of electrospinning, including ease of use and adaptability [11].

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Fig.1. Schematic illustration of electrospinning setup (left) (cited from the website
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http://weistron.com.cn/newsitem/277119212) and Taylor cone formation (right) (Reprinted with

permission from Ref. [11] . Copyright (2008) Elsevier).

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A simple electrospinning instrument consists of a syringe with a control pump, a

high- voltage power supplier, and a grounded collector (Fig. 1) [1, 11, 33]. To
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fabricate nanofibers, the collector is normally connected to a counter electrode, and

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the polymer solution is pumped through the needle of the syringe. The needle is in
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turn connected to a high- voltage power supplier, which supplies a voltage between 1
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and 30 kV. In the presence of an electric field, the polymer solution at the tip of the
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needle becomes electrostatically charged, and forms a Taylor cone. Once the

electrostatic force overcomes the surface tension, a jet of charged polymer solution is

ejected from the Taylor cone. The jet is accelerated by the electric field, and becomes

thinner as it moves toward the grounded collector. As this happens, the solvent

rapidly evaporates, and the polymer chains within the jet tend to stretch-out and

become oriented. Finally, the jet solidifies into a nanofiber (Fig. 1) [6, 10, 32, 34].

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2.2 Electrospinning parameters

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RI
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Fig.2. Schematic illustration of the effect of various electrospinning parameters on fiber

morphology. The schematic illustration of electrospinning setup (Left) cited from the website
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(http://weistron.com.cn/newsitem/277119212).
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The properties of nanofibers (like diameter, structure, porosity, surface area, and

mechanical strength) play vital roles in determining the pharmacokinetic properties

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of the nanofibers, and can be affected by a number of parameters during

electrospinning [35]. In order to produce nanofibers with better performance in drug

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delivery and other applications, care should be taken to study the parameters

involved in the electrospinning process. These parameters include process

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AC

parameters (e.g. applied voltage, solution flow rate, tip-to-target distance), solution

parameters (e.g. solution viscosity, polymer molecular weight and concentration,

solvent volatility and conductivity), and ambient conditions (e.g. temperature,

humidity) (Fig. 2).

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2.2.1 Process parameters

The applied voltage is a critical parameter for initiating electrospinning, and

consequently nanofiber formation. As mentioned above (see Section 2.1), the

electrostatic interaction forces, which are determined by the applied voltage, induce

the formation of a Taylor cone, and when the electrostatic forces overcome the

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surface tension force, the Taylor cone is distorted, and the polymer jet is ejected [34,

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36]. As shown in Fig.1, higher applied voltages could result in the decrease of the

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volume of the pendant drop at the tip of the capillary [11]. An increase in the applied

voltage will increase the electrostatic forces, thus increasing the charge density and
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accelerating the polymer jet. This results in the fiber to stretch more leading to the
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reduction in the nanofiber diameter [34]. Furthermore, greater Coloumbic forces in

the jet may break the jet apart into little droplets resulting in the more bead formation
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[37, 38]. Ki et al [38] found the fiber diameter distribution was slightly broadened at
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a higher voltage because more beads and droplets tends to be generated due to very
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high electric field. However, in some cases, researchers found lower applied voltages

can decrease the diameter of fiber due to the decreased flight speed which may allow
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the jet to split [39-41].

The flow rate and tip-to-target distance can also have an important effect on

fiber morphology during electrospinning. Either an increase in the flow rate or a

decrease in the tip-to-target distance can lead to insufficient time available for the

solvent to evaporate, causing the polymer strands to fuse together, leading to bead

formation. Simultaneously, incomplete drying for fibers can lead to ribbon- like or

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flattened fibers formation instead of fibers with a circular cross section [11]. A higher

flow rate can supply more polymer solutions to replace that ejected as the fiber jet

leading to the increase in fiber diameter. After reducing the tip-to-target distance, the

jet has less time to stretch and orient, and the fiber will stretch less resulting in larger

fiber diameter. Phase separation is considered to be the mechanism in the pore

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formation in electrospun fibers [42]. During solvent evaporation, the polymer

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solution is thermodynamically unstable leading to phase separation. The polymer

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concentrated phase forms the matrix of fibers, while the polymer lean phase forms

the pores [42]. Both an increase in the flow rate or a decrease in the tip-to-target
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distance can maintain sufficient solution supply for the fiber jet. Thus, their phase
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separation is more obvious compared to their counterparts leading to the increase in

both pores numbers and sizes [34, 42, 43].

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2.2.2 Solution parameters

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Fig.3. Influence of polymer concentration and molecular entanglement on the morphology of the

nanofibers deposited on the collector plate during electrospinning [34]. Reprinted with

permission from Ref. [34]. Copyright (2008) Taylor & Francis.

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Viscosity of the polymer solution used in electrospinning is controlled by a

combination of the polymer concentration and the type of solvent used. Viscosity is a

key parameter that determines the spinnability of the solution. It is important

because it affects the entanglement of the polymer molecules, which is critical for

the formation of a continuous jet of polymer solution instead of droplets [44]. In

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general, a lower viscosity will result in a smoother and less beaded fiber with a small

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diameter and good mechanical strength [33]. However, if the viscosity is too low, as

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might be the case with a very dilute solution, the polymer molecules will not be

entangled, and the electrospinning process might result in the formation of beads or
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droplets instead of fibers. On the other hand, an extremely high viscosity will cause
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the polymer solution to obstruct the flow through the capillary, leading to the

formation of a localized gel, which will prevent the formation of nanofibers (Fig. 3)
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[45].
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In addition, a volatile solvent must be used in order for sufficient solvent

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evaporation to occur as the polymer jet moves toward the grounded collector. The

solution volatility is particularly important when the nanofibers are to be used for
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drug delivery, because a higher volatility usually leads to the formation of nanofibers

with more porous structures, and larger surface areas [33]. In contrast, solvents with

poor volatility usually form nanofibers with increased pore sizes and lower surface

areas [42], which would be less suitable for drug delivery applications.

Finally, the conductivity of the polymer solution can also have an important

influence on the fiber morphology. Solutions with higher conductivity can form a jet

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with a greater charge, resulting in stronger electrostatic forces. Consequently, the jet

experiences a greater tensile force and is stretched more, which yields nanofibers

with reduced diameters, and less bead formation [11, 46]. The conductivity of the

polymer solution can be increased by adding ionic salts or polyelectrolytes [34, 47,

48].

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2.2.3 Ambient conditions

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Ambient conditions, such as temperature and humidity, also play a significant role in

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the electrospinning process. Higher temperatures result in lower nanofiber diameters,

while increased humidity leads to more pore formation on the nanofiber surface
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[49-51].
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3. Recent advances in the development of electrospun starch nanofibers

Starch is one of the most abundant, renewable, and inexpensive natural biopolymers
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found on Earth. It is composed of linear amylose and branched amylopectin, and is a

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popular natural material for replacing synthetic materials owing to its biocompatible,
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biodegradable, and bioabsorbable properties. Compared to synthetic polymers, starch

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is more hydrophilic, and can be absorbed by the human body without causing any
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allergic reaction or toxic effects. Thus, nonwoven starch nanofibers may find uses in

biomedical applications [52, 53]. For example, in the last 10 years, starch-based

fibers have shown promising potential in drug delivery, tissue engineering and

wound dressing. Based on the data of Web of Science, the number of publications on

starch fibers exhibit an upward trend (Fig. 4). Simultaneously, an increasing number

of research studies and patents have focused on enectrospun starch fibers, aiming to

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explore suitable fabrication methods and extend their applications. Recent advances

in the development of electrospun starch fibers are reviewed below.

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Fig.4 The annual number of publications on the subject of: (A) “starch fiber”, (B)
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“electrospun starch” OR “electrospinning starch” analyzed by Web of Science from 2007 to Feb

25th , 2017.
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3.1 Electrospinning of starch

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Early studies on starch nanofibers attempted to fabricate amylose fibers by using the
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linearity of amylose, and its ability to align and aggregate [52, 54, 55]. In some cases,
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an amylose solution obtained by dissolving amylose in aqueous sodium hydroxide

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was extruded into an acid bath as a coagulation bath. A fiber was obtained using this
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technique, but the fiber was very weak. Muetgeert patented a process for

synthesizing amylose fibers that involved extruding an amylose solution dissolved in

aqueous sodium hydroxide into concentrated aqueous ammonium sulfate [56]. When

the amylose solution is extruded, it instantaneously coagulates, and a fairly strong

and resilient fiber is obtained. However, amylose is a minor component in common

starches, and purifying amylose is expensive. As a result, these drawbacks are major

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obstacles for the large-scale production of amylose nanofibers by these techniques

[52].

Amylose is linear, and so has sufficient freedom of molecular movement that it

can be preferentially oriented into parallel alignments leading to the formation of

hydrogen bonds. In contrast, amylopectin is highly branched, so cannot move very

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freely, or align and associate readily [57]. Theoretically, the presence of amylopectin

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will adversely affect the spinning process, and the strength of the fibers [57].

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However, amylopectin is the major component in natural starch; therefore,

approaches for electrospinning fibers from natural starch, even though it is high in
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amylopectin, are needed to make the synthesis of starch nanofibers economically
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feasible on a commercial scale.

Many attempts have been made to fabricate electrospun fibers using native
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starch (Table 1). For example, Kong and Ziegler used a dimethyl sulfoxide
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(DMSO)/water solvent medium to synthesize p ure starch fibers via electrospinning

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(Fig. 5A) [55, 58-60]. This solvent can cause starch molecules to dissociate and

adopt a coil conformation, which leads to sufficient molecular entanglement for

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electrospinning to be achieved [52]. However, pure starch fibers are usually brittle

and water-sensitive, which limits their applications. The mechanical strength and

water-stability of starch fibers can be improved by using a post-spinning heat

annealing treatment at 65°C, or by cross-linking the starch fibers with glutaraldehyde

in the vapor phase [55]. The diameter of the starch fibers obtained according to

Kong’s method is in the order of microns (minimum fiber diameter: 3.98 μm) [59].

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T ED

Fig.5. Scanning electron micrographs of pure starch fibers synthesized via electrospinning.
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(A) Common starch-based electrospun fibers: A-1: 8% (w/v) gelose (80% amylose) in 95%
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DMSO; A-2: 8% (w/v) Hylon VII (70% amylose) in 95% DMSO; A-3: 8% (w/v) Hylon V (55%
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amylose) in 95% DMSO; A4: 7% (w/v) mung bean starch (35% amylose) in 95% DMSO [58].

Reprinted with permission from Ref. [58]. Copyright (2012) American Chemical Society. (B)

High-amylose based electrospun fibers: B-1: 17% (w/v) Hylon VII (70% amylose) in 100%

formic acid; B-2: 17% (w/v) Hylon VII (70% amylose) in 90% formic acid; B-3: 17% (w/v)

Hylon VII (70% amylose) in 80% formic acid [61]. Reprinted with permission from Ref. [61].

Copyright (2015) American Chemical Society. (C) Common starch-based electrospun fibers

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fabricated by centrifugal spinning using a 2% (w/w) caustic soda solution as solvent: C-1: 15%

(w/w) amylose-rich corn starch (77.66% amylose); C-2: 14% (w/w) amylopectin-rich corn starch

(31.11% amylose); C-3: 11% (w/w) amylopectin-rich potato starch (26.65% amylose) [62];

Reprinted with permission from [62]. Copyright (2016) Elsevier.

The fabrication of starch fibers with nano-scale diameters ranging from 80 to

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300 nm was achieved by electrospinning high-amylose starch from a 17 wt%

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aqueous formic acid solution (Fig. 5B) [61]. Formic acid plays a crucial role in the

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dispersing medium for electrospinning because it can solubilize and esterify starch,

thus disrupting the starch structure and leading to a loss of crystallinity. Compared to
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native starch products, the starch fibers synthesized in the presence of formic acid
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appear to be more amorphous without preferential molecular orientation, while the

value of elongation at break increased over 13 times for the starch fibers electrospun
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from pure formic acid dispersions (elongation at break ε*=26%) [61]. These
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nano-scale starch fibers possess promising potential as low-cost and sustainable

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biomaterials in the food and pharmaceutical industries.

Although the presence of amylopectin will adversely affect the electrospinning

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process and the strength of fibers [57], pure starch-based fibers have recently been

fabricated from amylopectin-rich starch (with an amylopectin content above 65%)

(Fig. 5C). For example, starch fibers with sub- micron average diameters have been

successfully fabricated by centrifugally spinning amylopectin-rich starch solutions,

prepared by dissolving amylopectin-rich corn (68.89% amylopectin content) and

potato (73.35% amylopectin content) starches in a 2% (w/w) caustic soda solution

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[62]. These results reveals good starch-based fibers can only be fabricated when the

starch solution reaches a critical concentration (c* ). The minimum c* /ce (where ce

represents the entanglement concentration) values of the above amylopectin-rich

corn and potato starches were 3.5-4 and 4.5-7, respectively. However, using this

process, the waxy corn starch failed to form fibers with changing concentration from

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8-16% (w/w) owing to its poor molecular entanglement for its highly branched

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structures. Till now, waxy starch based fibers has not been successfully fabricated

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because a ce value was not obtained, while sufficient starch molecular entanglement

is the prerequisites for forming fibers [62]. In the future studies, a proper solvent or
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new electrospinning techniques might be helpful for solving this problem.
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3.2 Electrospinning of modified starches

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A number of modification techniques, such as physical, chemical, and enzymatic

modifications, have been employed to enhance or inhibit the inherent properties of

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native starch, or to endow it with specific properties to meet the requirements of

certain applications [24, 25].

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As mentioned previously, electrospun fibers from pure native starch materials

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typically have low water stability and weak mechanical properties, and are difficult

to process, limiting their applications [61]. Thus, several researchers have attempted

to develop modified starches that can be used for the electrospinning of nanofibers

with better properties [63]. Nevertheless, only a few trials demonstrating the

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electrospinning of modified starch-based fibers have been reported in the literature to

date (Table 1).

Table 1 Summary of studies on electrospun fibers synthesized from pure starch.

Electrospinning materials Solvent Fiber Referenc

characteristics e
Pure High-amylose starch Dimethyl sulfoxide Diameters in the [55,
starch (DMSO)/water order of microns 58-60]

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High-amylose maize 17 wt% aqueous formic Nano-scale [61]
starch (70%) acid solution diameters

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ranging from 80
to 300 nm

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Amylopectin-rich corn 2% (w/w) caustic soda Sub-micron [62]
(68.89% amylopectin solution average
content) and potato diameters
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(73.35% amylopectin
content) starches
Waxy rice starch Water High porosity; [64]
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multiple flaky
layers; tendency
to swell
Pure High-amylose starch Ionic liquid Continuous and [65]
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modifie (70%)/acetic anhydride 1-allyl-3-methylimidazoliu smooth fibers;

d starch m chloride Diameters range
from several
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tens to several
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hundreds of
nanometers
High-amylose maize Formic acid Tensile strength [66]
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starch (70%)/acetic of the

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anhydride nanofibers
depended on the
starch-to−acetat
e ratio,
annealing time,
and degree of
substitution
(DS).
High amylose maize Dimethyl sulfoxide Ultrafine fibers [67]
starch (50%)/acetic (DMSO)
anhydride
High-amylose maize 17 wt% aqueous formic Nano-scale [61]

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starch (70%)/formic acid solution diameters

acid ranging from 80
to 300 nm;
higher
elongation at
break than
native starch
fibers
Starch (soluble)/ Water/DMSO Highly porous [68]
poly(ethylene-alt-malei 3D nanofiber

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c anhydride) mesh structure;
insoluble in

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water; large
surface area;

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uniform
nanopores
Acidified-oxidized DMSO Smooth fibers at [69]
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potato starch concentrations
up to 19 wt%;
native starch
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only produced
fibers at
concentrations
up to 5 wt%.
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Researches have found that esterified starch possesses better mechanical

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properties than native starch, and therefore is a good candidate to fabricate

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nanofibers. Esterifying starch with acetic acid or acetic anhydride in the presence of
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a catalyst results in the formation of starch acetate (S A). Volkert and the coauthors
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[70] found acetylation of starch can enhance mechanical properties with a tensile

strength of 30 MPa, while that of native starch was less than 10 MPa. Zhou

successfully fabricated electrospun high-amylose SA nanofibers using the ionic

liquid 1-allyl-3- methylimidazolium chloride as the reaction medium [65]. The

resulting SA fibers were continuous and smooth, with diameters ranging from

several tens to several hundreds of nanometers. Electrospun SA nanofibers have also

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been fabricated from an SA solution using a formic acid/water system [66]. The

tensile strength of the SA nanofibers could be controlled by varying the SA

concentration, the annealing time, or the degree of substitution (DS). The tensile

strength of SA nanofibers increased from 5.9 MPa to 16.2 MPa when the SA

concentration increased from 12% to 20% (wt%), while as the SA increased from 20%

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to 24%, the tensile strength of SA nanofibers decreased to 12 MPa. When the

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annealing time increased from 0 min to 180 min at 120℃, the tensile strength of SA

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nanofibers firstly increased from 10 MPa to a maximum of 18.1 MPa (annealing

time: 120 min), then reduced to 7.2 MPa (annealing time: 180 min). when the DS
NU
values increased from 1.1 to 2.3, the tensile strength decreased from 17.92 MPa to
MA

16.19 MPa [66]. Ultrafine SA fibers have also been obtained using dimethyl

sulfoxide (DMSO) as a solvent [67].

ED

Starch undergoes rapid esterification, known as o- formylation, in formic acid.

T

Lancuski used a one-pot method to gelatinize starch from formic acid solutions, and
EP

process it into electrospun fibers [61, 71]. The resulting electrospun formylated

starch (FS) nanofibers, with diameters ranging from 80 to 300 nm, exhibited less
C
AC

tendency to break than native starch fibers. FS fibers featured higher elongation at

break (ε*=26%) compared to native fibers (ε*=1.92%). This suggests that

electrospun FS nanofibers have good potential for drug delivery, tissue engineering,

and wound dressing applications [71].

The reaction between starch and poly (ethylene-alt- maleic anhydride)

(PE-alt-MA) results in esterification of the hydroxyl groups in the starch backbone.

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Oktay prepared spinning solutions by mixing starch and PE-alt-MA, and then

successfully fabricated starch-based nanofiber meshes via electrospinning [68]. The

electrospun starch/PE-alt-MA nanofibers in these meshes possessed a high surface

area to volume ratio, and uniform nanopores, which may mean they have potential

applications in tissue engineering, and drug delivery.

PT
In addition to the esterified starches described above, acidified-oxidized potato

RI
starch has been used to fabricate nanofibers via electrospinning [69].

SC
Acidified-oxidized starch was prepared by adding ammonium persulfate as an

oxidizing agent and hydrochloric acid as a catalyst to a starch solution. Smooth

NU
fibers were subsequently obtained by electrospinning acidified-oxidized
MA

starch/dimethyl sulfoxide (DMSO) solutions.

Poor water stability, processability and mechanical properties are the main
ED

shortfalls for native starch and limit its applications. Starch modifications are
T

optional methods to overcome these problems. Thus, modified starches are a

EP

potential source of fibers for industrial applications. However, researches into the

use of modified starches for fabricating electrospun fibers is limited. Pure starch
C
AC

fibers fabricated in the published papers are usually brittle and water-sensitive,

which limits their applications. Thus, there is much room to investigate and expand

the use of modified starches in electrospun fibers in order to solve these problems.

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3.3 Starch electrospinning assisted by other polymers

Natural materials commonly lack the desired properties, or are difficult to use to

form electrospun fibers on their own [16]. As previously discussed, pure starch

materials, for instance, are rather brittle, water-sensitive, and difficult to process [61].

In order to overcome these shortfalls, non-starch components such as other polymers,

PT
plasticizers, or cross- linkers, can theoretically be added into the polymer solutions

RI
[55]. For example, the addition of a second polymer can help promote entanglement

SC
of starch molecules. Likewise, the addition of starch can provide the ability to adjust
NU
the surface properties of polymer fibers. Many hybrid systems have been described

in the literature, and recent cases where starch has been co-electrospun with other
MA

polymers are reviewed below (Table 2).

Table 2 Summary of studies on electrospun fibers synthesized from blends of starch

ED

with other polymers.

T

Electrospinning materials Solvent Fiber Referenc

characteristics e
EP

Polycaprolactone Starch/PCL Acetic acid or chloroform Diameters of [72]

(PCL) (30/70 wt%) 130 to180 nm;
C

highly porous
nanofibers can
AC

be fabricated
Starch/PCL Chloroform/dimethylforma Diameters in the [73]
(17% w/v) mide (DMF) (7:3) range of 400 nm
to 1.4 μm; the
fibrous structure
provides the
required
mechanical
stability
Starch/PCL Chloroform/DMF (7:3) Diameter [74]
(30/70 wt%) approximately

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400 nm; fine

morphology; no
beads
Starch/PCL Chloroform (40% w/v) Produced by wet [75]
(30/70 wt%) spinning;
diameter of 100
µm; mean pore
size of 250 µm
Poly(vinyl alcohol) Potato starch Ethanol (5 wt%) It is possible to [76]
(PVA) (5 wt%)/PVA form nonwoven

PT
material from
the nanofibers

RI
Soluble Water Good [77]
starch/PVA morphology and

SC
(1:1 or 1:3) spinnability
Oxidized Water Morphology and [78]
starch diameter of the
NU
(OS)/PVA fibers were
clearly affected
by the weight
MA

ratio of PVA/OS
and the solution
concentration;
hydrogen bonds
ED

were formed
between the
molecular OS
T

and PVA in the

EP

PVA/OS fibers.
Cationic Water Best results [79]
Starch were obtained
C

(CS)/PVA using a PVA/CS

AC

(3:1) solution with a

solid
concentration of
8 wt%
Cationic Ethanol/water More stick [80]
starch nanofibers were
(CS)/PVA formed from the
PVA/homogeniz
ed CS (hCS)
solution; the use
of an
ethanol/water

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mixture causes
the formation of
thicker
nanofibers.
Poly(ethylene Hydroxyprop Water It is feasible to [16]
oxide) (PEO) yl starch produce
(HPS)/PEO nanofibers of
HPS/PEO
blends with a
high proportion

PT
of starch;
potential to be

RI
used as
scaffolds in

SC
tissue
engineering
applications
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Poly Starch/PLGA Starch in Dimethyl sulfoxide The [81]
(lactide-co-glycoli (DMSO); and PLGA in hydrophilicity
de) (PLGA) tetrahydrofuran and degradation
MA

(THF)/N,N-dimethylformam rate of the

ide (DMF) (3:1) PLGA fibers
were improved
by adding
ED

starch.
Polylactic acid Cassava PLA in dichloromethane, Smooth [82]
(PLA) starch/PLA cassava starch in dimethyl electrospun
T

sulfoxide (DMSO) fibers were

EP

obtained.

3.3.1 Starch and polycaprolactone (PCL)

C

Starch/polycaprolactone blends have been employed to fabricate porous nanofibers

AC

via electrospinning. For example, Jukola successfully produced electrospun

nanofibers using a high concentration (15 wt%) starch/PCL (30/70 wt%) solution

[72]. The fibers were highly porous with a diameter ranging from 130–180 nm

showing potential for obtaining highly porous 3D scaffolds, which means they can

provide a high surface area for cell attachment and proliferation. Other researchers

have used the electrospinning technique to successfully develop a hierarchical

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starch-based scaffold made from a blend of starch and PCL [73]. This multilayer

scaffold is composed of parallel aligned starch/PCL fibers, and can significantly

increase cell proliferation and osteoblastic activity. Similar results were also obtained

in Tuzlakoglu’s work [74, 75].

3.3.2 Starch and poly(vinyl alcohol) (PVA)

PT
PVA is soluble and highly penetrable in water [83], and it can readily interact with

RI
other crossing- linking agents to form gels [84]. Pure starch materials lack

SC
mechanical strength, and have low water stability, thermostability, and processability,

while pure PVA has a low biodegradation rate, and poor moisture barrier properties
NU
[85, 86]. However, many of these drawbacks are mitigated in starch/PVA blends,
MA

which consequently have many potential applications. Starch/PVA blends do not thin

when they are subjected to low shear rates, and they only thin slightly when
ED

subjected to high shear rates. Furthermore, they have good spinnability, and the
T

starch/PVA nanofibers fabricated via electrospinning have smooth morphology and

EP

uniform in diameter [77, 87]. Bicomponent nanofibers made from PVA and modified

starch, such as oxidized starch or cationic starch, have also been fabricated using the
C
AC

electrospinning technique [78-80]. The morphology and diameter of the nanofibers

were affected by the weight ratio of PVA and starc h. Wang, et al. [78] found the

diameter of the nanofibers decreased from 460 nm to 147 nm when the weight ratio

of PVA/starch decreased from 1:1 to 1:4. The nanofibers with ratios of 1:1 and 1:2

were smooth and uniform in diameter, while their counterparts with ratios of 1:3 and

1:4 were irregular and interspersed with shuttle-shape beads. The influence of

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ethanol in the spinning solutions has also been investigated. Research shows that the

addition of ethanol has a positive influence on the electrospinning process, but

causes the formation of thicker nanofibers with a larger diameter [76, 79, 80].

3.3.3 Starch and poly(ethylene oxide) (PEO)

Nanofibers have also been fabricated using a hydroxypropyl starch (HPS)/PEO

PT
blend, with water as the solvent [16]. HPS is a biodegradable water-soluble polymer,

RI
and blends with a very high starch content (up to 80%) can be successfully

SC
electrospun into nanofibers by adding PEO. The fibers were subsequently coated

with hydrophobic poly(methyl methacrylate) (PMMA) to enhance the ir stability.

NU
HPS-rich fiber mats were not cytotoxic toward human fibroblast cells, indicating that
MA

the fibers have great potential to be used as scaffolds in tissue engineering.

3.3.4 Starch and poly(lactide-co-glycolide) (PLGA)

ED

PLGA is hydrophobic and lacks bioactivity. In contrast, starch is bioactive and

T

hydrophilic, although it cannot be electrospun easily on its own. As a result, the

EP

properties of PLGA fibers synthesized via coaxial electrospinning can be improved

by adding starch. PLGA solution was used as the core fluid, and starch solution was
C
AC

used as the shell polymer fluid. The resulting PLGA/starch coaxial fibers have

higher hydrophilicity and degradation rate than pure PLGA fibers [81]. The average

contact angle of PLGA/starch fibers (contact angle: 96.09°) was lower than that of

PLGA fibers (contact angle: 130.33°) indicating the hydrophilicity of the fibers has

been improved. After immersed in phosphate buffer solution for two weeks, the mass

loss rate of pure PLGA fibers was 4.18%, while the degradation rate of PLGA/starch

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fibers was higher with a mass loss rate of 17.31%. Thus, after coaxial electrospun

with starch, both the hydrophilicity and degradation rate of the composite fibers were

improved [81].

3.3.5 Starch and polylactic acid (PLA)

Polymer composite electrospun fibers can have improved chemical and physical

PT
properties compared to pure electrospun fibers. For example, the addition of starch

RI
provides the ability to adjust the surface properties of polymer fibers, such as

SC
improved hydrophilicity, porosity and degradation. PLA/starch fibers have been

obtained via a single nozzle electrospinning process using methanol as a conjugated

NU
solvent. The mixed solution was immiscible for PLA in dichloromethane (DCM) and
MA

starch in dimethylsulfoxide (DMSO). This immiscible solution system can fabricate

electrospun fibers for the requirement of carrying multiple components [82].

ED

4. Pharmaceutical applications of starch-based nanofibers

T

Electrospun nanofibers has gained great interest for applications in drug delivery,
EP

tissue engineering and wound dressing in the last 20 to 30 years. Extremely high
C

specific surface area, superior mechanical performance, high porosity, and ease of
AC

fabrication permit the provision of ideal vehicles for drugs, bioactive compounds,

growth factors, and even cell, DNA and RNA , and scaffolds for cell adhesion and

proliferation [11]. Starch, as a natural carbohydrate polymer, is cheap, abundant,

renewable. Furthermore, biodegradability, biocompatibility and bioabsorbility make

starch suitable for pharmaceutical applications [52]. Starch fibers can be thoroughly

absorbed in human body without any allergic or toxic side effects [53, 63]. The

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interaction via functional groups in both starch matrix and compounds can

strengthen the capacity to bind and entrap a wide range hydrophilic and hydrophobic

compounds. In contrary to the lipid or protein based carrier, starch-based delivery

systems are better protective shell for bioactive compounds at high processing

temperature due to their thermal stability [88]. The above advantages of starch

PT
materials together with the flexibility in starch modification and nanofiber

RI
fabrication make starch and its derivatives ideal candidates for use in drug delivery,

SC
tissue engineering and wound dressing.
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4.1. Drug delivery
MA

Electrosprinning can embed target compounds in starch nanofibers based on

encapsulation technique to act as delivery systems in pharmaceutical formulations

ED

[71, 87]. A wide range of functional compounds including drugs (antibiotics,

anticancer drugs), protein, peptides, enzymes, cells, DNA/RNA, virus, antimicrobial

T
EP

agents, antioxidants, can be delivered via electrospun nanofibers [11, 89]. The most

common and basic delivery model is directly electrosprinning after dissolving or

C

dispersing the target compounds into the starch nanofiber matrix [6]. Advanced
AC

delivery systems based on starch nanofibers have been developed in order to meet

specific requirements, such as coaxial electrospinning, emulsion electrospinning,

synergistically combining nanofibers with nanocontainers, and

surface-functionalization of electrospun nanofibers [71].

The electrospun starch nanofibers possess a high surface area to volume ratio

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allowing target substances release into the medium through a large surface area.

Both the drug release behavior and bioavailability can be controlled and tailored by

the composition and morphology of starch nanofibers attributing to the flexibility in

dimensions and surface properties [9]. Compared to spherical vehicles whose

specific surface area can only be controlled by diameter, more factors of the fiber

PT
matrix can be tailored, such as length, diameter [9]. Furthermore, nanofibers show

RI
some promise for drug delivery with high drug loading and encapsulation efficiency

SC
[7, 31].

Unlike nonbiodegradable polymers, the drug release mechanism from

NU
biodegradable starch nanofibers is more complicated. Drug release profiles are
MA

associated to drug diffusion and matrix degradation [90]. For nonbiodegradable

fibers, the drug release is only controlled by diffusion. In a starch fiber system, the
ED

drug release is dominated by the combination of diffusion and degradation [11, 14].
T

Commonly, drug release from electrospun fibers tend to be faster than that from
EP

corresponding film mat due to the the larger surface area properties of fibers [91].

Starch nanofibers are hydrophilic and degradable. The drug release profiles are
C
AC

usually an initial burst release followed by a long-period sustained release. The quick

diffusion of drugs deposited on the surface of fibers results in the initial release,

while the sustained release was controlled by the drug diffusion and matrix

degradation [91].

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4.2. Tissue engineering

Electrospun scaffolds have been applied for tissue engineering including bone,

cartilage, skin, nerve, tendon, ligament [14]. The morphology properties make the

electrospun starch nanofibers similar to the natural extracellular matrix (ECM), such

as high specific surface area, high porosity, permeable and well interconnected pore

PT
struture [74]. Electrospun nanofibers with nonwoven porous structure can form

RI
supportive meshwork around cells and provide anchorage to the cells promoting the

SC
cell adhesion and proliferation [16]. NU
Starch is biodegradable and biocompatible. Biocompatible materials are favored

in fabricating electrospun scaffolds in order to minimize the toxicity, inflammatory

MA

and immune responses to the host organism [9, 11]. Biodegradability of the scaffolds

can eliminate a second surgery to remove the implanted mats [11, 92]. An ideal
ED

tissue engineering scaffolds should be with an adequate degradation rate. The tissue
T

regeneration will be impeded if the degradation rate is too slow, while the drug
EP

release and mechanical stability will be compromised with a too fast degradation rate
C

[14]. Furthermore, starch and its derivatives are good candidates to hydrogel.
AC

Hydrogel is a three-dimensional network formed by immobilizing large amounts of

water. The soft and rubbery consistence make starch hydrogel closely resemble

living tissues. This property contributes to the excellent biocompatibility of starch

materials, and are beneficial for the non-denaturing to bioactive cargo for tissue

engineering [93, 94].

The porous structure of starch nanofibers can increase the surface area of the

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mat [1]. Both the pores and pore size can influence the development of cells

including adhesion, migration, proliferation, and differentiation [11, 14]. Adequate

pore size and degradation rate, controlled porosity, as well as appropriate biological

response and mechanical properties are the prerequisites for an ideal tissue

engineering scaffold [95].

PT
4.3. Wound Dressing

RI
Electrospun nanofiber nonwovens can provide a biomimetic environment for the

SC
regeneration of skin cell during wound healing [2, 15]. A good wound dressing
NU
should protect the skin surface, maintain moisture, delivery growth factors, and
MA

induce tissue remodeling and shorten the recovery period [96, 97]. Starch nanofiber

nonwovens are good candidate for wound dressing due to their attractive properties,
ED

such as high specific surface area, high porosity, flexibility in surface functionalities.

Single or multiple growth factors can be encapsulated and delivered by starch

T
EP

nanofibers for the regeneration of dermal and epidermal layers and the facilitation of

angiogenesis. Starch nanofiber nonwovens can provide three-dimensional physical

C

support and scaffolds for growth factors to wound healing [98].

AC

5. Challenges for electrospun starch nanofibers

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PT
Fig.6. Global statistical data on plant-based and animal-based materials used in nanofibers for

RI
drug delivery and tissue engineering [2]. Reprinted with permission from Ref. [2]. Copyright

SC
(2015) Royal Society of Chemistry.

During the past decade, there has been a notable expansion in the number of
NU
cost-effective natural materials in the field of nanotechnology, owing to the advent of
MA

electrospinning, and developments in the processing of natural polymers. Interest has

continuously been paid to animal-based natural materials, such as chitosan,

ED

hyaluronic acid, collagen, gelatin, and silk fibroin, for electrospun nanofibers and
T

pharmaceutical applications. In contrast, relatively little attention has been paid to

EP

plant-based materials (such as starch, cellulose, dextran, xylan, and soy protein) (Fig.

6). However, plant-based natural materials will be valuable for future research
C
AC

because of cost, availability, and commercial factors, as well as for cultural and

geo-political reasons [2].

The fabrication of nanofibers from starch materials is difficult owing to their

complex chemical structures, and wide range of molecular weights [6]. As

mentioned above, there has been limited research into starch-based electrospun

nanofibers. Nanofibers from pure starch materials usually lack mechanical strength,

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are water-sensitive, have low thermostability, and are difficult to process.

Furthermore, starch-based materials have poor melt extensibility, and have a high

incidence of defects when synthesized using conventional thermoplastic processing

techniques [57]. Non-starch components, including other polymers, plasticizers, and

cross- linkers, have been blended with starch materials to improve their spinnability

PT
and processability for electrospinning. However, the large amount of

RI
petroleum-based or synthetic polymers in these blends prevented the resulting fibers

SC
from expressing the properties of starch materials [62]. To date, these obstacles have

limited the development and utilization of starch-based fibers. Therefore, useful

NU
strategies to solve these drawbacks, and expand the applications of starch nanofibers
MA

need to be developed.

6. Strategies for pharmaceutical applications of electrospun starch nanofibers

ED

Electrospun starch nanofibers have shown great potential in drug delivery, wound
T

dressing, and tissue engineering, owing to their biodegradablility and

EP

biocompatibility. Critical future challenges for electrospun starch nanofibers may

C

include synthesis of modified starches, use of effective solvents, development of

AC

starch-based (alone or as the major component) hybrid blends, fabrication of

functionalized electrospun nanofibers, and fabrication of customized fibers and fiber

mats on demand. Strategies to meet these future challenges, enabling electrospun

starch nanofibers to be used in pharmaceutical applications, are summarized below.

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6.1 Starch modification and solvent selection

Starch-based electrospun nanofibers (made from starch alone, or from a blend where

starch is the major component) with improved mechanical strength and

water-stability can be successfully fabricated by modifying the starch, or by

selecting a suitable solvent. Starch modification techniques can be employed to

PT
enhance or inhibit the inherent properties of starch, or to endow it with specific

RI
properties to meet the requirements of certain applications [24, 25]. For example, the

SC
physicochemical properties of starch materials, like their stability against changes in
NU
temperature, shear and pH, solubility, retrogradation, and gel formation, can be

modified via different modification methods (Table 3). Cross- linking method can
MA

conquer the limitations towards native starches like low thermal, shear, pH resistance,

and can be used in industrial applications as viscosifiers and texturizers. Esterified

ED

starch can be applied in refrigerated and frozen products due to its lower tendency
T

towards retrogradation. Sufficient starch molecular entanglement and gel formation

EP

are prerequisites to starch fiber fabrication. Thus, cross-linked starch, esterified

C

starch and grafted starch maybe perform better in preparing electrospun starch
AC

nanofibers according to their physicochemical properties like improved viscosity,

permeability, water absorbency, gel formation, and so on.

Use of an effective solvent can cause the starch molecules to adopt a coil

conformation, which ensures there is sufficient molecular entanglement for

electrospinning. According to Kriegel’s theory, for a starch solution to be suitable for

electrospinning, it should have the following properties: a low surface tension that

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can be overcome by the electric field, a high enough charge density, and a suitable

viscosity for jet formation [34]. By combining starch modification with the use of an

effective solvent, these properties can be achieved and thus the difficulties in

electrospinning starch can be overcome. Investigation of starch modification

techniques, and identification of suitable solvents, for fabricating electrospun starch

PT
nanofibers are topics for future research.

RI
Table 3 Different starch modification techniques and the p roperties of the modified

SC
starches [99-102].

Modification Function of modification

NU
Physical Pregelatinization Cold water dispersibility + Viscosity +
Solubility - Swelling capacity -
Chemical Cross-linking Stability under high temperature, high shear and acidic
MA

conditions +
Stability against granule swelling +
Freeze–thaw stability + Granule stability +
Solubility - Enthalpy of gelatinization -
ED

Esterification Compatibility + Paste clarity + Moisture resistance +

Thermoplasticity +
Thermal stability - Biodegradation -
T

Retrogradation -
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Gelatinization temperature - Gels formation-

Etherification Clarity of starch paste + Viscosity + Solubility +
Thermal stability + Flowability +
C

Permeability + Strength +
AC

Syneresis - Freeze-thaw stability -

Oxidation Clarity, whiteness, and solubility +
Gelatinization temperature + Water absorbency +
Enthalpy values - Viscosity - Temperature stability -
Acidification Recovery + Solubility + Pasting viscosity +
Gelatinization enthalpy -
Grafting Biodegradability + Thermal stability +
Hydrodynamic radius and hydrodynamic volume +
Water absorbency + Film formation +
Enzymatic Hydrolysis Retrogradation + Setback value +
Molecular weight - Viscosity -

+: Positive correlation -: Negative correlation

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6.2 Functionalization of electrospun starch nanofibers

Increasing attention has been paid to the functionalization of electrospun nanofibers

via different approaches, like blend electrospinning, coaxial electrospinning,

emulsion electrospinning, synergistically combining nanofibers with nanocontainers,

and surface-functionalization of electrospun nanofibers (Fig. 7).

PT
RI
SC
NU
MA
T ED
C EP
AC

Fig.7. (I) Schematic illustration of blend electrospinning, coaxial electrospinning, and emulsion

electrospinning [103]. Reprinted with permission from Ref. [103]. Copyright (2013) Royal

Society of Chemistry. (II) Synergistic combination of nanocontainers and nanofibers [44].

Reprinted with permission from Ref. [44]. Copyright (2014) Elsevier. (III)

Surface-functionalization of electrospun nanofibers [90]. Reprinted with permission from Ref.

[90]. Copyright (2009) Elsevier.

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Nanofibers fabricated by electrospinning of polymer blends usually have

combined properties from each constitutional polymer [34]. For example, the

mechanical strength of electrospun starch nanofibers can be improved by

co-electrospinning the starch with small amounts of a synthetic polymer.

Synergistic combination of nanocontainers and nanofibers gives the advantages

PT
of both of these types of material. Carefully designed nanocontainers, like micelles,

RI
dendrimers, liposomes, nanoparticles, and nanocapsules, are firstly prepared, and

SC
then electrospun into the nanofibers. This nanocontainer- in-nanofiber structure can

offer double protection for the active agents inside the nanocontainers [44].
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Multidrug loading and the programmable release of each drug can also be achieved
MA

via this multi-electrospinning technique. The simultaneous use of multiple

medications is popular, and is important in tissue engineering and disease therapy.

ED

Surface- functionalized electrospun nanofibers can also achieve sustained delivery

T

through physical adsorption, and have great potential for drug release and tissue
EP

engineering applications [90].

Plasma treatment, wet chemical methods, surface graft polymerization, and

C
AC

co-electrospinning of surface active agents and polymers can be employed to modify

the surface of nanofibers. These advanced electrospinning techniques can

inter-helically or intra- helically complex drugs, nutrients, or bioactive compounds

within the starch nanofibers, which is useful for the development of novel drug

delivery, tissue engineering, and wound dressing systems. Thus, these techniques

have a promising future in the design of pharmaceutical formulations, and may

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expand the use of starch nanofibers in drug delivery, tissue engineering, and wound

dressing.

6.3 3D printing technologies for the fabrication of electrospun starch nanofibers

on demand

PT
RI
SC
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Fig.8. (Ⅰ) Schematic illustration of extrusion-based 3D printing [32]. Reprinted with
MA

permission from Ref. [32]. Copyright (2016) Elsevier. (Ⅱ) SEM micrographs of the 3D printed
ED

starch-based hierarchical fibrous scaffolds [73]. Reprinted with permission from Ref. [73].

Copyright (2009) Wiley.

T

Over the past 15 years, three dimensional (3D) printing technology, based on
EP

digitally controlled deposition of materials to create freedom geometries, has been

C

increasingly utilized for pharmaceutical applications such as drug delivery, disease

AC

modeling, and tissue engineering (Fig. 8Ⅰ) [104, 105]. 3D printing technology

shows amazing potential for the fabrication of electrospun nanofibers. Fibers

fabricated via or assisted by 3D printing technology can create dosage forms with

tailored release profiles of one or multiple drugs. They can permit the provision of

customized and personalized medicine on demand which meet the needs of

individual treatments of the future [106]. The synthesis of starch-based scaffolds via

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3D printing has already been attempted by researchers, and the resulting

starch-based scaffolds have been proposed as candidates for tissue engineering (Fig.

8Ⅱ) [73]. In the future, it may be possible to design advanced drug delivery systems

that can be synthesized using the capacity of 3D printing to create micro- or

nano-scale structures. 3D printing shows clear future potential for obtaining highly

PT
sophisticated formulations with controlled or targeted release. However, suitable

RI
carrier materials based on starch still require further study. Nevertheless, 3D printing

SC
is likely to be of benefit for the development of personalized medicine in the

pharmaceutical industry, primarily owing to its high dosage flexibility.

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7. Conclusions
MA

Electrospun nanofibers synthesized using natural materials have shown great

potential in pharmaceutical applications, including drug delivery, tissue engineering,

ED

and wound dressing, owing to their advantages, such as extremely high surface area
T

to volume ratio, high porosity, and biocompatible, biodegradable, and bioabsorbable

EP

properties. Starch and its derivatives have been widely used in the paper, textile,
C

plastic, food, and pharmaceutical industries because starch is a natural and renewable
AC

polymer that is abundant in nature, inexpensive, biodegradable, and biocompatible.

Although electrospinning is a promising technique, there are many difficulties in

using electrospinning to fabricate starch nanofibers because of the shortfalls of starch

materials, such as their weak mechanical strength, and water-sensitivity. Many

strategies have been employed in an attempt to fabricate starch fibers via

electrospinning, including the selection of an appropriate solvent (e.g. DMSO,

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formic acid, acetic acid, chloroform, ionic liquids), starch modification (e.g.

acetylated starch, oxidized starch, cationic starch, hydroxypropyl starch), and use of

hybrid systems that contain a mixture of starch and other polymers (e.g. PCL, PVA,

PEO). However, there are still limitations to be overcome for the electrospinning of

starch. Critical future challenges in developing electrospun starch nanofibers include

PT
the synthesis of modified starches, selection of a more effective solvent, and

RI
application of advanced electrospinning techniques. In this review, we summarized

SC
the recent developments in the synthesis of starch fibers via electrospinning, and

analyzed the challenges and current strategies for the fabrication and application of
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starch fibers in drug delivery, wound dressing, and tissue engineering. Electrospun
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starch nanofibers are expected to have great potential in the pharmaceutical industry,

and so the strategies highlighted in this review are likely to be hot topics for future
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research.
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Acknowledgements
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This research was financially supported by the National Natural Science

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Foundation of China (No. 31571794 and No. 31371787), the Key Program of the
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National Natural Science Foundation of China (No. 31230057), and the Six Talent

Peaks Project in Jiangsu Province (No.NY-128).

References

[1] D. Li, Y. Xia, Electrospinning of nanofibers: reinventing the wheel?, Adv Mater, 16 (2004)

1151-1170.

40
 ACCEPTED MANUSCRIPT

[2] R. Sridhar, R. Laksh minarayanan, K. Madhaiyan, V.A. Barathi, K.H.C. Limh , S. Ramakrishna,

Electrosprayed nanoparticles and electrospun nanofibers based on natural materials: applications in

tissue regeneration, drug delivery and pharmaceuticals, Chem Soc Rev, 44 (2015) 790-814.

[3] A. Ditta, How helpful is nanotechnology in agriculture?, Advances in Natural Sciences:

Nanoscience and Nanotechnology, 3 (2012) 033002.

PT
[4] V. Shan mugam, S. Selvaku mar, C.-S. Yeh, Near-in frared light-responsive nanomaterials in cancer

RI
therapeutics, Chem Soc Rev, 43 (2014) 6254-6287.

SC
[5] B.D. Gates, Q. Xu, M. Stewart, D. Ryan, C.G. Willson, G.M. Whitesides, New approaches to

nanofabrication: molding, printing, and other techniques, Chem Rev, 105 (2005) 1171-1196.
NU
[6] A. Rezaei, A. Nasirpour, M. Fathi, Application of Cellulosic Nanofibers in Food Science Using
MA

Electrospinning and Its Potential Risk, Co mprehensive Rev iews in Food Science and Food Safety, 14

(2015) 269-284.
ED

[7] F.Y. Ding, H.B. Deng, Y.M . Du, X.W. Shi, Q. Wang, Emerging ch itin and chitosan nanofibrous
T

materials for biomedical applications, Nanoscale, 6 (2014) 9477-9493.

EP

[8] Y. Zhang, C.T. Lim, S. Ramakrishna, Z.-M. Huang, Recent develop ment of poly mer nanofibers

for biomedical and biotechnological applications, JMSMM, 16 (2005) 933-946.

C
AC

[9] F. Sharifi, A.C. Sooriyarachchi, H. Altural, R. Montazami, M .N. Ry lander, N. Hashemi, Fiber

Based Approaches as Medicine Delivery Systems, Acs Bio materials Science & Eng ineering, 2 (2016)

1411-1431.

[10] H.F. Liu, X.L. Ding, G. Zhou, P. Li, X. Wei, Y.B. Fan, Electrospinning of Nanofibers for Tissue

Engineering Applications, Journal of Nanomaterials, (2013).

[11] T.J. Sill, H.A. von Recu m, Electro spinning: Applications in drug deliv ery and tissue engineering,

41
 ACCEPTED MANUSCRIPT

Biomaterials, 29 (2008) 1989-2006.

[12] D.H. Reneker, I. Chun, Nano metre diameter fibres of poly mer, produced by electrospinning,

Nanotechnology, 7 (1996) 216.

[13] A. Frenot, I.S. Chronakis, Poly mer nanofibers assembled by electrospinning, Curr Op in Co llo id

In, 8 (2003) 64-75.

PT
[14] Y. Lu, J.N. Huang, G.Q. Yu, R. Cardenas, S.Y. Wei, E.K. Wujcik, Z.H. Guo, Coaxial electrospun

RI
fibers: applications in drug delivery and tissue engineering, Wiley Interdisciplinary

SC
Reviews-Nanomedicine and Nanobiotechnology, 8 (2016) 654-677.

[15] K.Y. Lee, L. Jeong, Y.O. Kang, S.J. Lee, W.H. Park, Electrospinning of polysaccharides for
NU
regenerative medicine, Adv Drug Deliver Rev, 61 (2009) 1020-1032.
MA

[16] I. Silva, M. Gu rruchaga, I. Gon i, M. Fernandez-Gutierrez, B. Vazquez, J. San Ro man, Scaffolds

based on hydroxypropyl starch: Processing, morphology, characterization, and biological behavior, J

ED

Appl Polym Sci, 127 (2013) 1475-1484.

T

[17] S.A. Sell, M.P. Francis, K. Garg, M.J. McClure, D.G. Simpson, G.L. Bowlin, Cross-linking
EP

methods of electrospun fibrinogen scaffolds for tissue engineering applications, Bio med ical Materials,

3 (2008) 045001.
C
AC

[18] Y.-F. Qian, K.-H. Zhang, F. Chen, Q.-F. Ke, X.-M. Mo, Cross-linking of gelatin and chitosan

complex nanofibers for t issue-engineering scaffolds, J. Bio mater. Sci. Poly m. Ed., 22 (2011)

1099-1113.

[19] C. Yang, X. Wu, Y. Zhao, L. Xu, S. Wei, Nanofibrous scaffold prepared by electrospinning of

poly (vinyl alcohol)/gelatin aqueous solutions, J Appl Polym Sci, 121 (2011) 3047-3055.

[20] S. Doi, J.H. Clark, D.J. Macquarrie, K. Milkowski, New materials based on renewable resources:

42
 ACCEPTED MANUSCRIPT

chemically modified expanded corn starches as catalysts for liquid phase organic reactions, Chem

Commun, (2002) 2632-2633.

[21] E.M. Ochubiojo, A. Rodrigues, Starch: Fro m Food to Medicine, Scientific, Health and Social

Aspects of the Food Industry, (2012) 355-380.

[22] M.W. Meshram, V.V. Patil, S.T. Mhaske, B.N. Thorat, Graft copoly mers of starch and its

PT
application in textiles, Carbohyd Polym, 75 (2009) 71-78.

RI
[23] Y. Du, Y.-H. Zang, J. Du, Effects of Starch on Latex Migrat ion and on Paper Coating Properties,

SC
Ind Eng Chem Res, 50 (2011) 9781-9786.

[24] A.-M. Hermansson, K. Sveg mark, Developments in the understanding of starch functionality,
NU
Trends Food Sci Tech, 7 (1996) 345-353.
MA

[25] S. Wang, L. Copeland, Effect of acid hydrolysis on starch structure and functionality: A review,

Crit Rev Food Sci, 55 (2015) 1081-1097.

ED

[26] M. M iyazaki, P. Van Hung, T. Maeda, N. Morita, Recent advances in application of modified
T

starches for breadmaking, Trends Food Sci Tech, 17 (2006) 591-599.

EP

[27] E. da Rosa Zavareze, A.R.G. Dias, Impact of heat-moisture treatment and annealing in starches:

A review, Carbohyd Polym, 83 (2011) 317-328.

C
AC

[28] Y. Hong, G. Liu, Z. Gu, Recent advances of starch-based excipients used in extended-release

tablets: a review, Drug Deliv, 23 (2016) 12-20.

[29] G. Liu, Y. Hong, Z. Gu, Z. Li, L. Cheng, Pullulanase hydrolysis behaviors and hydrogel

properties of debranched starches from different sources, Food Hydrocolloid, 45 (2015) 351-360.

[30] G. Liu, Y. Hong, Z. Gu, Z. Li, L. Cheng, C. Li, Preparat ion and characterizat ion of pullu lanase

debranched starches and their properties for drug controlled -release, RSC Advances, 5 (2015)

43
 ACCEPTED MANUSCRIPT

97066-97075.

[31] L.D. Sanchez, N. Brack, A. Postma, P.J. Pigram, L. Meagher, Surface modificat ion of

electrospun fibres for bio med ical applicat ions: A focus on radical poly merization methods,

Biomaterials, 106 (2016) 24-45.

[32] S. Qi, D. Craig, Recent developments in micro -and nanofabrication techniques for the

PT
preparation of amorphous pharmaceutical dosage forms, Adv Drug Deliver Rev, 100 (2016) 67-84.

RI
[33] A. Balaji, M.V. Vellayappan, A.A. John, A.P. Subraman ian, S.K. Jaganathan, E. Supriyanto, S.I.A.

SC
Razak, An insight on electrospun-nanofibers-inspired modern drug delivery system in the treat ment of

deadly cancers, Rsc Advances, 5 (2015) 57984-58004.

NU
[34] C. Kriegel, A. Arrechi, K. Kit, D.J. McClements, J. Weiss, Fabrication, functionalization, and
MA

application of electrospun biopolymer nanofibers, Crit Rev Food Sci, 48 (2008) 775-797.

[35] X.L. Hu, S. Liu, G.Y. Zhou, Y.B. Huang, Z.G. Xie, X.B. Jing, Electrospinning of polymeric
ED

nanofibers for drug delivery applications, J Control Release, 185 (2014) 12-21.
T

[36] G. Tay lor, Electrically driven jets, Proceedings of the Royal Society of London A:
EP

Mathematical, Physical and Engineering Sciences, The Royal Society, 1969, pp. 453-475.

[37] Y.J. Lee, D.S. Shin, O.W. Kwon, W.H. Park, H.G. Choi, Y.R. Lee, S.S. Han, S .K. Noh, W.S.
C
AC

Lyoo, Preparat ion of atactic poly (v inyl alcohol)/sodium alginate blend nanowebs by electrospinning,

J Appl Polym Sci, 106 (2007) 1337-1342.

[38] C.S. Ki, D.H. Baek, K.D. Gang, K.H. Lee, I.C. Um, Y.H. Park, Characterizat ion of gelatin

nanofiber prepared from gelatin–formic acid solution, Polymer, 46 (2005) 5094-5102.

[39] H. Jiang, P. Zhao, K. Zhu, Fabricat ion and characterizat ion of zein ‐based nanofibrous scaffolds

by an electrospinning method, Macromol Biosci, 7 (2007) 517-525.

44
 ACCEPTED MANUSCRIPT

[40] C. Yao, X. Li, T. Song, Electrospinning and crosslinking of zein nanofiber mats, J Appl Poly m

Sci, 103 (2007) 380-385.

[41] S. Zhao, X. Wu, L. Wang, Y. Huang, Electrospinning of ethyl–cyanoethyl

cellulose/tetrahydrofuran solutions, J Appl Polym Sci, 91 (2004) 242-246.

[42] S. Megelski, J.S. Stephens, D.B. Chase, J.F. Rabolt, Micro -and nanostructured surface

PT
morphology on electrospun polymer fibers, Macromolecules, 35 (2002) 8456-8466.

RI
[43] W. Zuo, M. Zhu, W. Yang, H. Yu, Y. Chen, Y. Zhang, Experimental study on relationship between

SC
jet instability and format ion of beaded fibers during electrospinning, Poly mer Engineering & Science,

45 (2005) 704-709.
NU
[44] S. Jiang, L.P. Lv, K. Landfester, D. Crespy, Nanocontainers in and onto Nanofibers, Accounts
MA

Chem Res, 49 (2016) 816-823.

[45] X. Zong, K. Kim, D. Fang, S. Ran, B.S. Hsiao, B. Chu, Structure and process relationship of
ED

electrospun bioabsorbable nanofiber membranes, Polymer, 43 (2002) 4403-4412.

T

[46] C. Zhang, X. Yuan, L. Wu, Y. Han, J. Sheng, Study on morphology of electrospun poly (vinyl
EP

alcohol) mats, Eur Polym J, 41 (2005) 423-432.

[47] W.K. Son, J.H. Youk, W.H. Park, Preparat ion of ult rafine o xidized cellulose mats via
C
AC

electrospinning, Biomacromolecules, 5 (2004) 197-201.

[48] W.K. Son, J.H. Youk, T.S. Lee, W.H. Park, Preparation of antimicrobial ultrafine cellu lose acetate

fibers with silver nanoparticles, Macromol Rapid Comm, 25 (2004) 1632-1637.

[49] V. Pillay, C. Dott, Y.E. Choonara, C. Tyagi, L. To mar, P. Ku mar, L.C. du To it, V.M . Ndesendo, A

review of the effect of p rocessing variables on the fabricat ion of electrospun nanofibers for drug

delivery applications, Journal of Nanomaterials, 2013 (2013).

45
 ACCEPTED MANUSCRIPT

[50] C.L. Casper, J.S. Stephens, N.G. Tassi, D.B. Chase, J.F. Rabolt, Controlling surface mo rphology

of electrospun polystyrene fibers: effect of humidity and molecular weight in the electrospinning

process, Macromolecules, 37 (2004) 573-578.

[51] C. M it‐uppatham, M. Nithitanakul, P. Supaphol, Ultrafine electrospun polyamide ‐6 fibers:

effect of solution conditions on morphology and average fiber diameter, Macro mol Chem Phys, 205

PT
(2004) 2327-2338.

RI
[52] L. Kong, G. R Ziegler, Patents on fiber spinning fro m starches, Recent patents on food, nutrition

SC
& agriculture, 4 (2012) 210-219.

[53] L.Y. Kong, G.R. Zieg ler, Formation of starch-guest inclusion complexes in electrospun starch
NU
fibers, Food Hydrocolloid, 38 (2014) 211-219.
MA

[54] A.C. Mendes, K. Stephansen, I.S. Ch ronakis, Electrospinning of food proteins and

polysaccharides, Food Hydrocolloid, (2016).

ED

[55] L.Y. Kong, G.R. Zieg ler, Fabrication of pure starch fibers by electrospinning, Food Hydrocollo id,
T

36 (2014) 20-25.
EP

[56] J. Muetgeert, P. Hiemstra, Process for the production of amylose articles by extrusion of aqueous

sodium hydroxide solution thereof into concentrated aqueous ammoniu m sulphate solution, US Patent,
C
AC

2,902,336, 1959.

[57] V.A. Bailey, L.N. Mackey, P.D. Trokhan, Starch fiber, US Patent, 7,704,328, 2010.

[58] L.Y. Kong, G.R. Ziegler, Role of Molecu lar Entanglements in Starch Fiber Format ion by

Electrospinning, Biomacromolecules, 13 (2012) 2247-2253.

[59] L.Y. Kong, G.R. Zieg ler, Quantitative relationship between electrospinning parameters and

starch fiber diameter, Carbohyd Polym, 92 (2013) 1416-1422.

46
 ACCEPTED MANUSCRIPT

[60] L. Kong, G.R. Ziegler, Methods and compositions relating to starch fibers, Google Patents, 2013.

[61] A. Lancuski, G. Vasilyev, J.L. Putaux, E. Zussman, Rheological Propert ies and

Electrospinnability of High-A my lose Starch in Formic Acid, Bio macro molecules, 16 (2015)

2529-2536.

[62] X.L. Li, H.H. Chen, B. Yang, Centrifugally spun starch-based fibers fro m amylopectin rich

PT
starches, Carbohyd Polym, 137 (2016) 459-465.

RI
[63] W.Y. Wang, X. Jin, Y.G. Zhu, C.Z. Zhu, J. Yang, H.J. Wang, T. Lin, Effect o f vapor-phase

SC
glutaraldehyde crosslinking on electrospun starch fibers, Carbohyd Polym, 140 (2016) 356-361.

[64] P. Jaiturong, K. Sut jarittangtham, S. Eitsayeam, J. Sirithunyalug, Preparat ion of Glutinous Rice
NU
Starch Nanofibers by Electrospinning, in: T. Tunkasiri (Ed.) Bio materials and Applications , 2012, pp.
MA

230-233.

[65] Q.P. Zhou, J. Wu, J. Zhang, J.S. He, Z.J. Sun, Z.G. Zhang, Ho mogeneous synthesis of
ED

high-amy lose starch acetates and their ultrafine fibers prepared by electrospinning, Acta Poly m Sin,
T

(2007) 685-688.
EP

[66] W. Xu, W. Yang, Y. Yang, Electrospun Starch Acetate Nanofibers: Develop ment, Properties, and

Potential Application in Drug Delivery, Biotechnol Progr, 25 (2009) 1788-1795.

C
AC

[67] J. Yang, X. Jin, W.Y. Wang, Y.H. Zhu, Synthesis of Starch Acetates and Electrospinning, in: L. Yu,

W.P. Guo, M. Sun, J. He (Eds.) Current Trends in the Development of Industry, Pts 1 and 22013, pp.

1031-1035.

[68] B. Oktay, E. Basturk, N. Kayaman-Apohan, M.V. Kahraman, Highly porous

starch/poly(ethylene-alt-maleic anhydride) composite nanofiber mesh, Polym Co mposite, 34 (2013)

1321-1324.

47
 ACCEPTED MANUSCRIPT

[69] H.J. Wang, X. Jin, W.Y. Wang, C.F. Xiao, L. Tong, Preparation and Electrospinning of

Acidified-Oxid ized Potato Starch, in: C.X. Cui, Y.L. Li, Z.H. Yuan (Eds.) Advanced Engineering

Materials Ii, Pts 1-32012, pp. 2340-2344.

[70] B. Vo lkert, A. Leh mann, T. Greco, M.H. Nejad, A co mparison of different synthesis routes for

starch acetates and the resulting mechanical properties, Carbohyd Polym, 79 (2010) 571-577.

PT
[71] A. Lancuski, A. Abu Ammar, R. Avrahami, R. Vilensky, G. Vasilyev, E. Zussman, Design of

RI
starch-formate co mpound fibers as encapsulation platform fo r biotherapeutics, Carbohyd Polym, 158

SC
(2017) 68-76.

[72] H. Juko la, L. Nikko la, M.E. Go mes, R.L. Reis, N. Ashammakhi, Electrospun
NU
starch-polyeaprolactone nanofiber-based constructs for tissue engineering, in: G.H. Pau lino, M.J.
MA

Pindera, R.H. Dodds, F.A. Rochinha, E.V. Dave, L. Chen (Eds.) Multiscale and Functionally Graded

Materials, 2008, pp. 971-974.

ED

[73] A. Mart ins, S. Chung, A.J. Pedro, R.A. Sousa, A.P. Marques, R.L. Reis , N.M . Neves,
T

Hierarchical starch-based fibrous scaffold for bone tissue engineering applications, Journal of Tissue
EP

Engineering and Regenerative Medicine, 3 (2009) 37-42.

[74] K. Tu zlakoglu, N. Bolgen, A.J. Salgado, M.E. Go mes, E. Piskin, R.L. Reis, Nano - and
C
AC

micro -fiber co mb ined scaffolds: A new architecture for bone tissue engineering, J Mater Sci-mater M,

16 (2005) 1099-1104.

[75] K. Tuzlakoglu, I. Pashkuleva, M.T. Rodrigues, M.E. Go mes, G. Van Lenthe, R. Müller, R. Reis,

A new route to produce starch‐based fiber mesh scaffolds by wet spinning and subsequent surface

modification as a way to improve cell attachment and proliferat ion, Journal of Bio medical Materials

Research Part A, 92 (2010) 369-377.

48
 ACCEPTED MANUSCRIPT

[76] J. Su kyte, E. Adomav iciute, R. M ilasius, Investigation of the Possibility of Fo rming Nanofibres

with Potato Starch, Fibres Text East Eur, 18 (2010) 24-27.

[77] Z. Liu, J.H. He, POLYVINYL A LCOHOL/STA RCH COMPOSITE NA NOFIBERS BY

BUBBLE ELECTROSPINNING, Thermal Science, 18 (2014) 1473-1475.

[78] H.L. Wang, W.J. Wang, S.W. Jiang, S.T. Jiang, L.F. Zhai, Q. Jiang, Po ly(vinyl alcohol)/Oxid ized

PT
Starch Fibres via Electrospinning Technique: Fabrication and Characterization, Iran Po ly m J, 20

RI
(2011) 551-558.

SC
[79] J. Sukyte, E. Adomav iciute, R. Milasius, J. Bendorait ien e, P.P. Danilovas, Formation of

Poly(Vinyl A lcohol)/Cat ionic Starch Blend Nanofibres via the Electrospinning Technique: The
NU
Influence of Different Factors, Fibres Text East Eur, 20 (2012) 16-20.
MA

[80] E. Ado maviciute, R. M ilasius, A. Zemaitaitis, J. Bendoraitiene, M . Leskovsek, A. Demsar,

Methods of Forming Nanofibres fro m Bico mponent PVA/Cat ionic Starch Solution, Fibres Text East
ED

Eur, 17 (2009) 29-33.

T

[81] H.B. Zhang, M. Zhu, R.Q. You, Modified b iopolymer scaffolds by co -axial electrospinning, in:
EP

G.J. Zhang, J. Xu (Eds.) Materials Science and Engineering Applicat ions, Pts 1-32011, pp.

1062-1066.
C
AC

[82] J. Sunthornvarabhas, P. Chatakanonda, K. Piyachomkwan, K. Sriroth, Electrospun polylactic

acid and cassava starch fiber by conjugated solvent technique, Mater Lett, 65 (2011) 985-987.

[83] R. Hodge, G.H. Ed ward, G.P. Simon, Water absorption and states of water in semicrystalline

poly (vinyl alcohol) films, Polymer, 37 (1996) 1371-1376.

[84] M. Kru mova, D. Lopez, R. Benavente, C. M ijangos, J. Perena, Effect of crosslinking on the

mechanical and thermal properties of poly (vinyl alcohol), Polymer, 41 (2000) 9265-9272.

49
 ACCEPTED MANUSCRIPT

[85] J.A. Creek, G.R. Zieg ler, J. Runt, A my lose crystallization fro m concentrated aqueous solution,

Biomacromolecules, 7 (2006) 761-770.

[86] E. Fathi, N. Atyabi, M . Imani, Z. Alinejad, Physically crosslinked polyvinyl alcohol–dextran

blend xerogels: morphology and thermal behavior, Carbohyd Polym, 84 (2011) 145-152.

[87] S.S. Tang, Z.L. Zhao, G. Chen, Y.J. Su, L.T. Lu, B. Li, D.D. Liang, R.F. Jin, Fab ricat ion of

PT
amp icillin/starch/polymer co mposite nanofibers with controlled drug release properties by

RI
electrospinning, J Sol-gel Sci Techn, 77 (2016) 594-603.

SC
[88] M. Fathi, A. Mart in, D.J. McClements, Nanoencapsulation of food ingredients using

carbohydrate based delivery systems, Trends Food Sci Tech, 39 (2014) 18-39.
NU
[89] D. Kai, W. Ren, L. Tian, P.L. Chee, Y. Liu, S. Ramakrishna, X.J. Loh, Engineering
MA

Poly(lactide)-Lignin Nanofibers with Antio xidant Activity for Bio medical Applicat ion, Acs

Sustainable Chemistry & Engineering, 4 (2016) 5268-5276.

ED

[90] H.S. Yoo, T.G. Kim, T.G. Park, Surface-functionalized electrospun nanofibers for tissue
T

engineering and drug delivery, Adv Drug Deliver Rev, 61 (2009) 1033-1042.
EP

[91] E.-R. Kenawy, G.L. Bowlin, K. Mansfield, J. Lay man, D.G. Simpson, E.H. Sanders, G.E. Wnek,

Release of tetracycline hydrochloride fro m electrospun poly(ethylene -co-vinylacetate), poly(lactic

C
AC

acid), and a blend, J Control Release, 81 (2002) 57-64.

[92] P. Zhao, H. Jiang, H. Pan, K. Zhu, W. Chen, Biodegradable fibrous scaffolds composed of gelatin

coated poly(ϵ-caprolactone) prepared by coaxial electrospinning, Journal of Bio medical Materials

Research Part A, 83A (2007) 372-382.

[93] A.N. Zelikin, C. Eh rhardt, A.M. Healy, Materials and methods for delivery of biolog ical drugs,

Nature Chemistry, 8 (2016) 997-1007.

50
 ACCEPTED MANUSCRIPT

[94] S. Van Vlierberghe, P. Dubruel, E. Schacht, Biopoly mer-Based Hydrogels As Scaffolds for

Tissue Engineering Applications: A Review, Biomacromolecules, 12 (2011) 1387-1408.

[95] M .E. Go mes, J. God inho, D. Tchalamov, A. Cunha, R. Reis, Alternative tissue engineering

scaffolds based on starch: processing methodologies, morphology, degradation and mechanical

properties, Materials Science and Engineering: C, 20 (2002) 19-26.

PT
[96] N. Monteiro, M. Martins, A. Martins, N.A. Fonseca, J.N. Moreira, R.L. Reis, N.M . Neves,

RI
Antibacterial activ ity of chitosan nanofiber meshes with liposomes immob ilized releasing gentamicin,

SC
Acta Biomater., 18 (2015) 196-205.

[97] M. Sadri, S. Arab -Sorkhi, H. Vatani, A. Bagheri-Pebdeni, New wound dressing polymeric
NU
nanofiber containing green tea extract prepared by electrospinning method, Fibers and Poly mers, 16
MA

(2015) 1742-1750.

[98] H.-J. Lai, C.-H. Kuan, H.-C. Wu, J.-C. Tsai, T.-M. Chen, D.-J. Hsieh, T.-W. Wang, Ta ilored
ED

design of electrospun composite nanofibers with staged release of mu ltip le angiogenic growth factors
T

for chronic wound healing, Acta Biomater., 10 (2014) 4156-4166.

EP

[99] S.C. A lcazar-Alay, M.A.A. Meireles, Physicochemical properties, mod ifications and applications

of starches from different botanical sources, Food Science and Technology, 35 (2015) 215-236.
C
AC

[100] Q. Chen, H.J. Yu, L. Wang, Z. ul Abdin, Y.S. Chen, J.H. Wang, W.D. Zhou, X.P. Yang, R.U.

Khan, H.T. Zhang, X. Chen, Recent progress in chemical mod ification of starch and its applications,

Rsc Advances, 5 (2015) 67459-67474.

[101] F.F. Dias, Starch: Perspectives and opportunities, J Sci Ind Res India, 58 (1999) 403-413.

[102] J. Singh, L. Kau r, O.J. McCarthy, Factors influencing the physico -chemical, mo rphological,

thermal and rheological propert ies of some chemically modified starches for food applications - A

51
 ACCEPTED MANUSCRIPT

review, Food Hydrocolloid, 21 (2007) 1-22.

[103] K.A. Rieger, N.P. Birch, J.D. Sch iffman, Designing electrospun nanofiber mats to promo te

wound healing - a review, Journal of Materials Chemistry B, 1 (2013) 4531-4541.

[104] A. Shafiee, A. Atala, Printing Technologies for Medical Applicat ions, Trends Mol Med, 22

(2016) 254-265.

PT
[105] G. Jonathan, A. Karim, 3D printing in pharmaceutics: A n ew tool for designing customized drug

RI
delivery systems, Int J Pharm, 499 (2016) 376-394.

SC
[106] N. Sandler, M. Preis, Printed Drug-Delivery Systems for Improved Pat ient Treat ment, Trends

Pharmacol Sci, 37 (2016) 1070-1080.

NU
MA
T ED
C EP
AC

52
 ACCEPTED MANUSCRIPT

PT
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Graphical abstract
NU
Electrospun starch nanofibers have an extremely high surface area to volume ratio, high

porosity, and biocompatible, biodegradable, and bioabsorbable properties. As a result, starch

MA

nanofibers have great potential in pharmaceutical applications, including drug delivery, tissue

engineering, and wound dressing.

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