Varma (2019) - Plants and Plant-Based Polymers As Scaffolds For Tissue Engineering

Green Chemistry
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Plants and plant-based polymers as scaffolds for

Cite this: Green Chem., 2019, 21,
tissue engineering
4839
Siavash Iravani *a and Rajender S. Varma *b
Diverse scaffold materials created from a variety of biomaterials via a plethora of production methods
have been applied to redevelop varied tissues and body organs. Irrespective of the tissue type, a number
of factors such as biodegradability, biocompatibility, mechanical properties, scaffold architecture and
manufacturing technology are important when designing or determining the suitability of a scaffold for
usage in tissue engineering. The plant-based natural polymers, being derived from green and sustainable
sources, meet the requirements for such novel biomaterials with desirable properties for tissue engineer-
ing that require minimal chemical processing for industrial applications. The significant advantage of plant
scaffolds is the apparent ease with which they can be made and manipulated; they are quite pliable and
Received 12th July 2019, can be easily cut, fashioned, rolled or stacked to form a range of different sizes and shapes. They are also
Accepted 27th August 2019
renewable, easy to mass produce and are relatively inexpensive. This review describes the use of plants
DOI: 10.1039/c9gc02391g and plant-based polymers and highlights the collective roles of such biomaterials in the assembly of
rsc.li/greenchem greener and natural-based scaffolds for tissue engineering.
1. Introduction allograft or xenograft extracellular matrix, placing laminated cell

sheets with secreted extracellular matrix and injecting cell encap-
The burgeoning field of tissue engineering is extremely inter- sulated self-assembled hydrogels.5,6 Additionally, approaches of
disciplinary that connects experts from diverse fields of self-assembly including Langmuir–Blodgett approach for mono-
materials science, mechanical engineering, clinical medicine, layer preparation and electrospinning have been applied for
genetics, and related disciplines from both, engineering and bone and vascular tissue scaffold assembly.7,8
the biosciences. The domain depends heavily on the use of Typically, assorted groups of biomaterials, namely cer-
porous three-dimensional (3D) scaffolds to provide a suitable amics, synthetic polymers and natural biopolymers are applied
environment for the generation of tissues and organs. The for tissue engineering scaffolds preparation (Fig. 2). Natural
important steps of cell culture for tissue engineering fre- biopolymers such as animal- or plant-derived proteins or
quently include the use of living cells to repair or regrow tissue carbohydrates can play a central role in shaping cell behavior,
or an organ damaged by disease, or trauma (Fig. 1).1,2 Various mainly in regard to chemical signals and biocompatibility.3,9
scaffolds made from different materials using various pro- However, their efficiency is restrained by poor mechanical pro-
duction methods have been applied in the field to redevelop perties and rapid biodegradability. Nevertheless, these disad-
varied tissues and organs in the body. Irrespective of the tissue vantages can be circumvented by a post-spinning crosslinking
type, a number of factors such as biocompatibility, biodegrad- procedure with appropriate cross linkers, or by blending
ability, mechanical properties, scaffold architecture and manu- natural polymers with biocompatible synthetic polymers, poss-
facturing technology are vital when designing or determining ibly developing an ideal scaffold for tissue engineering appli-
the appropriateness of a scaffold for use in tissue engineering.3,4 cations. Plants and plant based-polymers comprise plant pro-
Scaffolds in engineered tissues are to mimic the extracellular teins (such as, soya protein, gluten, camelina protein and
matrix in native tissues, at least partially. Some important zein), plant polysaccharides (such as, cellulose, starch and
approaches for scaffolding process are: implanting cell-seeded pectin), lignin and constituents from plant extracts which are
pre-made porous scaffolds, imbedding cell-seeded decellularized routinely explored for sundry biomedical applications.10–18
This review describes the use of plants and plant-based
polymers and highlights the collective roles of such biomater-
a
Faculty of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical ials in the assembly of greener and natural-based scaffolds for
Sciences, Isfahan, Iran. E-mail: siavashira@gmail.com
b tissue engineering. Additionally, important issues for scaffolds
Regional Centre of Advanced Technologies and Materials, Department of Physical
Chemistry, Faculty of Science, Palacký University in Olomouc, Šlechtitelů 27, 783 71 production, and relevance of tissue engineering to green
Olomouc, Czech Republic. E-mail: Varma.Rajender@epa.gov chemistry are discussed.
This journal is © The Royal Society of Chemistry 2019 Green Chem., 2019, 21, 4839–4867 | 4839
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Critical Review Green Chemistry
2. Important issues for producing surgical procedures for harvesting the cells prior to a number
of weeks of in vitro culture before implantation. This is not
scaffolds achievable for some types of tissues though and in vitro engin-
eering prior to implantation is thus essential.5,6,22
Indeed, some very important challenges and issues should be (ii) Biodegradability and biocompatibility: These properties
addressed and evaluated in the production of scaffolds for tissue are critical as cells need to hold, perform typically, and move
engineering, which are summarized below (in Fig. 3 and 4): around to the surface and finally across the scaffold and start
(i) Scaffolding methods, tissue types and applications: For to propagate before putting down fresh matrix.
scaffold preparation, some important issues need to be Cytocompatibility testing and in vivo formulation evaluation as
addressed, especially, for the range of existing pore sizes that well as bioactivity and biocompatibility analyses should be per-
hinge on the applied cell type and engineered tissue. The formed. After grafting, the scaffold or engineered tissue con-
selection of scaffolding methods is specifically related to struct might cause an insignificant immune reaction for pre-
tissue and associated applications and should be noticed by venting the production of severe inflammatory response which
researchers for producing scaffolds.19–21 For producing tissue could decrease the healing or cause body rejection.
engineered constructs and scaffolds which can be applied Additionally, biodegradability is critical in scaffolds construc-
clinically and commercially, cost effectiveness is another tion, as the purpose of tissue engineering is to permit the
major issue; it should be possible to scale-up from research body’s own cells, to conclusively substitute the planted
laboratory to small batch production. Thus, the development scaffold or engineered tissue construct. Scaffolds for tissue
of scalable manufacturing processes to good manufacturing engineering can be prepared from natural sources (such as,
practice (GMP) standard is significantly crucial in ensuring alginate (natural polysaccharide derived from seaweed), silk,
successful translation of tissue engineering approaches to the and chitosan (natural polysaccharide isolated from chitin) and
clinic. Additionally, determination of how a product will be normally have high biocompatibility. Accordingly, scaffolds
delivered and made accessible for clinicians is another impor- were not designed as permanent implants, and should be bio-
tant concern. This will control how scaffolds and tissue engin- degradable for permitting the cells to produce their own extra-
eered constructs will be stored; clinicians generally desire to cellular matrix. Importantly, the by-products of this degra-
have off-the shelf availability without requisite of additional dation should also be non-hazardous and non-toxic, and be
Dr Iravani has worked on several Prof. Varma (H-Index 107;

academic research projects at the Highly Cited Researchers
Isfahan University of Medical 2016–18; Publons Awardee
Sciences (Faculty of Pharmacy 2018) was born in India (Ph.D.,
and Pharmaceutical Sciences), Delhi University 1976). After
including green and eco-friendly postdoctoral research at Robert
synthesis of nanomaterials, Robinson Laboratories,
plant-derived nanostructures, Liverpool, U.K., he was faculty
phytochemical analysis, gra- member at Baylor College of
phene-based nanocomposites, Medicine and Sam Houston
water treatment technologies, State University prior to joining
nanoparticles for drug delivery the Sustainable Technology
Siavash Iravani in cancer, nanocarriers, and Rajender S. Varma Division at the US
drug nanoparticles. His previous Environmental Protection Agency
experience, of more than seven years, centers on drug development in 1999. He has a visiting scientist’s position at Regional Centre of
and industrial pharmacy in various capacities including research Advanced Technologies and Materials, Palacky University at
and development, formulation, and quality control. Dr Iravani has Olomouc, Czech Republic. He has over 45 years of research experi-
authored over 50 peer-reviewed scientific publications including ence in management of multidisciplinary technical programs
twelve book chapters and one book. ranging from natural products chemistry to development of more
environmentally friendly synthetic methods using microwaves,
ultrasound, etc. Lately, he is focused on greener approaches to
assembly of nanomaterials and sustainable applications of magne-
tically retrievable nanocatalysts in benign media. He is a member
of the editorial advisory board of several international journals,
has published over 535 papers, and has been awarded 16 US
Patents, 6 books, 26 book chapters and 3 encyclopedia contri-
butions with 37 800 citations.
4840 | Green Chem., 2019, 21, 4839–4867 This journal is © The Royal Society of Chemistry 2019
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Green Chemistry Critical Review

Fig. 1 Cell culture steps for tissue engineering.
Fig. 2 Some key biomaterials for scaffolding. PEG: polyethylene glycol; PGA: polyglycolic acid; PLGA: poly lactic-co-glycolic acid; PDLLA: poly (DL-
lactic acid); PCL: polycaprolactone.
able to leave the body without intervention from the other connected porosity, preexisting vascular networks, and suit-
organs.19–21 The autologous, synthetic, and animal-derived able mechanical characteristics. Plant scaffolds, as renewable
grafts currently used as scaffolds for tissue replacement have and inexpensive materials, can be easily mass produced and
limitations because of their scarcity, poor biocompatibility, manipulated. But, these scaffolds should be tested in animal
and expensive nature. Plant tissues and plant-based materials models, and more elaborative studies in this field are needed.
have favorable properties which render them exclusively suit- Although it has been mentioned that toxicity issues are un-
able for applying as scaffolds, such as inexpensiveness, high likely, but potential for immune responses may still exist when
surface area, significant water transport and retention, inter- the plant scaffolds are affixed into a mammal; substantial
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Fig. 3 Important scaffolding approaches, and associated major issues.
Fig. 4 Critical parameters to be addressed for development of tissue scaffolds.
immune responses are less as the plant cells are eliminated is critical for producing valuable scaffolds. In addition, aca-
from the scaffolds.3,23 demic investigations are conducted to utilize the mechanosen-
(iii) Mechanical property: Scaffolds need to have mechani- sitive capacity of cells to develop scaffolds and biomaterials
cal properties according to the anatomical site into which it is with specific mechanical characteristics which can be used to
being implanted, and during the grafting, it should be direct the behavior of the cells with which they interact.24
sufficiently strong for surgical handling. One of the main chal- (iv) Architecture: Scaffold architecture is critical for tissue
lenges is for cardiovascular and orthopedic applications, as engineering. The prepared scaffolds ideally should consist of
the implanted scaffold for theses tissues may have enough an interconnected pore structure and high porosity to guaran-
mechanical integrity to perform from the implantation time to tee the cellular penetration and adequate dispersal of nutri-
the remodeling process completion. Furthermore, healing ents to cells within the construct and to the extracellular
rates differ with age; in young patients, fractures normally heal matrix prepared by these cells. Importantly, a porous intercon-
to the point of weight-bearing in about six weeks, with com- nected structure is needed to permit diffusion of waste pro-
plete mechanical integrity not returning until about one year ducts out of the scaffold, and the by-products might be able to
after fracture, but in the elderly the rate of overhaul decelerates leave the body without restriction from surrounding tissues
down. It is vital especially for organizing scaffolds for orthope- and the other organs. Additionally, it is essential that the
dic applications. Indeed, an appropriate balance among pores be sufficiently large to permit the cells for migration
mechanical characteristics and porous architecture adequate into the structure, where they finally become bound to the
to permit the infiltration of the cells and their vascularization ligands within the scaffold, but sufficiently small in order to
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establish the exact surface (show high specificity), leading to a ensuing 3D scaffolds were several orders of magnitude cheaper
minimal ligand density that permits appropriate binding of than commercial ones and the methodology applied for their
significant number of cells to the scaffolds.25 optimization is simple and eco-friendly.26
(v) Clinical status evaluations: Clinical evaluations of Indeed, synthetic methods for tissue regeneration must be
scaffolds are essential for validating the efficacy. Moreover, supplemented by generation and deployment of scaffolds that
micro-CT imaging is needed, and histological analysis should contain none or has minimal toxic effect in human body cells
be performed to evaluate the repair of organ defects with and life (Fig. 5).27,28 Various materials (natural or synthetic,
scaffolds. However, these findings are limited because of small biodegradable or non-biodegradable) have been investigated,
sample sizes, lack of a randomized control groups for compari- but importantly, it appears that some biodegradable scaffolds
son, and the inaccessibility of long-term studies and analyses. in cardiovascular tissue engineering show toxic degradation
In view of the limited sample size and smaller follow-up and inflammatory reactions and are potentially immunogenic,
period, researchers may miss rare adverse events or effects. thus researchers try to find materials of very low toxicity for
Additionally, long-term analysis can be achieved in a broader tissue engineering scaffolds.29
population that may generate important details if early risks Various techniques have been applied for producing
associated with the intervention can be offset by future scaffolds instead using real organ (Fig. 6) and nanofabrication
benefits.2 approaches summarized in Fig. 7 3,4 with some of their advan-
tages and drawbacks. The important challenges for imple-
menting these methods are to propagate safe industrial and
3. Green chemistry and tissue medical products and strategically eliminating or decreasing
engineering pollutants and toxic materials by appliance of agro-based
material for research and experimentation. Furthermore, bio-
Tissue engineering combines the principles of bioactive mole- materials have edge over other methods, as they can be pre-
cules, scaffolds, engineering, and material fabrication to con- pared in large amount with same physical, chemical, and
struct, reform, or treat damaged tissues or organs. Green structural characteristics for various tissue types. Polymer-
chemistry is the use of safe and clean materials and methods based biomaterials such as polysaccharides and proteins with
to reduce the toxic and harmful results of scientific research. different applications in tissue regeneration have been pre-
Thus, it uses safe ingredients, less energy and decreases the pared from both natural and synthetic materials. For instance,
generation of waste materials in various experimental and biocompatible and biodegradable polysaccharides with diverse
industrial synthetic approaches. The crucial purpose of chemical functions are promising materials in tissue engineer-
greener methods and technologies is to reduce the adverse ing during cellular functioning and differentiation.
effects of pollutants on the environment or humans. Apart Additionally, plant-based protein biomaterials can be applied
from the positive effects of ecofriendly options, there are some in various restoration or improvement scaffolds.27,28,30,31 The
shortcomings, such as higher costs, lack of complete infor- significant advantage of the plant-based scaffolds is the appar-
mation about applied chemical, raw materials, and techno- ent ease with which they can be assembled and manipulated;
logies. Several investigations have been directed toward the they are renewable, easy to mass produce, and are relatively in-
development of green chemistry approaches with a focus on expensive and therefore should be examined in animal
biocatalysis and bio-based materials. Researchers have investi- models. Additionally, plant-based scaffolds show favorable
gated renewable and sustainable materials that can be applied tissue compatibility, and the products of the scaffold degra-
for producing scaffolds for tissue engineering. Interestingly, dation do not injure the surrounding tissues (such as in the
the waste material from the beverage manufacturing industry case of zein). Although toxicity is unlikely an issue but there is
has been valorized as a renewable source for producing bioma- potential for immune responses if these plant scaffolds are
terials capable of performing as tissue engineering scaffolds; implanted into a mammal. Regardless of important develop-
Fig. 5 Green chemistry and tissue engineering: important issues.
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Fig. 6 Some important methods for fabricating scaffolds.
Fig. 7 Nanofabrication methods applied for producing scaffolds.
ments in the fabrication of bioengineered scaffolds for tissue as biocompatibility and biodegradability, silk fibroin has been
engineering, delivery of nutrients in complex engineered intensively explored for tissue engineering and improving
human tissues still is an important challenge.32 injured body organs as a natural, green, and safe material.33
The modification of 3D porous structure of silk fibroin using
3.1. Bone tissue graphene oxide by freeze-drying method and using exclusively
Advanced biocompatibility and significant mineralization are nontoxic solvent such as glycerol for the preparation and
essential for the composed scaffold in the treatment and res- modification of reactant confirmed adherence to green chem-
toration of the injured bone. Important green chemistry prin- istry. By applying graphene oxide, the average size of pores of
ciples that should be addressed in bone tissues are safer sol- the tissue decreased which improved the compressive silk
vents and auxiliaries, applying renewable feedstocks, design- structure significantly. The findings on biological activity of the
ing safer chemicals, and atom economy. For instance, based silk fibroin/graphene oxide tissues contained degradability,
on excellent biological strength and mechanical strength, such drug release, and biocompatible characteristics. In comparison
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with the silk fibroin alone, tissues indicated that the modifi- tissue engineering comprise the combined application of cells
cation with graphene oxide accelerated the applicability of the and scaffolds for treatment of the injured muscles40 with a
tissues to resist enzyme degradation.33 Additional, investi- critical element to produce functional scaffold like native
gations have demonstrated that the existence of greener and muscle which have the capability of contracting.41 A green
safer materials in nature, with chemical structural similarity to method is needed to produce scaffolds which are composed of
natural bone, is a positive point in bone tissue engineering. biomaterials or naturally derived compounds, such as extra-
The efficiency of produced bone tissues could be examined by cellular matrix (ECM), to provide a muscle tissue or muscle
cell attachment, infiltration, morphogenesis, proliferation, and regenerative environment. Mimicking the nanofibrous struc-
differentiation, which are indicated or hardly affected by the ture and conductivity of the ECM for electrical distribution of
chemical component, construction, physical, and biomedical the origin myocardium should be enough for cardiac scaffolds
characteristics of scaffolds.31,34–36 Moreover, collagen/hydroxy- and cardiomyocyte (CM)-based bio-actuators; CMs have intrin-
apatite fibrous composite prepared via electrospinning sic electroactivity property and can spontaneously show
approach was applied to support the cells’ adhesion and bone response against electrical signal. Therefore, to simulate the
regeneration.37 In this study, an effective and greener approach origin myocardium, biomaterials should contain ECM-liked
for producing collagen/hydroxyapatite composite fibers nanofibrous structures and electrical conductivity to permit
demonstrated that the green product not only had 40 times electrical transmission. There are ongoing discussions for pro-
higher mechanical properties than previously reported instance, ducing such appropriate materials for cardiac tissue engineer-
but also had an excellent microstructure similar to that of ing and CMs-based bio-actuators. It is imperative to have elec-
natural bone. By dissolving type I collagen in eco-friendly phos- trically conductive and flexible green materials to generate the
phate buffered saline/ethanol solution instead of the frequently- elastic scaffold and to arrange cell distribution during scaffold
applied cytotoxic organic solvents, followed by the key step of treatment. To address these challenges, various new conduc-
desalination, co-electrospinning the collagen solution with the tive and degradable polyurethane-urea copolymers with elasto-
hydroxyapatite sol, produced a collagen/HAP composite with a meric characteristics were produced by using an amine-capped
uniform and continuous fibrous morphology. The prepared com- aniline trimer, dimethylol propionic acid, polylactide, and
posite exhibited a great enhancement in mechanical character- hexamethylene diisocyanate; compounds have great potential
istics, after cross-linking with 1-ethyl-3-(3-dimethyl-aminopropyl)- for the treatment or regeneration of elastic tissues for skeletal
1-carbodiimide hydrochloride/N-hydroxysuccinimide.37 muscle, cardiac muscle, and nerve.42
3.2. Skin tissue

Safer solvents and auxiliaries, less hazardous materials, apply- 3.4. Neural tissue
ing renewable feedstocks, and designing safer chemicals are Neural tissue engineering includes approaches to remove
important aspects that should be adhered to for generating inflammation and fibrosis upon implantation of foreign
scaffolds in tissue engineering.38 Biomaterials including poly- material into the nervous system. The requirement for neural
saccharides have been applied as green source for the regener- tissue engineering arises because of the difficulty of the nerve
ation of skin tissues. For instance, an impressive nanofibrous cells and neural tissues to produce on their own after neural
of Beta vulgaris was produced through electrospinning. injury.43 Myelination of Schwann cells (SCs) is very crucial for
Consequently, immunocytochemistry and mechanical strength the nervous tissue preparation and materials which can be pro-
of the ensuing composites were comparable to the native skin duced from SCs as tissues. Applying polyurethane by the poly-
tissues. The results demonstrated that the original functions condensation of poly(glycerol sebacate) and aniline pentamer
of keratinocytes were significantly maintained using the green to regenerate SC myelin gene expression and neurotrophin
composite scaffolds.38 Furthermore, hydroxyethyl cellulose/ secretion is an example of a greener entity in nerve tissue
silver NPs has been produced, via a safe and nontoxic engineering. The generation of neurotrophin secretion from
approach, as a valuable candidate for skin regeneration or SCs on conductive films has been evaluated by measuring the
improvement; aqueous solution of substrates with varying dependence of intracellular Ca2+ levels and SC myelination.
amounts of silver nitrate was produced in hydroxyethyl cell- Findings showed that electroactive and biodegradable poly-
ulose. Thus, desirable morphology, improved degradability, urethanes had an adequate potential for nerve tissue engineer-
and higher water absorption capacity in all the composites ing.44 Green and safe system for generating SCs is another
were reported and the absence of any toxicity bodes well for example for the treatment of peripheral nerve damages. For
their application as a promising material in skin tissue instance, the peripheral blood-derived mesenchymal stem
regenerating.39 cells could be inspired into SC-like cells, displaying SC-specific
markers and functional parameters. Application of induced
3.3. Muscle tissue peripheral blood-derived mesenchymal stem cells for treating
Important green chemistry principles which need to be incor- injured rat sciatic nerves showed encouraging results as the
porated in muscle tissues are safer and eco-friendly solvents produced scaffold can treat a wrap in a sciatic nerve to nerve
and auxiliaries, enhancement of mechanical and biological maintain, axonal restore, and remyelination, nerve conduction
properties, biocompatibility, and biodegradation.40 Muscle in the target muscle.45
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4. Plant-based scaffolds for tissue Chien et al.63 fabricated soy protein-based porous scaffolds
via two methods, viz. freeze drying and 3D printing and their
engineering acute immune response were evaluated by implanting them
Plants and plant-based natural polymers, as green and sustain- subcutaneously in mice and comparison with collagen
able sources with properties of renewability, inexpensiveness, scaffolds. Eosin and hematoxylin staining revealed that the
and ease of mass production, meet the requirement for inno- better penetration of cells with freeze-dried soy protein
vative materials with necessary characteristics for tissue engin- scaffolds occurred compared to collagen scaffolds. Although
eering which require minimal chemical processing for indus- higher concentrations of soy proteins in freeze-dried (3.0 wt%)
trial applications. In this section, we focus on the application and in bioplotted (20 wt%) forms altered the degradation rate
of plants and plant-based polymers and highlight the roles of of these scaffolds, but that was not effective for low concen-
such biomaterials in the assembly of greener and natural- tration in freeze-dried scaffolds (about 1.0 wt%). Eosin and
based scaffolds for tissue engineering with good tissue com- hematoxylin staining also showed that the penetration of cells
patibility and low toxic effects (as discussed comprehensively was hindered in the denser bioplotted soy (20 wt%) scaffolds,
in the following sections): causing slower degradation compared to collagen scaffolds.
Porosity, degradation rate and density of scaffolds need to be
established as they all have significant effect on the in vivo
4.1. Plant proteins response.63 Chien et al.64 deployed soy protein modified with
Plant proteins such as zein, soy proteins, wheat gluten and heat treatment and enzymatic crosslinking using transglutami-
camelina protein are abundant and inexpensive and can be nase in maltodextrin to fabricate porous 3D scaffolds via freeze
transformed into fibers and films with characteristics that are drying; treatment by enzymes accelerated the scaffolds stability
appropriate for regenerative medicine, tissue engineering, and and their degradation time, but did not affect the scaffold in
biomedicine. These proteins have inherent water stability terms of mechanical properties. These modifications in
because they contain abundant intra- and intermolecular di- scaffold degradation changed the seeded human mesenchy-
sulfide bonds. Importantly, plant-derived proteins are bio- mal stem cells growth and morphologies. Cell proliferation
degradable, and possess less immunogenicity potential.46–48 was enhanced in scaffolds containing 3.0 wt% SPI treated with
Additionally, they have a comparatively low molecular weight one unit of transglutaminase; enzyme treatment of SPI was
compared to animal-derived proteins and display higher found to be effective in controlling the degradation time of the
polarity, and thus being hydrophilic are potentially effective scaffolds and optimizing cell growth.64
for cell attachment. Because of these advantageous attributes Luo et al.65 constructed nerve guide conduit from SPI-modi-
of plant-derived proteins, increasing attempts are being dis- fied cellulose; three types were formed from cellulose/SPI
pensed to utilize them for biomedical applications including hollow tube (CSC), CSC combined with Schwann cells (SCs)
tissue engineering,49,50 drug delivery systems,51,52 and wound termed (CSSC), and CSSC linked to pyrroloquinoline quinone
dressings.53,54 (PQQ) labeled (CSSPC). They were deployed for the reconstruc-
4.1.1. Soy proteins. Soy protein is a spherical protein iso- tion and reparation of the rats’ sciatic nerve defect; newly-
lated from soy beans and it has long storage stability. Because formed regenerative nerve fibers were seen 12 weeks after the
of its biocompatibility, and biochemical similarity to the surgery in all tested groups. Findings revealed that the CSSPC
natural constituents of the ECM, it has been considered for group has great potential for the reparation and reconstruction
tissue engineering proposes.55 Most plentiful among plant of nerve functions and structure in comparison to the CSSC
proteins, soy, consists of polar, nonpolar, and charged amino and CSC groups, due to the extensive involvements from
acid residues including lysine, tyrosine, leucine, phenyl- hollow CSC tube, SCs and PQQ. Thus, CSSPC might be applied
alanine, aspartic, and glutamic acid. It is composed of a as nerve guide conduits in nerve tissue engineering.
mixture of albumins and globulins56 and could interact with Silva et al.66 fabricated cross-linked porous scaffolds based
various bioactive molecules and drugs.57,58 Their most fre- on a chitosan-soy protein blend; addition of tetraethyl orthosi-
quent interactions are hydrophobic interactions, hydrogen licate cross-linker improved the contact among the two poly-
bonds and van der Waals attraction.59 Soy proteins have been mers improving mechanical characteristics and the rate of
used extensively in adhesives, coatings, hydrogels and emulsi- degradation. Moreover, the presence of silanol group may
fiers. They essentially have three different forms based on the induce apatite layer development under physiological circum-
protein content: soy flour (SF, 54% protein), soy protein con- stances. The produced hybrids were applied for cartilage tissue
centrate (SPC, 65–72% protein), and soy protein isolates (SPI, engineering as tetraethyl orthosilicate promoted the porosity
≥90% protein).60 Generally, the production of SPI, with and also improved the interconnectivity between pores in the
highest protein content than other soy protein products, scaffold.66 Additionally, Luo et al.67 prepared cellulose and SPI
entails an aqueous extraction of protein at elevated pH, separ- membranes with porous structure for tissue engineering. The
ation, neutralization, and drying;56,61 they could form diverse SPI-containing membranes showed enhanced mechanical pro-
shapes from globular structures to small water-soluble aggre- perties, biocompatibility and biodegradability as well as cell
gates, which is usually the case in presence of solvents or growth both, in vitro and in vivo compared to pure cellulose
crosslinking agents.62 membranes. However, human umbilical vein endothelial cells
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(ECV304) being small in pore size, attached only to the surface increasing SPI concentrations due to the increase in electro-
and barely entered into the membrane. Subsequent to pure spun fiber diameter; increase of the PEO concentration also
cellulosic sponges, the same group68 prepared SPI–cellulose enlarged the thickness of the fibers e.g. from 30 to 150 nm.
sponges by freeze-drying protocol which showed improved bio- Nanometer sized electrospun fibers were produced from SPI in
compatibility and biodegradability (both in vivo and in vitro). order to improve the scaffolds for tissue engineering appli-
This improvement is due to the larger pore size with thinner ances by adding PEO to accelerate the preparation of fibers.
walls which were created by deployment of SPI. The higher The influence of processing parameters such as applied
penetration, distribution and production of L929 fibroblast voltage, SPI and PEO concentrations, and PEO molecular
cells in membranes and the better viability of cells have been weight on the electrospun fiber morphology was also investi-
observed than that found in pure cellulose sponges; the fabri- gated; ensuing SPI/PEO mats were crosslinked by carbodiimide
cated scaffolds are thus suitable for bone and cartilage tissue (RNvCvNR) to accelerate construct robustness. Mechanical
applications.68 The preparation of multifunctional bioinspired characteristics and in vitro biocompatibility of crosslinked elec-
tissues with vascularization and its treatment applications is trospun scaffolds were analyzed. Electrospinning and solution
noticeable in bone scaffolds.31,34–36 parameters affected the size range of SPI/PEO fibers (about 50
Fibrous scaffolds can mimic the structure of the extracellu- and 270 nm). The Young’s modulus for 7% SPI/3% PEO and
lar matrix, and are thus attractive for tissue engineering.4 12% SPI/3% PEO electrospun scaffolds was found to be 75 and
These biomaterials normally offer an appropriate circumstance 252 kPa, respectively. Investigations on stem cells (human
for cell growth and orientation. With the capability of forming mesenchymal) revealed successful adhesion and propagation
nano-fibrous structures, the demand for mimicking the ECM of cells on the SPI/PEO fibers. The structural and biological
and assembling the scaffolds, which are compatible for tissue properties of these SPI electrospun scaffolds suggest their pro-
formation with artificial extracellular matrix, began in earnest. spective appliances in tissue engineering.70
These nano-fibrous scaffolds attempt to mimic collagen, a 4.1.2. Zein. Zein, the main storage protein in corn, is a pro-
natural ECM material, and may offer a better circumstance for lamine-rich protein containing hydrophobic amino acids,
tissue formation in tissue engineering systems. Three steps for proline, and glutamine71,72 and possesses characteristics such
the preparation of nano-fibrous components entail phase sep- as, biocompatibility, and biodegradability besides being easy
aration, electrospinning and self-assembly and the ensuing to electrospun73,74 Zein is categorized into four categories,
product have exclusive set of properties that are responsible namely α-zein (19 and 22 kDa), β-zein (14 kDa), γ-zein (16 and
for their development as a scaffolding system. As an example, 27 kDa), δ-zein (10 kDa). It comprises hydrophobic, neutral
self-assembly could produce nano-fibers with small diameter and polar amino acid residues and shows an amphiphilic be-
at the lowermost limit of the range of natural ECM collagen, havior, making it capable of self-assembly to form mesostruc-
while electrospinning produced nano-fibers with only large tures with application in foods and pharmaceuticals; the
diameter at the higher end of the range of natural ECM col- chemical structure stability being attained via van der Waals
lagen. Additionally, phase separation method produced nano- interactions and intramolecular hydrogen bondings.71,75,76 It
fibers in the equivalent range as natural ECM collagen and could be easily produced in different shapes and structures
permitted the fabrication of macropore structures. These such as microparticles, nanoparticles, micelles, films and
attempts at an ECM have the ability to hold cells and steer gels.77 Due to its brick-like tertiary structure, zein has an
their augmentation following tissue regeneration.4 ample room for drug entrapment. To this end, apolar side
Soy proteins have been electrospun into 3D and 2D ultra- chains are aligned toward the interior portion of the molecule,
fine fibrous scaffolds for soft tissues engineering by dissolving evading an interaction with the polar solvent, whereas the
SPI in an aqueous solvent system containing cysteine as reduc- polar side chains are oriented toward the surface of molecule
tant;69 ensuing scaffolds displayed significant water stability interacting with polar solvents and thus improving its solubi-
by retaining their fibrous morphologies after incubation in lity.78 Several drugs and bioactive compounds such as ivermec-
phosphate-buffered saline (PBS) for 28 days. It was shown that tin, gitoxin, essential oils, food grade antimicrobials, coumarin
the 3D scaffolds appropriately supported constant distribution and 5-fluorouracil (5-FU) have been encapsulated and stabil-
and adipogenic segregation of adipose-derived mesenchymal ized in zein protein nanoparticles and are used as
stem cells on the surface and under the spaces of scaffolds riv- nanomedicine.72,79–84 The isoelectric point of zein is 6.8; thus,
alled with the 2D scaffolds. This was most likely because of the the zein-based colloidal systems’ pH should be carefully
tight fiber packing and lack of spaces in the thickness direc- checked to maintain its colloidal stability.85,86
tion for cell penetration in 2D structures. Thus, the 3D ultra- Recently, zein has been probed for its potential as implant
fine fibrous soy protein scaffold could be attractive option in biomaterial because both zein and its products display favor-
soft tissue engineering domain.69 able tissue compatibility, in vivo.49,87 A non-toxic crosslinking
SPI/poly(ethylene oxide) (PEO) electrospun fibers have been process for electrospun protein fibers was developed by Jiang and
produced for tissue engineering which showed that the mor- co-author88 to improve their stability in water and cytocompatibil-
phology of electrospun fibers was affected by the concentration ity for applications in the biomedical field; electrospun zein
of both SPI and PEO, as well as the molecular mass of PEO.70 fibers could be cross-linked with citric acid using non-toxic cata-
The tensile strength of SPI/PEO fibers was enhanced by lysts. Even after soaking in PBS at 37 °C for more than 15 days,
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they retained their ultrafine fibrous structures. Additionally, the Biodegradable recombinant human bone morphogenetic
cross-linked electrospun zein scaffolds, exhibited improved protein-2 (rhBMP-2) loaded zein-based macroporous scaffolds
attachment, fibroblast cells distribution and proliferation com- have been produced; SBA-15 NPs and hydroxypropyltrimethyl
pared with uncross-linked electrospun zein and polylactide ammonium chloride chitosan (HACC) were incorporated into
fibers, and cross-linked zein films. These results affirmed that the scaffolds to prepare composite with anti-infective pro-
the electrospun scaffolds could provide better support for the perties appropriate for the delivery of osteogenic factor in the
growth of fibroblast cells than films as scaffolds.88 functional repair of bone defects.92 The silica/HACC/zein
Zhang and co-authors89 produced zein/hydroxyapatite scaffolds demonstrated biocompatibility, bioactivity, and
fibrous membranes by electrospinning the zein/hydroxyapatite effective antibacterial activity. After more than five days, zein-
solution mixed by means of a magnetic stirrer or under ultra- HACC-S20 sample exhibited antibacterial activity against
sonic power; homogeneous hydroxyapatite nanoparticles dis- Escherichia coli and Staphylococcus aureus. Even after 27 days,
tribution in the membranes were observed when electrospun at a low amount of rhBMP-2 (ca. 80 mg), the scaffolds released
under ultra-sonication. The use of magnetic stirrer enhanced rhBMP-2 protein ably but at a slow rate. The scaffolds of zein-
the wettability of zein/hydroxyapatite nanocomposite fibrous HACC-S20 showed extremely early osteogenic differentiation
membranes, while showing no significant effect on their in vitro and ectopic ossification in vivo. In a rabbit model of
tensile strength. In vitro study of control zein and zein/hydroxy- serious-sized radius bone defects (20 mm in length and 5 mm
apatite membranes displayed that both types of the mem- in diameter), they were almost completely repaired, and bone
branes can support cell proliferation. The cells cultured on the marrow cavity recanalization was identified by 3D micro-com-
zein/hydroxyapatite membranes electrospun by magnetic puterized tomography (CT) method and histological evaluation
stirrer with 5 wt% hydroxyapatite displays considerably higher after twelve weeks. Optimization on scaffold formulation was
proliferation compared to the control zein membranes, on the performed using in vitro cytocompatibility testing and in vivo
seventh day. This study indicated that, addition of the hydroxy- ectopic bone formation evaluation, and the ability of rhBMP-2-
apatite nanoparticles to the zein nanofibers is a sound strategy loaded silica/HACC/zein scaffolds to repair critical-sized bone
to acquire nanofibrous membranes with higher biological per- defects has been analyzed. Histological analyses of rabbit
formance, which are more interesting specifically for bone specimens demonstrated that each group of zein-based
tissue engineering. scaffolds underwent fast degradation from week 8 to week 12,
By solvent casting-particulate leaching approach, Wu et al.90 among which the SBA-15 free groups (i.e. pure zein and zein-
prepared porous scaffolds of zein/poly(ε-caprolactone) (PCL) HACC scaffolds) demonstrated slower degradation. It was con-
biocomposite using NaCl salt particles as the porogen to cluded that disparity was attributable to the different rates of
regenerate bone; biocomposite-based scaffolds with extreme neo-bone generation. Because of the newly deposited matrix,
porosity (about 70%) and well-interlocked network have been the zein-based scaffolds were eliminated by a cell mediated
made. The zein and PCL incorporation delivered the hydrophi- process instead of random dissolution. Additionally, the pro-
licity development in biocomposite scaffolds; ensuing biocom- ducts of zein scaffold degradation did not injure the surround-
posite scaffolds degradation rate was faster than the PCL ing tissues based on the histological analyses, indicating that
scaffolds, after steeping in PBS for 28 days. This study revealed these zein-based scaffolds hold considerable promise for bone
that the rate can be customized by altering the quantity of zein repair through tissue engineering (Fig. 8 and 9).92
in the composite to match with the rate of tissue regeneration. Zein films (∼100–500 and 500–2500 nm) were produced as
Zhijiang et al.91 produced zein/poly(3-hydroxybutyrate-co-4- scaffolds for mice fibroblast cells (NIH3T3) and human liver
hydroxybutyrate) (P(3HB-co-4HB)) blended fiber scaffolds via cells (HL-7702);49 after three hours of seeding, over 60% of
electrospinning for tissue engineering application. The porous both HL-7702 cells and NIH3T3 cells were attached to zein
scaffolds with extreme porosity (85 ± 2.1%–92 ± 2.6%), well films. Moreover, zein film, which was made of tinier particles
interconnected pores and large specific surface area were pro- at the lowermost content, presented a very good capability for
duced by the ultrafine fibers (60–650 nm in size). By blending proliferation of the both cell-types compared to other polymers
with P(3HB-co-4HB), the mechanical attributes of zein electro- such as, polylactic acid.49 Wang et al.87 produced zein films (as
spun fiber scaffold were greatly enhanced. However, zein hin- coating materials) for their improved biocompatibility with
dered the P(3HB-co-4HB) crystallization because of the creation platelets and human umbilical vein endothelial cells; zein and
of feeble intermolecular contacts, which caused a reduction in heparin-loaded zein microsphere films, efficiently stopped
crystallinity and an enhancement in the glass transition temp- adhesion of platelet in addition to displaying higher anti-
erature contrasted with pure P(3HB-co-4HB) electrospun fibers. coagulation properties.87
The in vitro investigations revealed that the blended scaffolds Dhandayuthapani et al.93 made a fluorescent nano-
are non-cytotoxic for NIH3T3 fibroblast cells and MG-63 osteo- composite comprising cadmium sulfide (CdS) and zein as a
blast cells and provided a support to enable cell adhesion, dis- scaffold for the attachment and the proliferation of the fibro-
tribution and proliferation. This study showed that the as-pre- blasts and mesenchymal stem cells. These cells retained their
pared electrospun Zein/P(3HB-co-4HB) blended fiber scaffolds normal cell shape and combined well with nearby fibers high-
should be more promising for applications as tissue engineer- lighting the significance of QD-encapsulated fluorescent zein
ing scaffold.91 nanofibers as tissue engineering scaffolds. Yan-Zhi et al.94 fab-
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Fig. 8 SEM and EDS analysis of rhBMP-2 loaded silica/HACC/zein composite scaffolds after 5 days immersion in simulated body fluid. The apatite
crystals in a leaf-like shape have been detected on the surface of the scaffold struts. EDS analysis revealed that Ca/P-containing particles are de-
posited on the surface of scaffolds for SBA-15 doping groups. Reproduced with permission from ref. 92.
ricated zein-based scaffold for healing periodontal tissue mately 80%) and tensile strength of 1.36–3 MPa with an
imperfections which displayed high porosity and wall structure elongation of 19.13–44.06% suitable for skin tissue engineer-
with open pore, and suitable biocompatibility for the developing. SEM analysis of degraded specimens showed that the
ment of periodontal ligament cells. scaffold retained its fibrous structure during its destruction.
The porous nanofiber scaffolds have been prepared via Bacterial evaluations showed that the scaffold containing gum
electrospinning to compensate deep skin damages;95 mixture Arabic had antibacterial characteristics. Furthermore, in vitro
of zein, polycaprolactone and gum Arabic was applied in analysis validated promising L929 cells proliferation compared
varying concentrations and ratios. Zein and gum Arabic poly- to tissue culture polystyrene (the control).95
mers were utilized as a protein and polysaccharide component 4.1.3. Wheat glutenin. Wheat (Triticum aestivum L.) is one
of the scaffold and polycaprolactone polymer for elasticity, of the significant crops worldwide and is a valuable source of
strength and time-bound degradability of scaffold. SEM results protein, thiamin, riboflavin and potassium, and an appropri-
showed that the produced scaffolds had a porous structure ate source of dietary fiber, niacin, iron, zinc, vitamin B6, mag-
with bimodal diameters distribution and they demonstrated nesium, phosphorus, copper, selenium and manganese. The
high hydrophilic characteristics, appropriate porosity (approxi- wheat flour gets its main functional and structural character-
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perties, but they did not dissolve in many typical solvents;

thus, their electrospinning and freeze-drying are very challen-
ging processes. To date, fibrous structures containing WG have
been successfully fabricated by engaging either cytotoxic pro-
teins or blending them with synthetic polymers after hydro-
lysis of WG. Woerdeman and co-authors,104 achieved electro-

spinning of wheat gluten by blending WG with gliadin which
was among the first plant protein to be electrospun. Soluble
wheat gluten has also been blended with polyvinyl alcohol and
then electrospun.105 Nevertheless, gliadin showed cyto-
toxicity,46 while polyvinyl alcohol could notably decline the
tendency of scaffold–cell interaction. The disulfide crosslinks
in WG need to be cleaved while the backbones should be pre-
served before WG could be dissolved and electrospun into 3D
structures.106 Xu and coauthors,107 dissolved WG in aqueous
solvent with sodium dodecyl sulfate (SDS) and then electro-
spun into 3D fibrous scaffolds to simulate native extracellular
matrices of soft tissues. The 3D fibrous WG scaffolds exhibit
better support proliferation and adipogenic differentiation of
adipose-originated mesenchymal stem cells than 2D ultrafine
fibrous WG and commercial 3D non-fibrous scaffolds.107
4.1.4. Camelina protein. Camelina protein (CP) is bio-
degradable and biocompatible and has a potential to be devel-
oped into water stable scaffolds for biomedical appliances as
CP films for tissue engineering.108 It has high degree of di-
sulfide cross-linkage and CP was dissolved in a system com-
prising cysteine/urea and SDS; they had a weight loss of
approximately 12% after seven days of incubation in PBS and
supported cells for up to 18 days without being broken. It was
found that the properties of the CP films dependent on pro-
Fig. 9 Histological analysis of new bone generation stimulated by duction conditions such as SDS concentrations and aging
rhBMP-2 loaded (a) pure zein scaffold, (b) zein-HACC, (c) zein-S20, and
time, which affected the film stiffness. Mouse fibroblasts
(d) zein-HACC-S20 scaffolds for 8 and 12 weeks. M: materials, NB: bone,
F: fibrous tissue. Reproduced with permission from ref. 92.
seeded on the CP films presented greater degrees of metabolic
activity in comparison to collagen films under the similar
culture conditions.108
istics from components such as starch and gluten;96 four 4.2. Plant polysaccharides
major protein types being, water soluble albumins, salt solu- Generally, polysaccharides such as, gums, chitosan, alginate,
tion globulins, ethanol soluble prolamins, and alkali soluble hyaluronan and cellulose can been applied for nanomedicine,
glutelins. The gluten proteins are classified as alcohol-soluble biomedicine and tissue engineering.109–111 Several scaffolds pre-
gliadins and alcohol-insoluble glutenins.97–100 pared from polysaccharides are summarized in Table 1, although
Wheat glutenin (WG) has inherent aqueous stability due to in this section, polysaccharides acquired from plants including
the presence of 2% cysteine in the disulfide crosslinked cellulose, starch and pectin are emphasized, as we focused on
molecules.101,102 Different forms of wheat proteins such as plant polysaccharides for tissue engineering scaffolds.
films, fibers, and hydrogels have been investigated for con- 4.2.1. Cellulose. Cellulose is a natural linear polysaccharide
trolled release applications and tissue engineering. Gliadin with specific characteristics, including biodegradability and
nanoparticles have been deployed as transporters for vitamin biocompatibility and is a complex carbohydrate, including
E, linalyl acetate, and benzalkonium chloride. Gliadin films, many cyclic glucose molecules. It is an endless source of bio-
owing to their drug releasing capability, have been used as polymers from plant cell walls that can be considered as the
chewable gums and soft capsules. On the other hand, glutenin most sustainable naturally occurring compounds.130 Based on
has been recommended more for tissue engineering appli- the source of this biopolymer, its flat ribbon-like structural
cations since it could promote the attachment and prolifer- conformation involves a chain of several hundred to many
ation of fibroblasts and osteoblasts better than synthetic thousands of β(1→4) linked D-glucose units.131,132 Different
polymer films.97,103 WG films possess good water stability and types of cellulosic nanostructures with diverse crystallite sizes
better support attachment and proliferation of osteoblasts are obtainable from diverse sources such as cotton, wheat
than PLA films.48 These films displayed high crosslinking pro- straw, ramie, sugar beet pulp, soy hulls, sisal, bagasse, palm
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Table 1 Polysaccharide materials for preparation of tissue scaffolds
Polysaccharide materials Applications Ref.
Chitosan, PCL & polypyrrole Neural tissue substitute 112

Gelatin and carboxymethyl chitosan Dermal tissue engineering 113
Maleiated chitosan & thiol-terminated polyvinyl alcohol Engineering of chondrocytes 114
Chitosan & collagen Hepatocyte attachment 115

Alginate & some surfactants Delivery of mesenchymal stem cells 116
Alginate Soft tissue repair 117
Alginate & single-walled carbon nanotubes Proliferation of endothelial cells 118
Quaternized chitosan polyaniline and oxidized dextran In situ forming antibacterial and electroactive hydrogels 119
Pullulan-dextran Adherent cell growth 120
Arginine–glycine–aspartate peptide functionalized dextran Cell-homing scaffold 121
Maleiated hydroxyapatite/thiol-terminated poly (ethylene glycol) In situ formable scaffolds 122
Chitosan, hydroxyapatite & andrographolide Wound care scaffold 123
Thiophene ethylamine modified hydroxyapatite Hepatocytes culture 124
Thiolated hydroxyapatite Culture of fibroblasts and chondrocytes 125
Hydroxyapatite & collagen Brain tissue engineering 126
Hydroxyapatite, gelatin & chondroitin sulphate Retinal regeneration 127
Dextran & poly(lactic acid-co-glycolic acid) Fibroblast/macrophage co-culture 128
Dextran & chitosan Wound healing 129
trees, corncob, carrots, fruit peels, grasses, bamboo, seaweeds, tically investigate the biocompatibility of their degradation
wood and bleached Kraft pulp.133 The lateral and length byproducts. For instance, the production of immunogenic sub-
dimensions of a nanoscaled cellulose extracted from a wood stances during the degradation of cellulose should be evalu-
source could be around 3–5 and 100–300 nm, respectively, ated in vivo before translating the hybrid hydrogels for clinical
while a counterpart extracted from tunicate showed lateral and applications.136
length dimensions of around 15–30 and 1000–1500 nm, Thunberg et al.161 modified the surface of electrospun cell-
respectively.134 Based on the reported data, there are two ulose nanofibers by conductive polypyrrole (PPy) to prepare
forms of nanoscaled cellulose namely nanocrystals and nano- scaffolds for neural tissue engineering. PPy (as small particles)
fibrils synthesized via chemical or mechanical techniques; adhered to the cellulose nanofiber surface and produced sub-
highly crystalline cellulose as nanocrystals were of smaller stantial upsurge in conductivity in comparison to the
length than that of nanofibrils which comprise crystalline and unchanged cellulosic nanofibers; non-toxic property of electro-
amorphous phases.135 spun cellulose was retained after PPy treatment. The adhered
Cellulose encompasses some important properties, such as small particles of polypyrrole increased the roughness of the
biocompatibility, renewability, biodegradability, cost-effective- nanofibers and consequently promoted SH-SY5Y cell adhesion
ness, hydrophilicity, and mechanical resilience.136 Cellulose and their viability up to 15 days of differentiation in the
nanofibrils are attractive for biomedical applications because scaffolds.161 Similarly, Novotna et al.162 prepared 6-carboxycel-
of their good mechanical properties and biocompatibility. lulose with 6.6 or 2.1 wt% of –COOH groups for tissue engin-
Recently, tissue engineering scaffolds of cellulose fiber have eering applications (Fig. 11). To balance the relatively acidic
been applied to culture cells, both on unmodified character of oxidized cellulose molecules, the biomaterial
cellulose137,138 and on surface-modified cellulose.139 Moreover functionalization was achieved by arginine or chitosan, and
due to the micro structure, proliferation and cell attachment then was seeded with vascular smooth muscle cells (VSMC).
are affected by the surface chemistry of the scaffold. Thus, Carboxycellulose with 2.1 wt% of –COOH groups was reported
surface-modified and composite fibers have been electrospun to be more appropriate for cells colonization.162 Alternatively,
to improve proliferation and cell attachment on scaffolds.139 chitosan enhanced the muscle cells adhesion and growth in
Some salient properties of cellulose applied for construction of compared to the control polystyrene dishes. However, the cells
scaffolds in the field of tissue engineering are summarized in proliferation on cellulosic materials was relatively subdued
Fig. 10; additionally, some important types of cellulose and suggesting that these biomaterials could be applied where
modifications applied to cellulose materials to be used as high propagation activity of cells was not necessary, for
tissue scaffolds are summarized in Table 2. A series of cellulo- example, the VSMC proliferation on vascular prostheses.162
sic scaffolds have been prepared with lipophilic, oleophilic The contractile phenotype of VSMC in vitro might be restored,
and hydrophobic properties140 wherein they showed a highly at least partially, by the culture conditions including appropri-
interconnected porous structure which initially composed of ate dynamic cultivation, composition of cell culture media,
extremely esterified, strong network of ultrathin cellulosic and the chemical and physical characteristics of the growth
layers. For tissue engineering and controlled/targeted drug substrates. The maturation of VSMC towards the contractile
delivery, this class of scaffolds is very promising. phenotype was most pronounced on materials based on 6-car-
It should be noticed that polysaccharides are typically bio- boxycellulose bearing 2.1 wt% of –COOH groups.
compatible and nontoxic, but care should be taken to systema- Immunofluorescence demonstrated that the cells on these
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Fig. 10 Significant properties/advantages of cellulose for tissue engineering scaffolds, and its modifications for tissue scaffolds.
Table 2 Cellulose and its modifications as applied to materials for use as tissue scaffolds
Cellulose Scaffold forms Modifications Ref.
Nanocrystalline 3D porous scaffold (for neural tissue engineering) Dialdehyde cellulose crosslinked with collagen 141
cellulose (NC)
NC Interconnected highly porous scaffold (hydrophobic and Acetate esterification 142
lipophilic scaffolds)
NC Thin films (in vitro cell culture and in vivo tissue regeneration) Phosphorylation 143
NC Scaffold soaked in doubly concentrated simulated body fluid Oxidized cellulose grafted with soybean protein isolate 144
(biomimetic calcium phosphate mineralization)
NC 3D nanocomposites Copolymer dispersed with cellulose nanocrystals 145
NC Nanocomposite film (antibacterial activity) CNC and reduced graphene oxide blended in PLA 146
matrix
NC CAD generated porous structure Nanocellulose blended with nanochitin 147
Microfibrillated Regenerated modified cellulose films Cationization and glyoxalation 148
cellulose (MC)
MC Hydrogels (cell attachment) Cellulose–chitosan infusions 149
MC Electrospun fiber meshes (bone tissue) Oxidation followed by sulfonation 150
MC 3D cellulose scaffolds (in vitro culture of mammalian Decellularization followed by glutaraldehyde 151
cells in a 3D environment) crosslinking
MC Electrospun PLA/CNF composite nanofibres Dopamine coated 152
(accelerate cell biocompatibility)
MC Electrospun nanofibres Polyurethane coated in a CNF dispersion 153
Cellulose Biocompatible and hydrolytically degradable scaffold Hydroxypropyl cellulose (HPC) crosslinked by 154
derivatives (CD) (for long term cell culture) methyl acrylate
CD Electrospun nanofibres Ethyl hydroxyethyl cellulose (EHEC) crosslinked 155
with citric acid
CD 3D hydrogel constructed with interconnecting pores (adipose HPC modified with methacrylic anhydride 156
tissue)
CD Hydrogel with perfusable vascular networks Crosslinked gelatin/carboxymethyl cellulose (CMC) 157
(engineering vascularized and cell-dense 3D tissues and organs) blend
CD Lyophilized hydrogels CMC/MFC/pectin blend 158
CD Electrospun nanofiber mats (antifouling surface) Cellulose acetate with polymer graft and polydopamine 159
(PDA) coating
CD Electrospun nanofiber mats (biomineralisation) Cellulose acetate blended with PLA or PDO 160
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altered with chitosan. Furthermore, the actin and myosin

fibers in these cells were less distinguishable, because the
cells on these materials were markedly elongated along the
cellulose fibers, and therefore, very thin (Fig. 12 and 13).
Carboxymethylcellulose ( plant-derived polysaccharide) was
chemically altered to include sulfate groups for acceleration in

binding of cationic growth factors.163 It was reported that the pre-
pared injectable scaffold system was appropriate for growth
factor presentation to seeded cells for improved chondrogenesis,
and it could be applied as injectable and macroporous scaffold
for cartilage tissue engineering. When seeded with infrapatellar
fat pad derived mesenchymal stem cells, the scaffolds showed
improved chondrogenesis after 28 days of in vitro culture as com-
pared to controls.163 These scaffolds showed high resilience and
shape memory, thus making them injectable via a 14G needle
for up to 4–6 aspiration and injection cycles. Moreover, the
scaffolds may sequester cationic proteins and growth factors
(TGF-β1) via affinity-based interactions.163
An alternative approach was put forward by He et al.164 to
produce a silk fibroin/cellulose nano whiskers-chitosan
(SF/CNW-CS) composite scaffold with outstanding mechanical
characteristics and bio-compatibility through layer-by layer
assemblage of CNW and CS on a porous SF scaffold. The
mechanical properties of the SF/CNW-CS composite scaffold
were significantly enhanced by growing the number of self-
assembled layers. They showed a fourfold upsurge in the com-
Fig. 11 SEM images of 6-carboxycellulose with 2.1 or 6.6 wt% of pressive strength and a slight reduction in porosity compared
–COOH groups. Reused from ref. 162, an open access article, © The
to the SF scaffold. The SF/CNW-CS composite scaffold could
Author(s) 2013.
meaningfully support the proliferation, adhesion, and the
expression of bone formation markers in MG-63 osteoblasts,
and thus may be a favorable material for bone tissue repair
materials as well as on the polystyrene dishes were brightly and regeneration applications.164
stained for α-actin and SM1 and SM2 myosins, mainly the cells Modulevsky et al.151 generated an apple-derived 3D cell-
on 6-carboxycellulose bearing 2.1 wt% of –COOH groups ulose-based scaffolds and used that for in vitro cell culture of
Fig. 12 Surfaces of 3D reconstruction of 6-carboxycellulose with 2.1 wt% of –COOH groups without functionalization. Reused from ref. 162, an
open access article. © The Author(s) 2013.
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Fig. 13 Immunofluorescence staining of alpha-actin (a, c, e) and SM1 and SM2 myosins (b, d, f ) in cells growing on 6-carboxycellulose with 2.1 wt%
of –COOH groups (a, b). Reused from ref. 162, an open access article. © The Author(s) 2013.
three mammalian cell lines: human HeLa epithelial cells, water-insoluble methods resulted in scaffolds with 70–75%
mouse NIH3T3 fibroblasts, and mouse C2C12 myoblasts. and 91–93% porosity, respectively. X-ray diffraction showed
These cell lines were capable of proliferation and remained lower crystallinity of the regenerated cellulose/β-cyclodextrin
viable in the 3D cellulosic scaffold for more than twelve weeks, scaffolds as compared to pure regenerated cellulose.166 The
reaching cell densities similar to the other natural and syn- scaffolds produced by water-insoluble leaching approach
thetic bio-based materials.151 3D cellulose acetate (CA)-based demonstrated the uppermost water uptake characteristics. By
scaffolds were produced using the wet-electrospinning tech- applying dimethylthiazol diphenyl tetrazolium bromide (MTT)
nique and used for skin tissue engineering;165 various concen- cytotoxicity test, it was shown that the produced scaffolds were
trations of CA (4–10, 12 and 14% (w/v)) were dispersed in cytocompatible.166
acetone for scaffolds preparation. The samples with concen- Hydrogels fabricated from natural polysaccharides can
trations of 4–7% (w/v) formed only droplets while the beaded serve as ideal scaffolds for tissue engineering because of their
fibers were prepared with the concentration of 8% (w/v), and similarity to the extracellular matrices. For instance, hydrogel
beyond this content, the fibers approximately oriented in acci- scaffolds with bubble-like porous structure were produced
dental and dispersive manner, and shaped non-woven struc- from hydroxyethyl chitosan and cellulose by a combination of
ture morphology. These hydrophobic scaffolds could not meet chemical crosslinking, particle-leaching using silicon dioxide
the appropriate porosity percentage of over 80%; the highest particles as porogen and freeze-drying approach. These
porosity percentage being 69.5% for the 12% (w/v) scaffolds. scaffolds exhibited good comprehensive performances and
All the scaffolds showed a non-toxic environment and could reach equilibrium swelling state in water within 20 s.
improved cell proliferation and attachment of L929 mouse Furthermore, findings from in vitro biocompatibility analysis
fibroblast cell.165 Regenerable cellulose/β-cyclodextrin tissue by using SEM, live/dead cell viability and MTT assays revealed
engineering scaffolds have been produced by two particulate that the scaffolds could well support the attachment, spread-
leaching methods using eco-friendly 1-butyl-3-methyl- ing and proliferation of osteoblastic MC3T3-E1 cells and
imidazolium chloride ionic liquid.166 In one case, the pore demonstrated good biocompatibility, and thus can be applied
inducing particles were water-soluble (edible salt) and in the for bone tissue engineering applications.167
other, they were water-insoluble poly (methyl methacrylate). 4.2.2. Pectin. Pectin, a natural polysaccharide extracted
Consequently, the water-soluble particulate leaching and from the cell walls of plants with a chemical structure compar-
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able to alginate, provides attractive attributes as artificial ECM. which were perfect for applications in tissue engineering;
Ninan and co-authors158 prepared pectin/carboxymethyl cell- additionally, they exhibited the highest cell viability on
ulose/microfibrillated cellulose ( pectin/CMC/MFC) scaffolds NIH3T3 fibroblast cell line compared to other composite
with varying concentrations of MFC (0–0.4%) for applications scaffolds (Fig. 14 and 15).158
in tissue engineering. The composite scaffolds with 0.1% MFC Pectin modified with an arginine–glycine–aspartate-con-
demonstrated highest porosity (88%), compression modulus taining oligopeptide or unmodified pectin has been used as
(about 3.987 MPa), thermal stability and low degradation rate an ECM alternative to immobilize cells for regeneration of
Fig. 14 Preparative method for pectin/CMC/MFC composite scaffold. Reproduced with permission from ref. 158.
Fig. 15 SEM images (a–c) depicting the highly porous structure of the produced scaffold; pore size, ranged from 30–300 µm in case of C (0%) and
10–250 µm in case of C (0.1%). The slight decrease in pore size may be due to incorporation of filler (MFC), which impart suitable interaction with
the polymers. Reproduced with permission from ref. 158.
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bone tissue.168 The metabolic activities, viability, morpho- scaffolds being 45 °C. A higher homogeneous scaffold was
logies, and immobilized MC3T3-E1 preosteoblats osteogenic achieved when the procedure was performed at lower press-
differentiation revealed the capability of these polysaccharides ures. In vitro studies showed that SPCL scaffolds which were
to endure the immobilized cells viable and differentiating. seeded by fibroblasts are not cytotoxic and can protect cell
Preosteoblasts immobilized in both types of pectin micro- growth and proliferation.171
spheres preserved a persistent viability more than 29 days and Biodegradable polymers do not present satisfactory bone
were capable of differentiation. It was found that the chemical bonding, osteoconductive and osteoinductive properties. One
attachment of the peptide containing the arginine–glycine– solution is the deposition of a calcium phophate (Ca–P) layer
aspartate sequence on pectin structure enhanced preosteo- on the surface of the polymeric 3D porous scaffolds, a compo-
blasts cell adhesion, stimulating their metabolic activity and sition comparable to the inorganic element of bone. Salgado
differentiation. Additionally, the cells might develop inside or et al.172 treated blend of corn starch/ethylene-vinyl alcohol
extend from the microspheres, and attained 3D structure for scaffolds by calcium-phosphate (Ca–P) for bone tissue engin-
themselves thus creating a mineralized ECM; pectin could eering.172 Human osteoblast (SaOS-2) cells were seeded in
thus be offered as an injectable cell vehicle for bone tissue scaffold and allowed to grow for two weeks; cells could grow in
engineering.168 the modified scaffolds and remain viable after two weeks in
Innovative porous 3D scaffolds from silk fibroin and func- culture. After this time, osteopontin and collagen type I were
tionalized (amidated and oxidized) citrus pectin have been fab- being expressed by SaOS-2 cells seeded on the altered scaffold.
ricated for appliance in skin tissue engineering.169 After Additionally, the activity of alkaline phosphatase (ALP) was sig-
freeze-drying and methanol treatment, plasma treatment (10 nificant in the collected supernatants (from the pre-minera-
W, 3 min) was used for removing the surface skin layer pro- lized scaffold) in comparison to non-treated scaffold. The find-
duced on scaffolds; 3D matrices had high porosity (83%) and ings revealed a faster mineralization of the ECM occurred, pre-
interconnectivity with pore size about 120 µm thus providing pared on the pre-mineralized scaffold, in comparison to non-
appropriate microenvironment for cells. The produced treated scaffolds. These results showed that biomimetic pre-
scaffolds demonstrated low weight loss (21.3% in 40 days) and mineralization of starch based scaffolds can be a suitable
high-water uptake capability for phosphate-buffered saline method for applying these biomaterials on bone tissue
(800% in 24 h). Mechanical characteristics of 3D matrices engineering.172
revealed an approved stability of scaffolds under compressive In a similar study by Salgado and co-author,173 three starch-
stress and supported adhesion, proliferation and penetration based scaffolds groups: a 50/50 (wt%) blend of corn starch and
of fibroblast cells.169 ethylene-vinyl alcohol (SEVA-C), the alike composition altered
4.2.3. Starch. Starch is a natural polymer made of a with a calcium phosphate (Ca–P) layer (SEVA-C/CaP), and a 50/
mixture of two polymeric carbohydrates, amylose and amylo- 50 (wt%) blend of corn starch and cellulose acetate (SCA) were
pectin. This polymer can be applied as a cell support material produced, and consequently implanted in rats; all scaffolds
in combination with synthetic polymers including PCL, poly- were well joined in the defect site and surrounding marrow.
lactic acid (PLA), ethyl vinyl alcohol (EVOH), and cellulose The main changes between the three assessed scaffolds were
acetate (CA) giving rise to a blend which can be expected to recorded with information on the degrees of direct bone/
bring better outcomes. Starch-PCL (SPCL) scaffolds for carti- scaffold contact, which was only obvious in the case of SCA
lages tissue engineering approach were fabricated by Oliveira scaffolds. No bone contact was observed by SEVA-C at any
et al.170 wherein SPCL scaffolds could support bovine articular moment, only finite bone contact was reported with SEVA-C/
chondrocytes adhesion, differentiation and proliferation, for CaP at three weeks, but SCA demonstrated direct bone contact
in excess of 6 weeks of culturing and were compared to the at six weeks, where about 56.23% of the scaffold surface was
non-woven polyglycolic acid (PGA) scaffolds. The PGA scaffolds filled up by bone. Moreover, all the scaffolds showed a promis-
revealed a central area of depletion of cells, a condition that ing bony response with rapidly generating initial connective
was not seen in the SPCL scaffolds, which presented homo- tissue observed around all scaffolds.173
geneous cell colonization all over the scaffold construction Martins and co-authors174 prepared a hierarchical starch-
indicating the much higher biocompatibility of the starch- based scaffold, by blending of SPCL micro- and PCL nano-
based scaffolds. The results achieved for toluidine blue stain- motifs, respectively via instant prototyping and electro-
ing and immune-localization of collagens types I and II were spinning strategies. The SEM evaluations demonstrated multi-
very comparable for both the scaffold materials. However, PGA layer scaffolds fabrication in a grid-like arrangement compris-
scaffolds presented higher quantities of glycosaminoglycans in ing parallel aligned microfibres, interposed through a mesh-
comparison to the SPCL scaffolds. A polymeric blend of SPCL like structure with arbitrarily dispersed nanofibers. The
has been prepared by supercritical-assisted phase inversion to human osteoblast-like cells were seeded on the scaffolds and
develop 3D structures of scaffolds for tissue engineering appli- cultured for seven days; nanoscale fibers integrated into 3D
cations.171 Different processing parameters including pressure rapid archetype scaffolds and meaningfully accelerated the cell
(80–150 bar) and temperature (45 and 55 °C) were applied, and proliferation, attachment and osteoblastic activity on the hier-
the effects of these conditions on the scaffolds morphologies archical fibrous scaffolds. The results revealed that the nano-
was assessed, the best operating temperature to process SPCL fibers incorporation into 3D rapid prototype scaffolds signifi-
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cantly improved their biological performance in bone tissue surface for greatest osteoblast adhesion, proliferation, alkaline
engineering methods.174 phosphataseactivity, and mineralization in comparison to
Several methods have been used to develop porous green other scaffolds.179 Additionally, fine fibers of biopolymer, poly-
scaffolds of different shape, size and 3D geometry of starch- hydroxybutyrate (with an average diameter of 1.8 µm) were
based materials for tissue engineering applications including obtained via a centrifugal spinning method180 using Texas
supercritical immersion precipitation method for preparation sour orange juice as a natural antibacterial agent and infil-
of scaffolds by starch and poly(l-lactic acid).175 In the experi- trated within the fibrous membranes. The antibacterial activity
ment, varying parameters such as polymer concentration, analysis of the produced scaffold demonstrated antibacterial
pressure and temperature which have the important effects on activity of up to 152% and 71% against Staphylococcus aureus
the porosity of the scaffolds, were tested; scaffolds prepared and Escherichia coli, respectively. The cell evaluations showed
with SPLA 50 : 50 wt% displayed a bi-continuous structure. an appropriate environment for cell growth and cell
Findings showed that pressure was the most affected para- attachment.180
meter on the interconnectivity, porosity and pore size of the 4.3.1. Aloe vera. Aloe vera (AV) gel has been used to
produced scaffolds, but the initial concentration of polymer improve structure, composition, biodegradability and cell pro-
solution and temperature did not influence the scaffolds mor- liferation of scaffolds. Additionally, AV can be applied as a
phology or porosity.175 promising candidate for tissue regeneration because of its
Pashkuleva et al.176 produced interlocked and highly ability to stimulate cell migration, proliferation and growth,
porous and fiber web scaffolds from starch blended with poly especially in wound healing. AV has attracted research atten-
(ethylene-co-vinyl alcohol) (SEVA-C) via a wet spinning fabrication because of its biocompatibility, and low toxicity.181 AV
tion. This strategy allowed creation of the SEVA-C fibers from a based scaffolds can be produced by applying various methods.
solution instead of a melt; ensuing fibers presented some fea- Electrospinning, and freeze drying (or, thermal induced phase
tures which distinguish them from the formerly reported melt- separation) are often used for the generation of AV based
spun fibers. They were about five times thinner, much stiffer scaffolds; additionally, molecular self-assembly, and phase
and they had rough surface which is favorable for in vitro bio- separation induced by non-solvent are two potential methods
logical performance. The in vitro evaluations with osteoblast applied to produce AV-based scaffold.182
cell line approved this trend; extraordinarily improved osteo- Addition of varying concentrations (about 0.1–0.5%) of AV
blasts adhesion and proliferations have been reported. The to collagen–chitosan scaffolds accelerated the thermal stability
prepared SEVA-C scaffolds were upgraded by surface and hydrophilicity and reduced tensile scaffolds. The scaffold
functionalization, with a model plasma modification. The exhibited enhanced growth and proliferation of fibroblasts
in vitro findings revealed that osteoblast-like cells proliferate (3T3L1) without showing any signs for toxicity.183 Kim and co-
faster on the altered scaffolds compared to the unchanged authors,184 fabricated transparent ultrathin film scaffolds with
SEVA-C fibers scaffolds.176 AV gel (obtained from leaves) and silk fibroin (SF) for corneal
endothelial cells (CECs). Field emission scanning electron
4.3. Plant extracts microscopy (FESEM) observations showed that the critical
Four different plant extracts, viz. Indigofera aspalathoides, morphology of CECs was shaped on the AV/SF blend rather
Memecylon edule (ME), Azadirachta indica, and Myristica anda- than in the scaffold with pure SF. Assimilation of a small quan-
manica were electrospun with PCL and used for skin tissue tity of AV gel improved the cell viability and sustained its func-
engineering.177 PCL/ME electrospun nanofibrous scaffold tions well. The scaffolds were applied for transplantation into
showed the highest cell proliferation ability for human dermal rabbit eyes where they integrated with surrounding corneal
fibroblasts amongst all diverse scaffolds, with a 31% greater tissue and attached to the surface of the corneal stroma
proliferation rate compared to a control PCL scaffold. without any major inflammatory reaction. The authors
Furthermore, PCL/ME nanofibers showed the lowest cyto- claimed that AV blended SF film scaffolds might be an appro-
toxicity among the all of the electrospun examples, with a pro- priate substitute for alternative corneal grafts for
motion of epidermal differentiation capacity toward adipose- transplantation.184
derived stem cells; PCL/ME could promote epidermal differen- Selvakumar et al.185 produced guided bone regeneration
tiation capacity against adipose-derived stem cells.177 (GBR) using an anti-infective electrospun scaffold by adorning
Cissus quadrangularis contains potential healing agents for segmented polyurethane (SPU) with two-dimensional AV
development of bone therapy.178 Suganya et al.179 exploited the wrapped nanorods of mesoporous hydroxyapatite (Al-mHA).
synergetic osteogenic effect of hydroxyapatite and The Al-mHA frame was presented into an unprecedented SPU
C. quadrangularis extract to generate PCL/C. quadrangularis/ matrix based on combinatorial soft fragments of PCL, poly
hydroxyapatite nanofibrous scaffold. The findings revealed (ethylene carbonate) (PEC), and poly(dimethylsiloxane)
that the cell proliferation on day 5 vs. day 15 was highest for (PDMS), via an in situ approach followed by electrospinning to
the C. quadrangularis-incorporated scaffold vs. the other nano- produce scaffolds. The scaffolds demonstrated great improve-
fibrous scaffolds, while a twofold promotion in proliferation ment in the mechanical characteristics (175%), biocompatibil-
was observed for the other scaffolds vs. the PCL control. The ity and biodegradation versus osteoblast-like MG63 cells
produced nanofibrous scaffold revealed the appropriate rough in vitro, with promising antimicrobial activities against
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different human pathogens; they were inserted in rabbit’s extracts, it was demonstrated that blend of 1% (w/v) AV and 1%
animal model. Compared to pristine SPU scaffold, endochon- (w/v) M. oleifera with Ca-alginate-PEGMA meaningfully improved
dral ossification, early cartilage production, and rapid bone the scaffolds cell proliferation (after ten days of analysis).188
healing at four weeks were reported in the defects filled with
Al-mHA adorned scaffold. The advantages of AV wrapped mHA 4.4. Lignin
frame in stimulating osteoblast phenotype development with Due to brittle nature and inadequate distribution of lignin in
microbial fortification for possible GBR applications were many composites, blending of lignin with other polymers is a
observed.185 challenging proposition. To overcome this drawback, Kai
Furthermore, PCL containing 5 and 10 wt% of lyophilized et al.189 prepared lignin-based functional copolymers with poly
AV powder was electrospun into fiber mats of nanoscale (methyl methacrylate) via radical-assisted polymerization
dimensions and contrasted with PCL/collagen mix for dermal which were further blended with PCL and electrospun into
substitutes.186 It was reported that PCL-AV 10% nanofiber nanofibrous composites. The incorporation of lignin-poly
scaffolds with finer fiber structure, enhanced hydrophilic and (methyl methacrylate) copolymers significantly enhanced the
mechanical characteristics required for skin tissue engineer- mechanical characteristics of the resulting nanofibrous com-
ing. Exudation of F-actin expression and collagen and were sig- posites. However, the morphology and mechanical character-
nificantly enhanced in PCL-AV 10% scaffolds in relation to istics of the electrospun nanofibers were extremely dependent
other nanofibrous scaffolds thus making them a promising on the lignin copolymers contents and their poly(methyl meth-
biomaterial for skin tissue regeneration.186 acrylate) chain lengths. PCL/lignin-poly(methyl methacrylate)
Indeed, some important limitations such as the lack of elec- containing 23% of lignin displayed the reinforcement in
trospinnability and suitable mechanical characteristics exist tensile strength (+32%), Young’s modulus (4 times) and
for AV extract to be applied in the form of nanofibrous storage modulus (4 times) compared to neat PCL. These PCL/
mats.187 In an interesting investigation, biopolymers namely lignin-poly(methyl methacrylate) nanofibers were found to be
gelatin and poly(ε-caprolactone), were applied to solve these biocompatible and promoted the proliferation, attachment
problems and double-nozzle electrospinning method was used and interactions of human dermal fibroblasts than control
to produce hybrid scaffold from gelatin/AV blend and poly(ε- material, PCL nanofibers; potential applications of lignin-
caprolactone) solutions; AV did improve the antibacterial based nanofibers would be developed in biomedical fields.
activity culminating in satisfactory in vitro biodegradation and Additionally, some important lignin-derived scaffolds for bone
accelerating the cell viability without any toxicity.187 Another tissue engineering are mentioned in Table 3.
study was undertaken for improvement of the handling, stabi-
lity in aqueous medium and healing characteristics of algi- 4.5. Plants tissues
nate-based 3D structures applied as wound scaffolds wherein Plant tissues have promising properties rendering them inimi-
Ca-alginate was plasticized with PEG-methyl ether methacry- tably suited for use as scaffolds, including high surface area,
late (PEGMA) and blended with the freeze-dried gel of AV and interconnected porosity, preexisting vascular networks, various
aqueous leaves extracts of Moringa oleifera.188 The produced range of mechanical properties, and superb water transport
scaffolds persisted structurally and was stable almost four and retention.23 Although important progress has been made
times longer than pure alginate materials, while a highly in the production of bioengineered scaffolds for tissue engin-
porous architecture required for tissue scaffolding applications eering, delivery of nutrients in complex engineered human
was maintained after alginate plasticization with PEGMA. It was tissues remains an important challenge. Exploiting the vascu-
reported that AV accelerated the water uptake capability of the lar structure similarities in tissues of animals and plants, the
scaffolds and M. oleifera offered antioxidant capacity, anti- decellularized plant tissues as a prevascularized scaffolds for
inflammatory characteristics and antimicrobial activities. In tissue engineering applications have been documented.3
comparison with scaffolds without incorporation of plant Perfusion-based decellularization was changed for various
Table 3 Some important examples of lignin for scaffolds in bone tissue engineering
Lignin Findings Ref.
Alginate-lignin aerogel Fluid uptake in Tris-HCl buffer of >1600%, good biocompatibility 190
Starch, lignin (from Kraft lignin) or hemicellulose Hydrogels prepared by reactive extrusion demonstrate pH dependent 191
swelling behavior; the amount of citric acid used as cross-linker also
influences both swelling and degradation of the hydrogels. Additional
catalysts used during extrusion slow down degradation
Agarose–lignin composites (lignin from Kraft black liquor) Cross-linked agarose–lignin hydrogels show accelerated mechanical 192
characteristics compared to pure agarose gels
Poly(lactic acid) with up to 15% lignin as filler (organosolv Higher lignin content leads to higher tensile strength, but also slightly 193
lignin from birch wood and Kraft lignin from softwood) decreased water sorption capacity. Organosolv lignin yields slightly better
mechanical results; good biocompatibility against SaOS-2 cells regardless of
lignin type; influencing mechanical properties
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kinds of plants, providing diverse scaffolds geometries. After Thus, the potential of decellularized plants as scaffolds for
decellularization, plant scaffolds were capable of transporting tissue engineering was demonstrated, that can finally provide
microparticles and remained patent. Recellularization of plant cost-efficient and green technology for regenerating large
scaffolds has been accomplished using endothelial cells from volume vascularized tissue mass.
humans which populated the inside surfaces of plant vascula- Adamski et al.23 described two protocols for plant decellu-
ture; pluripotent stem cell-derived- and human mesenchymal larization targeted to tissue engineering appliances; the first
cardiomyocytes-held to the plant scaffolds outer surfaces. used detergent baths to remove cellular matter, while the second
Cardiomyocytes exhibited calcium handling capabilities and one was a detergent-free approach adapted from a procedure
contractile purpose over the course of 21 days (Fig. 16 and 17).3 which isolated leaf vasculature using a hot bleach and salt soak
Fig. 16 Plant scaffolds portrayal before and after decellularization. Spinach leaf before (A) and after (B) decellularization; native (C) and decellular-
ized leaf (D) stained with Safranin and Fast Green. SEM image of surface landscape for both native (E) and decellularized (F) spinach leaves with
inserts showing higher magnification. The quantification of DNA content via CyQuant assay (G). Total protein before and after leaf decellularization
was quantified by Bradford assay (H). Decellularization procedure was used for other plant types and structures (I). Reused with permission from ref.
3. An open access article.
Fig. 17 Spinach leaf vascular scaffolds preserve patency and perfusion abilities after decellularization. Decellularized leaf before (A) and after (B)
perfusion of Ponceau Red. Video frames seizing microsphere location within a leaf vein over time, with the arrow tracing an individual microsphere
(C). Microspheres which crossed vascular walls were amassed and their fluorescence measured (D). Fluorescence images of leaf vasculature per-
fused with beads (E, F). Reused with permission from ref. 3. An open access article.
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to free the leaves and stems. Both approaches leave behind the simultaneous construction of new tissue along with the degra-
extracellular matrix of the plant tissues applied, which can then dation of the matrix. Considerably, the matrix should not be
be employed as scaffolds in tissue engineering. These strategies toxic so that the system can dispose it without disturbing other
presented scaffolds with comparable mechanical characteristics members.194–196,199,200 The biological properties of scaffolds are
and low cellular metabolic impact with ample details.23 an important modulating challenge, because it affects the
scaffolds interaction with tissues and organs. Due to the low

capacity of the biological material to cross-talk with the environ-
5. Assessment of scaffolds in tissue ment, investigations are focused on incorporation of the bioactive
engineering scaffolds to stimulate suitable cellular interaction, migration or
differentiation, tissue information, and incorporation into the
For scaffolds production, extracellular matrix (ECM) has host and to apply bioactive scaffolds for avoidance of unwanted
received significant attentions due to its high biocompatibility, procedures (e.g., scarring). Additionally, the scaffold should avoid
biodegradability, and the possibility for rapid remodeling host immune responses; the immune-inert biomaterials concept
in vivo.194 ECM mainly consist of proteins (such as collagen, has been implemented, and its immune modulatory regulates
fibrin, fibrinogen, gelatin, elastin, etc.), and polysaccharides the immune system (i.e., decreased natural killer cell activity and
(such as alginates, hyaluronic acid, cellulose, chitosan, etc.). T and B cells mediated immunity).199
This complex mixture provides biochemical and mechanical Biological tissue with extremely complex 3D structure has
support to surrounding cells and controls their performance complicated mechanical functions related to mass transport
in regeneration. The applied polymers have chemical charac- characteristics. Thus, important objective of tissue engineering
teristics which can be altered by introducing different chemi- is to abridge this structural complexity and function by apply-
cal moieties that produce derivatives possessing enhanced ing biological scaffolds which offer cells, proteins, and genes
adhesion, cross-linking, and biodegradability properties.194 for tissue reconstruction. It is obvious that the biological
Thus, fabricating biologically mimetic and functionalized materials and structures cannot replicate complex tissue
scaffolds such as bio-active ECM is essential for producing an environments, including different cell types which interact
in vivo-like microenvironment thus mimicking biological enti- with various cytokines to produce extracellular matrices within
ties and stimulating cell-specific responses that lead to tissue cells with hierarchical properties showing mechanical function
regeneration and repair.195,196 Generally, the natural polymers with high non-linearity. Additionally, the porosity of the
are cost-effective, environment-friendly, highly biodegradable, scaffold should enhance its mechanical properties to support
less toxic, and renewable, as well as they reduce low manufac- cell growth; the scaffold with suitable pore size augments the
turing and disposal costs.197 Additionally, they have important quality of cell migration and water absorption, and can stimu-
directing features which significantly control the success of lates the high mass transfer of oxygen throughout the
tissue regeneration including remodeling, biological signaling, scaffold.201 For instance, an ideal scaffold for cartilage tissue
cell responsive degradation, and cell adhesion. However, the engineering is the one with high porosity and pore-to-pore
rapid degradation of the natural polymers is an important interconnectivity; it provides adequate space for in vitro cell
challenging issue. Further, the threats of immune rejection adhesion, in-growth, and restructuring of cells. Interconnected
and disease transmission demand strict monitoring and puri- porous organization facilitates the cell migration, spread of
fication of the natural polymer. The defects of natural and syn- physiological nutrients and gasses to the cells, and discharge
thetic polymers can be compensated by applying composite of metabolic waste and side-products from the cells.202 In the
scaffolds made of some polymers, and their functionalization case of starch/cellulose nanofibers composites, they have been
which offer suitable conditions for tissue regeneration.197,198 applied with proper porosity pore size, mechanical strength,
It should be noticed that suitable scaffolds must be capable and biodegradability for cartilage tissue engineering. All
of repairing body tissues with minimum requirements for cell samples have interconnected porous morphology; however, an
growth, proliferation, vascularization, and host integration. increase in pore interconnectivity is observed when the
Additionally, materials should be degraded naturally during or sodium chloride ratio is increased in the salt leaching.
after the healing procedure. A scaffold has precise character- Scaffolds show adequate mechanical properties for cartilage
istics related to the biological aspect, structure, and chemical tissue engineering applications. The water uptake ratio of
composition.199 The biological aspects of scaffolds consist of nanocomposites can be significantly enhanced by adding 10%
their biocompatibility and non-toxicity features. Indeed, cells cellulose nanofibers. The scaffolds are partially destroyed due
grown in scaffolds should be capable of reproduction and dis- to low in vitro degradation rate after more than 20 weeks.
crimination freely without interference to generate a new Cultivation of isolated rabbit chondrocytes on the fabricated
matrix.200 Thus, an ideal scaffold for tissue engineering is the scaffold reveal that the incorporation of nanofibers in starch
one that can mimic the properties of ECM of tissues for quali- structure improve the cell attachment and proliferation.203
fied and complete regeneration; the function of the supporting Additionally, in some cases, in vitro studies show that the
cell depends on some important factors, including the selected material itself may destroy the results of ex vivo tissue for-
cell lines, underlying materials, surface characteristics, and mation compared to natural tissue matrices. Thus, in the
scaffolding structures. Furthermore, biocompatibility permits in vivo situation, impaired regeneration can be significantly
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influenced by material immunogenicity, unexpected degra- lenges such as donor-site morbidity, the deficiency of resili-
dation time, and curtaining the side effects from degradation ence and mechanical power, regular loss of volume and
products. Considerably, it appears that the matrices closest to fibrous capsular structure still exist. These issues can be
the natural extracellular matrix are the most promising in solved by applying bio-absorbable tissues with high resilience
tissue engineering.201 and large strains.206 Researchers have explored the use of
Indeed, the regeneration and restoration of tissue functions various plants to produce an efficient, inexpensive and scalable
are very challenging. Generally, regenerative therapy using technology for making miniaturized structures which could be
absorbable scaffolds have shown promising results in vivo and applied to repair the muscle, organs and bone via stem cells.
in clinical cases. During the tissue regeneration processes (e.g., Suitable and significant potential of plants structures (such as,
bone), scaffolds may act as a temporary supporting structure to strength, rigidity, porosity, low mass and surface area) may
ensure that the defect/regeneration space is suitable for tissue assist the future explorers to address some of the important
growth, maturation and remodeling thus providing mechani- lingering challenges and limitations in the field of tissue
cal functionality for suitable transfer of loads acting on engineering. Plants display very high surface area to volume
scaffolds to the adjacent host tissues while tissue regenerates; ratio, and their pore structure is uniquely well-made for fluid
so, facilitating in-growth of tissue and vasculature to accelerate transport. For instance, decellularized husks of plants such as
tissue regeneration. Additionally, the scaffolds’ architecture parsley, vanilla and orchids do produce 3D scaffolds which can
plays a critical role during tissue regeneration processes. be primed and seeded with human stem cells to optimize
Because of the intricate relationships between scaffold geome- their growth in the lab dish and, finally, generate innovative
tries, mechanical characteristics, biomaterials and biological biomedical implants.207
processes, investigations in tissue engineering has been domi- An important challenge is the lack of vascularity in
nated by trial-and-error approach-whereby an existing design is scaffolds. The advancement in vascularization approaches is
altered based on the experimental outcomes. Undeniably, the the most needed enquiry in the field of tissue engineering. In
mentioned approach typically needs costly protocols and time- the case of cartilage tissues, which do not have the capability
consuming experiments. In this regard, topology optimization of regenerating themselves up on injury, prolonged in vitro
methods have shown their potential as a powerful tool for the tissue engineering can be the only solution to prevent the
design of scaffold architectures. Topology optimization is a requirement of an eventual joint arthroplasty.208 Plants host a
numerical procedure which iteratively distributes a given similar-looking vascular structure to that found within human
amount of material within a given design space under specific tissues and organs as has been demonstrated recently for
constraints so that the final structure meets specific design decellularized spinach leaf that could grow cardiac tissue. As
targets. This technique has been applied to design scaffolds to these studies continue to explore cellular growth methods with
topologically gain the optimized architecture to match the innovative lab software, an implantable heart with a spinach
desired porosity, elastic modulus and fluid permeability.204 backbone may become a reality. Body tissues are not hom-
The major important scaffold associated issue is the production ogenous structures, and blood vessels are woven throughout
of scaffold in a way that exactly replicates the native features of epithelial tissue and muscle. This vasculature is important for
the tissue. Several natural and synthetic materials have been moving necessary molecules but is tiny and puzzling to re-man-
investigated, but it appears that more efforts are needed in this ufacture on laboratory scale. Haphazard induction of angio-
regard. It is still a challenge to develop optimal stimuli capable genesis might stimulate tumorigenesis, and 3D printing is not
of supporting the cells proliferation and differentiation, produ- yet specific enough to print capillaries; full-size organs tend to
cing suitable and sufficient ECM components, and secreting use a scaffold or template. Leaves have a branched vascular
enzymes that can alter the prepared ECM. As has been men- structure which bears a striking resemblance to several human
tioned before, the ideal biomaterial should be biocompatible, tissues. Although the underlying structure may be quite similar,
non-toxic, non-stimulatory of inflammatory cells, and non- the overlaid tissues are vastly different between plants and ver-
immunogenic. It should also have some precise features tebrate. Modifying strategies related to one species may first be
helping sufficient cell adhesion, proliferation, differentiation modelled using inventive lab software to simplify the transition
into specific phenotype like the mechanical support of the from one model organism to another. Scientists have already
engineered tissue and having porosities permitting diffusion of decellularized a spinach leaf successfully via an altered deter-
nutrients and waste products. Additionally, these materials gent perfusion method. The remaining cellulose structure was
should be biodegradable and allow remodeling as the new evaluated to guarantee that it maintained its transport capacity.
tissue forms and substitute the original build besides being After ensuring that the vasculature was complete, human endo-
decay-resistant at physiological pH and body temperature.205 thelial cells were used afterward, mesenchymal stem cells and
pluripotent stem cells derived from cardiomyocytes. Over 21
days, the heart cells showed contractile function. Finally, the
6. Challenges and opportunities functional cardiac tissue has been grown by applying plant vas-
culature as a model. Subsequently, scientists applied compli-
Tissue regeneration applications have been clinically effective cated computer models to earnestly evaluate and design the
in the treatment of injured body organs, but various chal- transition from bench to bedside.3,23
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One of the vital points of tissue engineering is to harness issue for the generation and storage of the material.210–213
the innate regenerative capacity, and one approach is that the Lately, further eco-friendly sources for biomaterial fabrication
scaffold itself offers regenerative signals to the cells which have been studied, such as syntheses from vegetable oils and
might negate the obligation for prolonged in vitro culture prior polymerization of natural bio-polymers (e.g., cellulose). By
to implantation. Thus, more innovative investigations might exploiting the benign chemistry of plant tissue scaffolds, it
be done to develop further high quality biomimetic biomater- could address many limitations and high costs of synthetic,
ials with added levels of complexity to incorporate multi- complex composite materials. Additionally, there are various
functionality.25,208,209 Applications of scaffolds as delivery issues in the mass production of materials that could be over-
systems for adhesion peptides, growth factors, and cytokines come from using plant tissue. Plants can be easily grown using
are receiving numerous attentions by researchers in the area of good agricultural practices (GAP) and under controlled
regenerative medicine, tissue engineering, and biomedicine. environments.210–213 Moreover, by uniting the eco-friendly
Moreover, the combination of inflammatory inhibitors and plant tissues with perfusion-based decellularization, it has
antibiotics into scaffolds has been used as an approach to shown that there can be a sustainable solution for pre-vascu-
decrease the possibility of infection after surgery. Additionally, larized tissue engineering scaffolds; decellularized plants offer
the use of scaffolds as delivery systems for therapeutic genes is sustainably generated scaffolding for tissue engineering.3,23
undergoing innovative researches. Gene therapy techniques But, it appears that further investigations are needed to under-
which utilize DNA encoding for therapeutic genes potentially stand further applications of this novel technology as it has
offer a valuable method to permit sustained and controlled the potential to develop into a greener solution pertinent to a
release of therapeutic factors.5,6 It should be noted that while myriad of regenerative medicine applications. Moreover,
the challenges are considerable, the opportunities for improv- regarding the use of plants and plant-based polymers as
ing human health in a whole variety of areas are great. Using scaffolds for tissue engineering, further investigations about
plants and plant-derived polymers for the production of the toxicity and health issues should be done, comprehensively.
scaffolds showed remarkable improvement in the mechanical
properties, biodegradation, and biocompatibility, but any
possible risk should be carefully considered. Certainly, further 7. Conclusion
innovative efforts will hasten the advancement of novel
approaches and methodologies in this field. In conclusion, tissue engineering is a fast progressing area in
For tissue engineering scaffolds, the application of plants nano-, bio- and regenerative medicine, with many investi-
as the foundation has various benefits outside their innate vas- gations targeted to the creation of newer biomaterial scaffolds
cular networks. There is a current push in technology develop- with customized properties to produce functional tissues for
ment to become greener and eco-friendly because of the con- specific applications. There are several strategies available to
cerns over anthropogenic climate change and dwindling produce green, natural and synthetic 3D scaffolds that sustain
supplies of natural resources. Typically, tissue engineered the propagation of mammalian cells. In this regard, 3D
scaffolds are fabricated either from animal-derived or synthetic scaffolds ideally embody the innate cellular microenvironment
biomaterials which are expensive and have large environ- and have various potential applications both, in vitro and
mental impact. Animal-derived biomaterials applied widely in vivo. It appears that green chemistry, eco-efficiency, environ-
include native ECM proteins such as collagen I or fibronectin mentally-friendliness and sustainable aspects have begun to
and whole animal tissues and organs. Because of significantly guide the improvement of a new generation of materials as an
large number of animals used, a lot of energy is essential for alternative to conventional biomaterials based on conversion
their upkeep and feeding as well as to dispose of the huge of fossil-derived carbon and finding technologies to decrease
amount of the ensuing waste. Along with this environmental the application of animal and human-derived biomolecules.
impact, animal research also has a plethora of ethical con- Scaffold modifications (e.g., chemical or biochemical) are valu-
siderations, which could be alleviated by forgoing animal able to lessen the reliance of matrix ligands for cell attach-
models in favor of more biologically relevant in vitro human ment, which are critical as the majority of matrix ligands today
tissue models. Synthetic biomaterials are generally fabricated are produced from foetal bovine serum, not a sustainable
from chemical processing of non-renewable resources, such as source for industrially applications because of batch variation,
petroleum, and their generation recurrently produces toxic extreme cost, and ethical considerations obtained from to its
and hazardous by-products. For instance, a biomaterial nega- origin. Moreover, for changing cell culture from simple assem-
tively affecting the environment can be found from Teflon blies to functional tissues, developing complex vascular-like
( polytetrafluoroethylene), an extensively applied synthetic bio- structural scaffolds is vital. Sourcing cellulose from decellular-
material in cardiovascular applications (e.g., tissue engineered ized plant tissue can decrease the cost and simplify the proces-
vascular grafts). Considerable amounts of ozone-depleting sing of scaffold while presenting scaffold vascularity.
gases (e.g., trifluroacetic acid and chlorodifluoroacetate) are Furthermore, in the case of cellulose, there are various oppor-
generated throughout high temperature generation of this bio- tunities to blend it with other biomaterials to acquire a
material. While this is not an issue in the body when Teflon is scaffold with the desired characteristics for specific appli-
applied as a graft, production of by-products is an important cations. As plants and plant-based polymers are derived from
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green and sustainable sources, they meet the requirement for 11 R. Mohammadinejad, S. Karimi, S. Iravani and
novel biomaterials with appropriate properties for tissue R. S. Varma, Green Chem., 2016, 18, 20–52.
engineering and require minimal chemical processing for 12 R. Mohammadinejad, A. Shavandi, D. S. Raie,
industrial applications. J. Sangeetha, M. Soleimani, S. S. Hajibehzad,
Eco-friendly greener and safer technologies can make sig- D. Thangadurai, R. Hospet, J. O. Popoola, A. Arzani,
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Varma (2019) - Plants and Plant-Based Polymers As Scaffolds For Tissue Engineering

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Green Chemistry

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Plants and plant-based polymers as scaﬀolds for

1. Introduction allograft or xenograft extracellular matrix, placing laminated cell

Critical Review Green Chemistry

Dr Iravani has worked on several Prof. Varma (H-Index 107;

Green Chemistry Critical Review

Fig. 1 Cell culture steps for tissue engineering.

Critical Review Green Chemistry

Fig. 3 Important scaﬀolding approaches, and associated major issues.

Fig. 4 Critical parameters to be addressed for development of tissue scaﬀolds.

Green Chemistry Critical Review

Fig. 5 Green chemistry and tissue engineering: important issues.

Critical Review Green Chemistry

Fig. 6 Some important methods for fabricating scaﬀolds.

Fig. 7 Nanofabrication methods applied for producing scaﬀolds.

Green Chemistry Critical Review

3.2. Skin tissue

Critical Review Green Chemistry

Green Chemistry Critical Review

Critical Review Green Chemistry

Green Chemistry Critical Review

Critical Review Green Chemistry

perties, but they did not dissolve in many typical solvents;

lysis of WG. Woerdeman and co-authors,104 achieved electro-

Green Chemistry Critical Review

Table 1 Polysaccharide materials for preparation of tissue scaﬀolds

Polysaccharide materials Applications Ref.

Chitosan, PCL & polypyrrole Neural tissue substitute 112

Chitosan & collagen Hepatocyte attachment 115

Critical Review Green Chemistry

Cellulose Scaﬀold forms Modifications Ref.

Green Chemistry Critical Review

altered with chitosan. Furthermore, the actin and myosin

chemically altered to include sulfate groups for acceleration in

Critical Review Green Chemistry

Green Chemistry Critical Review

Critical Review Green Chemistry

Green Chemistry Critical Review

Critical Review Green Chemistry

Lignin Findings Ref.

Green Chemistry Critical Review

Critical Review Green Chemistry

scaﬀolds interaction with tissues and organs. Due to the low

Green Chemistry Critical Review

Critical Review Green Chemistry

Green Chemistry Critical Review

Critical Review Green Chemistry

Green Chemistry Critical Review

4042–4051. 114 Y. Zhou, C. Zhang, K. Liang, J. Li, H. Yang, X. Liu, X. Yin,

Critical Review Green Chemistry

Green Chemistry Critical Review

184 D. K. Kim, B. R. Sim and G. Khang, ACS Appl. Mater. 1246–1262.

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