Biomedicine & Pharmacotherapy 111 (2019) 964–975

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Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha

Review

Bioaerogels: Synthesis approaches, cellular uptake, and the biomedical T

applications
Fatemeh Pashaei Soorbaghia,b,1, Mojgan Isanejadb,1, Sara Salatinc,d,1, Milad Ghorbanie,1,
⁎ ⁎
Samira Jafarif, , Hossein Derakhshankhahf,
a
Polymer Engineering Department, Faculty of Chemical Engineering, Tarbiat Modares University, Tehran, Iran
b
Andishehpardazan Avin Co., Tehran, Iran
c
Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tabriz University of Medical Science, Tabriz, Iran
d
Student Research Committee, Tabriz University of Medical Science, Tabriz, Iran
e
Department of Chemical Engineering, College of Engineering, University of Tehran, Tehran, Iran
f
Pharmaceutical Sciences Research Center, School of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran

A R T I C LE I N FO A B S T R A C T

Keywords: Aerogels are a class of porous structures with promising physicochemical properties. Among aerogels with
Bioaerogels various origins, polysaccharide aerogels (e.g., cellulose, chitosan, alginate, starch, agar, and so on) have received
Biomedical applications more attention. This group of aerogels can be classified as bioaerogels, which are originated from natural, semi-
Biopolymer synthetic, and synthetic sources with exceptional biomedical applications. This review focuses on bioaerogels
Cellular uptake
from the viewpoints of synthesis approaches, cellular uptake, toxicity, biodegradability, and the biomedical
application perspectives.

1. Introduction biocompatibility, biodegradability, and abundance which are among

Aerogels, as a novel class of porous materials, represent a group of
structures with outstanding characteristics, such as low density
(˜0.003–0.5 g cm−3), high porosity (80–99.8%), thermal resistance
(thermal conductivity of 0.005–0.1 W mK−1), high specific surface area
(500–1200 m2 g−1), ultralight weight, low dielectric constant
(k = 1.0–2.0), and low refractive index (˜1.05), which make them a
promising candidate for a wide extent of applications, namely thermal
insulation, energy storage devices, environmental clean-up, medical &
pharmaceutical applications, food industry, and etc. [1–3]. These solid
materials are formed by replacing the solvent trapped in the gel
structure by a gas (e.g., air) leading to an open-ended mesoporous
structure typically composed of 95–99% empty space [4]. Con-
ventionally, aerogel structures are fabricated based on organic com-
pounds [5], although they can be developed using a large number of
materials, such as metal oxides (e.g., SiO2, TiO2, Al2O3, and ZrO2),
polymers, carbon allotropes (e.g., nanotubes and graphene), transition
metals, polysaccharides, proteins, polymers extracted from biomass,
and etc. [1,6]. Despite the numerous types of materials that could be
utilized in fabrication of aerogel structures, bio/bio-inspired materials
have attracted tremendous interest of the researchers due to their
the most important criteria for potential biomedical applications, such
as tissue engineering, disease diagnosis, drug delivery, and bio-sensing
[7–9]. Polysaccharide-based aerogels prepared by the polymers with
natural resources, namely cellulose, chitosan, chitin, alginate, starch,
pectin, and agar are sustainable materials that properly substitute silica
aerogels in biomedical and pharmaceutical applications [10–12]. In a
recent work by Zhou et al., superhydrophobic cellulose aerogels with
ultralow density of less than 5.08 mg/cm3 and high porosity of 99.68%
were fabricated via a facile freeze-drying process in order to clean
polluted water from oil and organic solvents [13]. Mustapa et al. stu-
died the impregnation of herbal extracts (i.e., phytol and C. nutans) into
alginate and silica aerogels, respectively. The results indicated that al-
ginate aerogel with 53 m2/g specific surface area and average density of
0.18 g/cm3 showed higher phytol loading in wet impregnation and
better C. nutans release kinetics than silica aerogel [14]. Alginate
aerogels were also reported as superabsorbent materials which ab-
sorbed more saline water (0.9 wt.% NaCl solution) as compared to
distilled water, opposite to what regular absorbents do [15]. In another
research by Ding et al., chitin nano-porous aerogels with low density
(0.23–0.27 g/cm3) and superior specific surface area (366 m2/g) were
fabricated via a new method using NaOH–urea as solvent and ethanol

⁎
Corresponding authors.
E-mail addresses: Samiraa.jafari1362@gmail.com (S. Jafari), Derakhshankhah.hossein@gmail.com (H. Derakhshankhah).
1
Contributed equally.

https://doi.org/10.1016/j.biopha.2019.01.014
Received 15 December 2018; Received in revised form 1 January 2019; Accepted 5 January 2019
0753-3322/ © 2019 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/BY-NC-ND/4.0/).
F.P. Soorbaghi et al.
as coagulant. In addition to low density and large surface area, the
resulting aerogels exhibited thermal stability, high mechanical in-
tegrity, and biocompatibility which made it a promising candidate for
biomedical applications, as well as insulators and catalyst supports
[16].
From another perspective, to use the advantages of applying bio-
materials while overcoming the technical obstacles in preparation
procedure of aerogel structures, such as low solubility, severe
shrinkage, etc., many research have recently focused on hybrid organic-
inorganic aerogel structures. Regarding this idea, hybrid aerogel
structures benefit the intrinsic characteristics of biomaterials (i.e., non-
cytotoxicity, renewability, stability, gelation chemistry, etc.), as well as
improved and tunable mechanical and chemical properties [17,18].
Ayers et al. investigated chitosan-silica hybrid aerogels and concluded
that the ratio of chitosan to silica was a key parameter that potentially
determined physical properties of the aerogels. They also investigated
biocompatibility (i.e., hemolysis and cytotoxicity) of these composites
and introduced diverse applications for them, such as drug delivery and
wastewater treatment [19]. Martins et al. fabricated alginate-starch Ca-
crosslinked hybrid aerogels with surface area in the range of
183–544 m2/g via CO2 induced gelation method followed by super-
critical drying. Bioactivity behavior was observed due to the presence
of calcium in the matrix, showing that the structure was not cytotoxic,
and the cells were able to grow on it. Consequently, this hybrid material
in a scaffold structure was found to be an attractive candidate for tissue
engineering and regenerative medicine (TERM) applications [17].
The present review summarizes the articles focusing on aerogel
structures based on materials with natural resources (i.e., poly-
saccharides including chitosan, chitin, cellulose, alginate, and agar).
Regarding the mentioned biomaterials, synthesis and processing
methods as well as their biomedical applications reported in literature
are outlined, although the complete study of bio-aerogels from all as-
pects is much further than the focus and interest of this paper.
2. Synthesis
The key factor in preparation of aerogel structures is to form a 3D
network with high porosity and proper stability. The conventional
method commonly applied for preparation of almost all kinds of aero-
gels (e.g., organic, inorganic, and hybrid) is a wet chemical synthesis
approach called “sol-gel reaction”. The procedure generally consists of
the main steps of mixing precursors, hydrolysis, polycondensation,
gelation, aging, and drying, and every step is implemented by related
parameters, such as precursors’ concentration, pH, temperature, type of
solvent, time, etc., for tuning characteristics of the prepared aerogel
structure [20–22]. The hydrolysis and polycondensation reactions can
be catalyzed by using acidic or basic catalysts. Among the mentioned
steps, drying of the gels is the key step which determines many prop-
erties of the aerogels. It is expected that the solvent, residues, by-
products, and unreacted chemicals are removed, while the 3D network
is preserved intact. Selecting a suitable drying technology depends on
the end-product characterization that is needed. The most intensively
used methods for drying the wet gels are supercritical drying (high-
temperature and low-temperature), ambient-conditioned evaporation,
and freeze-drying [23]. Fig. 1 shows a schematic of aerogel conven-
tional synthesis procedure and the process parameters.
The above-mentioned conventional procedure is reported as the
most applied method for producing aerogels. Any other aerogel pre-
paration methods are a derivative or modification of the mentioned
procedure. The aerogels prepared by the conventional sol-gel method
possess a monolith structure, while there are many applications, such as
drug delivery systems that require microparticles with specific shapes.
To prepare these types of aerogels, new techniques have been applied
modifying the sol-gel process. For instance, Alnaief used emulsification
of the silica sol with an oil phase followed by supercritical drying step
of oil-gel dispersion for production of microsphere aerogels [23]. The
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Biomedicine & Pharmacotherapy 111 (2019) 964–975
processing steps for fabrication of polysaccharide-based aerogels are
basically similar to silica aerogels (conventional process) [1] as follows:
1) a hydrogel is formed from an aqueous sol induced by a chemical or
physical cross-linker promoter, 2) the water in the structure of the gel is
exchanged by alcohol to form an alcogel (note: this step can be cir-
cumvented if the prime gel is prepared by the alcohol as the solvent),
and 3) the final step is drying the wet gel by proper methods. It should
be noted that the main reason for replacing the water with another
solvent, such as alcohol or acetone is the low solubility of water in
supercritical CO2 in case of using SC drying method [24]. Some of the
key parameters to master the process for enhancing the performance of
bio-aerogels are the precursor content, pH, gel temperature, and aging
time [25]. The nature of polysaccharides with different surface func-
tional groups defines the solvents and gelling methods. In the following
subsections, some polysaccharides-based aerogels are briefly reviewed.
2.1. Chitin
In a research by Tsioptsias et al., chitin powder was dissolved in a
mixture of DMA and LiCl at room temperature. The solution was cast in
a mold and left at room temperature overnight followed by washing
with water to obtain solid chitin hydrogel. The hydrogel was then
converted to alcogel using methanol or propanol and dried by super-
critical drying method [26]. Chow et al. used the same procedure to
produce chitin aerogel with high density of 8 g/m2 and low porosity of
9.8% [27]. Silva et al. dissolved chitin in an ionic liquid (i.e., 1-butyl-3
imidazolium acetate) to produce aerogels with densities of
0.039–0.063 g cm−3 and porosities of 84.1–90.2%. They applied di-
verse drying methods including vacuum, freeze-drying, and super-
critical drying (SCF) to evaluate the impact of drying step on the shape
and morphology of the prepared aerogels and realized that the SCF was
significantly better than the others because the amount of remained
ionic liquid was noticeably trivial and thus could not influence the
phase behavior of the mixture considerably (Fig. 2) [28]. In a recently
published study, Dassanayake et al. prepared chitin aerogels through
dispersing chitin powder derived from shrimp shells in a sodium hy-
droxide-urea-water solution followed by several freezing/melting cy-
cles (from −20 °C to 5 °C) to attain a clear, viscous solution of chitin.
The produced chitin aerogels, formed by freeze-drying the chitin hy-
drogels, had a specific surface area of 14 (m2/g) and micropores volume
of 0.002 (cm3/g) (Fig. 3) [29]. Concluding the research on chitin
aerogels, chitin needs a modification/regeneration step prior to sol
preparation due to weak solubility associated with [16,30].
2.2. Chitosan
Several methods have been introduced for preparing chitosan hy-
drogels, such as ionically cross-linked hydrogels, polyelectrolyte com-
plexes, electrorheological fluids, and entangled gels [7]. In a commonly
used method, an aqueous solution of chitosan was prepared by dissol-
ving chitosan in an aqueous acetic acid solution, and then the gel
formed by adding the polymeric solution drop-wise to NaOH solution
(pH inversion) [25]. The research show that air-drying leads to col-
lapsing of the chitosan structure and huge shrinkage of it; therefore,
best drying method for chitosan hydrogels is CO2 supercritical drying.
In a work by Singh et al., chitosan-L-glutamic acid aerogel was prepared
using a similar process. The Water-soluble L-GA was added slowly to the
chitosan in an acetic acid solution to form the gel. The solvent was
exchanged to acetone and ethanol and subjected to supercritical drying
[31]. In another study, Zhang et al. fabricated chitosan aerogels with
and without polyvinyl alcohol (PVA), as a reinforcing element to im-
pede chitosan aerogel shrinkage, by preparing a homogenous chitosan
solution in acetic acid/ethanol (with volume ratio of 2/3) and o-
phthalaldehyde followed by addition of PVS solution. The resulting
solution (with and without PVA) were subjected to solvent exchange
process with ethanol and then were dried via CO2 supercritical fluid to
F.P. Soorbaghi et al.
Fig. 1. A schematic of aerogel conventional synthesis procedure.
form chitosan (control) and chitosan-PVA (P/CA) aerogels. As seen in
Fig. 4, the prepared P/CA aerogels (with specific surface area (SSA) of
425.92 (m2/g) and total pore volume of 2.055 (cm3/g)) exhibited al-
most no shrinkage as compared to control aerogels (with SSA of 307.68
(m2/g) and total pore volume of 0.9257 (cm3/g)) [32]. In a recently
published research, Radwan-Pragłowska et al. prepared chitosan aero-
gels via dissolving chitosan in a solution containing acetic acid and
Tiliaplatyphyllos extract (derived by grounding the dried flowers) fol-
lowed by adding aspartic and glutamic acid and propylene glycol. The
resulting mixture was put in a microwave reactor and then was washed
and dried through lyophilization. The prepared aerogels showed sui-
table 3D structure and excellent swelling properties [33].
2.3. Alginate
As reported by Robitzer et al., a 2% (w/w) alginate solution in
distilled water was prepared and added drop-wise to a salt solution of
MCl2 (M is Ca2+, Ba2+, etc.) or a molar HCl solution to form alginate or
alginic acid gels. The obtained aerogel was a loose network of inter-
connected fibrils retaining most of the gel volume [25]. In a similar
procedure, Wang et al. prepared calcium alginate aerogel (CAA) by
adding sodium alginate drop-wise to the CaCl2 solution at room
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temperature. The hydrogel was frozen at ultra-low temperature fol-
lowed by vacuum freeze-drying for 12 h to obtain CAA aerogels (Fig. 5).
The obtained product was used as a sorbent for removing Pb from
wastewater [34]. Mehling et al. fabricated alginate aerogels by dissol-
ving Na-alginate in water and adding the mixture to the solution of
CaCO3 and GDL. The resulted solution was cooled down to 4 °C, and the
final alcogel was subjected to supercritical drying [35]. In a research by
Pantic et al., alginic acid sodium salt was dissolved in water at room
temperature and added drop-wise to CaCl2 solution. The hydrogel was
then converted to alcogel by ethanol and dried at supercritical condi-
tion with CO2 to produce aerogels [36]. In a recent study, Para-
skevopoulou et al. fabricated native alginate and tungsten (W)-doped
alginate aerogels (W-alginate) for catalysis applications through pre-
paring a homogenous mixture of sodium alginate in water and CaCO3
solution followed by addition of δ-gluconolactone which was placed in
fridge to complete gelation process. Alginate wet-gels were then pro-
cessed for solvent exchange with ethanol/water mixtures and pure
ethanol followed by CO2 supercritical drying to form native alginate
aerogels, and W-alginate aerogels were prepared in a similar condition
via adding alginate wet-gels to a solution of ditungsten complex [W2(μ-
OEt)2(OEt)2(EtOH)2Cl4] and ethanol. Fig. 6 illustrates native alginate
aerogels (with a bulk density of 0.056 ± 0.008 (g cm−3) and specific
Fig. 2. Optical micrographs and SEM images of the pre-
pared chitin aerogels exposed to diverse drying methods:
(a) as-prepared, (b) Soxhlet extraction + vacuum, (c)
Soxhlet extraction + freeze-drying, (d) Soxhlet
extraction + SCF (step 2) and (e) Soxhlet extraction + SCF
(step 1 + step 2).
Reprinted from [39]. Copyright (2011), with permission
from Elsevier.
F.P. Soorbaghi et al. Biomedicine & Pharmacotherapy 111 (2019) 964–975

Fig. 3. FE-SEM images of chitin powder (A) and chitin aerogels (B).
Reprinted from [29]. Copyright (2018), with permission from Springer Nature.

Fig. 4. Photos of control (a) and P/CA (d) aerogels showing axial (b and e) and radial (c and f) shrinkage of each sample.
Reprinted from [84]. Copyright (2018), with permission from Elsevier.

Fig. 5. SEM images of the prepared CAA at low (A, B) and high (C, D) magnification.
Reprinted from [34]. Copyright (2016), with permission from Elsevier.

surface area of 481 (m2 g–1)) and W-alginate aerogels (with a bulk
density of 0.09 ± 0.01 (g cm−3) and specific surface area of 381
(m2 g–1)) [37]. In another recent research, Li et al. prepared alginate/
clay aerogels via adding the same weight percentage of alginate and
clay to a solution of water and sodium salt followed by drop-wise
adding of p-toluenesulfonic acid monohydrate to the prepared solution
to achieve pH 6 and/or pH 8. The resulting mixture was frozen and then
freeze-dried to obtain alginate/clay aerogels, and it was found out that
the specific density of the aerogels prepared at pH 6 (equal to
393 ± 54 (cm3/g)) was significantly greater than that of pH 8 (equal to
232 ± 20 (cm3/g)) without affecting the density noticeably [38].
As a conclusion, alginate dissolves in water at about 85 °C, forms

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F.P. Soorbaghi et al.
Fig. 6. SEM image of native alginate aerogel (A), photos of native alginate aerogel (B, left) and W-alginate aerogel (B, right), and SEM image of W-alginate aerogel
(C).
Reprinted from [37]. Copyright (2018), with permission from Elsevier.
strong gel structure at room temperature, and is added to a salt solution
of MCl2 (M is Ca2+, Ba2+, etc.) drop-wise. The hydrogel is converted to
alcogel, and the final aerogel is obtained by drying the wet gel via the
supercritical or freeze-drying method.
2.4. Agar
The notable characteristic of Agar is the high difference between
melting and gelling temperatures (normally about 45 °C) and forming a
double-helix state while cooling. Robitzer et al. prepared agar hydrogel
beads by rapidly heating a 2% (w/w) of agarose solution in a micro-
wave oven at 85 °C and adding the polymeric solution drop-wise to a
cooled water bath. The solvent was then replaced with ethanol and
subjected to supercritical drying [25]. In another research by Zhang
et al., a solution of 0.4% agar in water was prepared at room tem-
perature and heated until a clear solution obtained. The process was
followed by adding ZIF-8/C3N4 to the solution for preparing a hybrid
aerogel (Fig. 7). The obtained hydrogel was cooled down at room
temperature followed by freeze-drying process at −80 °C to form
aerogels [32]. As stated by Mikkonen et al., agar gels retained their
structure after freeze-drying, while showed a lower density as com-
pared to supercritical drying method, and the structure was collapsed
via air-drying method [10]. In a recent study, Tan et al. fabricated
graphic carbon nitride (g-C3N4)-agar hybrid aerogels via preparing
their hybrid hydrogels by thermo reversible phase transition which
were then subjected to cryo-drying process to produce hybrid aerogels.
The prepared aerogels had a specific surface area of 38.04 (m2 g−1)
with proper 3D structure [39].
As a conclusion, agar (consisting of agarose and agapectin fractions)
dissolves in water at about 85 °C and forms strong gel structure at room
temperature. The final aerogel is obtained by drying the wet gel via
supercritical drying.
2.5. Cellulose
Highly porous cellulose aerogels can be fabricated from micro-
fibrillated cellulose hydrogels by vacuum freeze-drying to be used as an
oil absorbant [40]. Sehaqui et al. studied the effect of solvent exchange
Fig. 7. Resulted SEM images of hybrid aerogels with 50.0% ZIF-8/C3N4 at diverse enlargements (A and B) and SEM-EDX elemental mappings of C, N, and Zn for
hybrid aerogels (C).
Reprinted with permission from [32]. Copyright (2017) American Chemical Society.
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methods on aerogel density. The general procedure was dispersing
nanofibrillated cellulose in water and mixing the aqueous solution with
other solvents (i.e., tert-butanol or ethanol). The mixture was subjected
to centrifugation and freeze-drying to form NFC-aerogel (Fig. 8) [41].
Hoepfner et al. prepared nanofibrillar cellulose aerogel by adding Ca
(SCN)2_4H2O to a mixture of cellulose in deionized water while stirring
at 110 °C until dissolution of cellulose. The gelation occurred while
cooling to about 80 °C, and the gel was then washed with ethanol (or
water) and, after several days of aging, dried via supercritical (freeze-)
drying method to form aerogel (cryogel) [42]. Recently, Zeng et al.
prepared cellulose aerogels by denim fabrics, cotton linter, and mi-
crocrystalline cellulose (avicel) powder as diverse kinds of cellulose.
Each cellulose type was underwent a dissolution process at 100 °C in
ionic liquids followed by immersion in distilled water to form hydro-
gels, which were then dried through freeze-drying or supercritical
dying to produce cellulose aerogels. They evaluated the impact of
drying method and denim concentration on the structure of aerogels
and gathered that biggest surface area (equal to 374 (m2 g−1)) and pore
volume (equal to 4.10 ((cm3/g)) were achieved by supercritical drying
at the concentration of 6 wt% [43].
Some of the recent researches on polysaccharide-based aerogels are
listed in Table 1.
3. Biomedical applications of bioaerogels
Recently, aerogel formulations with a unique set of properties have
attracted plenty of attention for applicability in biomedicine. However,
all types of biomaterials employed in the medical fields need to be
previously assessed for any adverse biological effects like inflammatory
response, allergic, coagulation/hemolysis, and carcinogenic responses.
Therefore, the biocompatibility of aerogels is a particular property that
must be initially tested before being addressed for any biomedical ap-
plication. Polysaccharide-based aerogels combine the intrinsic char-
acteristics of the aerogel structure and those of the biocompatible
polysaccharides, signifying that they are suitable for biomedical ap-
plications [44]. In fact, the development of bioaerogels to mimic ex-
tracellular matrices (ECM) in body has enabled their different biome-
dical applications, such as drug delivery, tissue engineering scaffolds,
F.P. Soorbaghi et al.
Fig. 8. SEM images of surface (A) and cross-section (B) of an NFC aerogel (density 30 kg m−3).
Reprinted from [41]. Copyright (2011), with permission from Elsevier.
Table 1
Examples of the investigated polysaccharide based aerogels.
Natural compound Structure Ref.
Chitin [16,26,47]
Chitosan [7,19,31]
Alginate [14,15,34,85]
Agar [8,25]
Cellulose [40,42,48,86]
and biosensing [1,45]. Here we address the very recent utilizations of
bioaerogels in the field of biomedical applications.
3.1. Drug delivery
During the last decades, a wide variety of novel delivery systems
have been developed and reported for the prolonged and controlled
release of pharmaceuticals and other bioactive compounds through
different routes of administration. However, the desired formulations
are considered to be able to precisely protect the loaded cargo against
degradation in physiological environment resulting in the predictable
controlled drug release, minimizing adverse effects, and reducing the
administered dose. Bioerogels provide a good biocompatibility, large
surface inner areas, and high surface to volume ratios allowing for high
drug loadings. Therefore, they have been widely recognized as pro-
mising biomaterials to design drug delivery carriers. Different techni-
ques have been developed for loading drug molecules into aerogels,
such as the addition of drug to the reaction mixture before the gelation,
the addition of drug through the aging step, and the addition of drug
during adsorption/precipitation in the synthesized aerogels (Fig. 9) [3].
There are definite advantages to be gained by the addition of drugs
before the sol-gel process because of its simplicity and flexibility for
pharmaceutically active agents. For this, drug molecules are initially
dissolved in a suitable solvent and are subsequently entrapped in the
aerogel network through the gelation step. After aging, solvent ex-
change, and drying steps, it is expected that the drug molecules to be
loaded into the aerogel. The secondary strategy is based on the diffusion
of drug molecules into the pores of the alcogel from the aging solution.
Herein, the diffusion rate of drug molecules into the alcogel pores may
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Biomedicine & Pharmacotherapy 111 (2019) 964–975
take a long time depending on the size of pores, size of the drug mo-
lecules, and the initial concentration of the aging solution [9]. The third
method includes contacting a drug solution with the aerogel following
the super-critical drying step giving rise to the diffusion of drug mole-
cules into the pores of aerogel and surface adsorption. The solvent can
subsequently be removed in order to obtain a drug loaded aerogel [10].
The structure, composition, and hydrophobic nature of biopolymer
aerogels predetermine the features, such as the dispersion of the drug in
the aerogel matrix, the crystalline/amorphous phases of drug, as well as
the accessibility of the loaded drug for solvent through release process.
The drug release profile from aerogels is also determined by a combi-
nation of these properties. Moreover, Veronovski and co-workers de-
monstrated the volume and surface area of the aerogel as key para-
meters controlling the release of drug [6]. Notably, drug loading
capacity can be increased with an increase in carrier porosity. Besides,
carriers with higher surface area bring about a rise in diffusion and
solubility of the drugs. Nonetheless, there has been no more systematic
effort to investigate the relationship between the drug release profile
and the structure (composition) of aerogels.
Polysaccharide aerogel-based dried particles can be considered as
potential drug carriers to successfully reach the lungs by inhalation due
to their high porosity and low density, offering a superior air flow
ability. Gonzalez et al reported the first systematic study for using
bioaerogels from starch, pectin, and alginate in the form of micro-
spheres as pH-responsive delivery systems of ketoprofen and benzoic
acid. Aerogel matrix was investigated to control the release profiles of
drugs via a pH-dependent mechanism [46]. Some polysaccharides, such
as chitosan and alginate with known mucoadhesive properties can be
also used for prolonging the residence time of drug delivery systems on
the mucosal surfaces and thereby improving the drug absorption. In this
regard, alginate based aerogels in the form of microparticles (< 50 μm)
were developed as mucosal matrices for the mucosal dual delivery of
ketoprofen and quercetin [42]. Another group of researchers prepared
3D multi-membrane alginate-based aerogels with onion-like archi-
tectures, forming free spaces perfectly suited for cell or drug in-
corporation. So that, the more the number of membranes, the more
increased drug loading and prolonged drug release [47].
Cellulose is another promising candidate for aerogel synthesis and is
one of the most abundant polysaccharides found in the earth. Bacterial
cellulose aerogels encapsulating dexpanthenol and L-ascorbic acid were
prepared for potential applications as wound dressing. The results
showed the dependency of drug loading capacity and release kinetic
profiles to the bioaerogel thickness and the solute concentration of the
bath solution. However, bioaerogels based on the bacterial cellulose
suffer from some disadvantages, such as drying shrinkage during the
preparation process leading to severe inconsistencies in pore structures.
In this regard, Zhao and co-workers reported the designing of the cel-
lulose bioaerogel from bamboo as a pH-responsive drug delivery carrier
[48]. Cellulose nanofibers can be converted into the bioaerogel form
through the physical drug adsorption and subsequent freeze-drying,
providing a foam-like structure with very light weight for oral
F.P. Soorbaghi et al.
Fig. 9. Preparation methods of drug-loaded biaerogels: addition of drug to the reaction mixture before the gelation (A), addition of drug through the aging step (B),
and addition of drug during adsorption/precipitation in the synthesized bioaerogels (C).
controlled drug delivery. It was found that the produced aerogel pro-
vided 5.66 and 3.25 times increase in the oral bioavailability of bend-
amustine hydrochloride as compared to the intravenous and oral
bioavailability of the pure drug solution, respectively. Besides, the
mucoadhesive property and the floating tendency of cellulose bioaer-
ogel suggested it as a successful gastroretentive drug delivery system
[40].
More importantly, the efficiency of polysaccharide aerogel-based
carriers can be ameliorated using hybrid aerogels comprised of dis-
similar inorganic and organic (polysaccharide) materials. These hybrid
materials can embrace the intrinsic properties (i.e., high porosity and
surface area) of aerogels along with the biodegradability of biopolymers
and the mechanical properties of inorganic components, resulting in a
novel system with the ideal physicochemical properties [49,50]. The
design and application of a novel layered material consisting of two
distinct aerogels were firstly reported by Ulker and Erkey using a silica
aerogel core encapsulated by an alginate aerogel layer as a delivery
device capable of carrying molecules with different sizes. It was shown
that the alginate bioaerogel layer played a key role to protect the hy-
drophilic silica aerogel core and inhibit burst drug release at the same
time for sequential release of compounds [51]. In a very recent study,
López-Iglesias et al. prepared alginate aerogels loaded with Salbutamol
by the means of inkjet printing for prolonged pulmonary delivery. As a
result, they witnessed the controlled release of Salbutamol from the
aerogels in PBS (pH 7.4) in comparison with the burst dissolution of
free Salbutamol in the same condition (Fig. 10) [52].
3.2. Tissue engineering scaffolds
Traditional techniques of tissue engineering are based on the use of
harvested autologous, allogeneic or xenogeneic tissues or organs.
However, these techniques encounter serious challenges, such as donor
shortage, the risk of pathogen transmission, and unwanted immune
reactions [53]. Therefore, the most current efforts in tissue engineering
have been made to develop naturally 3D scaffolds with good capability
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Biomedicine & Pharmacotherapy 111 (2019) 964–975
of supporting cell attachment, spreading, and proliferation to re-
generate a patient’s own tissue and organ possessing biological func-
tions [54]. Smetana et al. also reported that ratio between surface hy-
drophilicity and hydrophobicity was a key factor in determining the cell
adhesion virtue of the scaffolds [55,56].
During recent decades, the application of aerogels have attracted
plenty of attention in the foregrounds of cell culture and tissue en-
gineering technologies. Due to the desired physical properties of aero-
gels over many other types of organic polymer scaffolds, a variety of
aerogels have been and are currently used as scaffolds in the re-
generative medicine and have made possible to conduct a growth
substrate for cells within the system. In fact, the outstanding properties
of aerogels, such as the highly high 3D porous structure for cell at-
tachment along with a tunable network of interconnected pores for the
nutrient and oxygen supply to the cells and the elimination of cellular
metabolic by-products make them ideally suited for regenerative
medicine purposes [41]. Alginate is the most commonly used poly-
saccharide bioaerogel in tissue engineering owing to its relatively low
cost, biocompatibility, low toxicity, and simple gelation mechanism.
However, the protein adsorption of alginate is limited due to its hy-
drophilic nature leading to inhibition of the cell adhesion and therefore
its limited applications for tissue engineering [57]. A number of at-
tempts have been made to overcome this drawback including blending
alginate with other polymers [58], chemical grafting with oligopeptides
[59], and the addition of hydroxyapatite [60]. In a recent study, hybrid
alginate–lignin aerogels have been generated to function as efficient
cell-scaffolds. It was expected that lignin would be able to reduce the
alginate hydrophobicity and thus create an ideal environment to sup-
port the adhesion, growth, and differentiation of the cells. Besides, in
the presence of lignin, the scaffold degradation rate might become very
low and match with the rate of new bone tissue regeneration [61]. A
similar system developed with the chemical interaction between the
cationic chitosan and negatively charged molecules of gelatin to gen-
erate hybrid bioaerogels with a network organization and enhanced
mechanical properties suitable for bone tissue engineering [62]. Porous
F.P. Soorbaghi et al.
Fig. 10. SEM image of salbutamol (3% (w/w)) loaded porous alginate aerogel particles produced by inkjet printing (A) and in vitro salbutamol release profile from
alginate aerogels in PBS (pH 7.4 P solution (37 °C, 100 rpm) (white circles) and dissolution profile of salbutamol (black squares) at the same conditions (B).
Reprinted from [52]. Copyright (2019), with permission from Elsevier.
chitosan aerogel-based scaffolds were also fabricated using lyophiliza-
tion and supercritical carbon dioxide drying techniques. The obtained
results displayed that the scaffold treated with supercritical carbon
dioxide possessed a much greater surface area, providing a high por-
osity for cell proliferation as compared to the lyophilized one [63].
Swollen 3D nanocellulose aerogels with desirable properties (i.e.,
specific surface area up to 308 m2/g and porosity up to 99.7%) have
been demonstrated as efficient scaffolds in supporting cell growth and
proliferation [64]. In another study, dual-porous cellulose aerogels
were prepared via filling the voids of a temporary template of fused
porogen with cellulose solution and subsequent supercritical carbon
dioxide drying. This process resulted in production of promising aero-
gels in terms of homogeneity with improved mechanical properties and
biocompatibility after seeding fibroblasts cells on the surface of the
prepared scaffolds (Fig. 11) [65]. Among different aerogel formula-
tions, microsphere structured aerogels have been shown as excellent
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Biomedicine & Pharmacotherapy 111 (2019) 964–975
options for biomedical applications, such as tissue engineering, and,
until now, a wide variety of aerogel microspheres have been designed
and investigated for these purposes [66,67]. It was reported that the
highly porous structure of cellulose nanofibril aerogel microspheres
provided a large surface area, low bulk density, and high water ab-
sorption capacity to support cell growth and differentiation [66]. Be-
sides, cellulose aerogel scaffolds and their hybrid forms with other
biomaterials, such as chitosan, alginate, and agarose have been devel-
oped for different tissue engineering applications [68]. A hybrid aerogel
scaffold designed by Lu and co-workers using nanocellulose fibers de-
rived from bacterial cellulose to immobilize collagen for tissue en-
gineering applications. They linked the aldehyde groups created by the
oxidation of hydroxyl groups on nanocellulose fibers and the amino
groups of collagen. This aerogel passed cell culture and MTT assays
suggesting that it could support the growth and proliferation of cells for
scaffolding applications [66].
Fig. 11. (A) SEM images of dual-porous cellu-
lose aerogels (porogen size 100–200 mm) re-
inforced by infusion with poly(methyl metha-
crylate) PMMA at the lyogels step via infusion
bath concentrations of 20 mg.ml−1 (a: E/W/
20; b: E/P/20) and 80 mg.ml −1 of PMMA in
acetone (c: E/P/80). (B) Fluorescence (λex
= 460 nm, 100-fold enlargement) images of
fibroblast cells on the surface of dual porous
cellulose aerogels upon 7 days of cultivation
and visualization by DAPI staining. E/W/0 (a),
E/P/0 (b), C/P/0 (c), E/W/80 (d), E/P/80 (e),
and C/P/20 (f).
Reprinted from [65]. Copyright (2015), with
permission from Wiley Online Library.
F.P. Soorbaghi et al.
3.3. Biosensing
A biosensor is known as an analytical device that combines a bio-
logical component with a physicochemical detector and is used to de-
tect very small amounts of an analyte. Overall, the biosensing perfor-
mance is affected by the spatial structure feature and the size of
analytical device. The use of 3D frame materials has offered a crucial
strategy to overcome the challenges of the low instability and sensi-
tivity associated with 1D and 2D materials [69].
The application of bioaerogels as the 3D host matrices for biosensors
to improve biosensing technologies capable of detecting proteins or
large biomolecules is growing. In fact, the unique properties of
bioaerogels, such as biocompatibility, mechanical stability, and porous
architectures are salutary for loading of biomolecules and maintaining
biological activity, as well as providing a large surface area for in-
creasing liquid diffusion and transfer of electrons. Over the last years,
the removal of excessive harmful amounts of proteolytic enzymes (e.g.,
serine protease human neutrophil elastase (HNE) and matrix metallo-
proteases (MMP)) from chronic wounds, which are responsible for the
degradation of growth factors and the ECM proteins, has been given a
top priority in wound healing. In this regard, Edwards et al. fabricated a
single dressing platform based on nanocellulosic aerogels for the si-
multaneously detection and wound dressing treatment of chronic
wounds. As nanocellulosic aerogel acted as the transducer surface in
which the transducer was conjugated to a fluorescent peptide substrate
providing the selectivity and specificity needed for detecting HNE in
chronic wound fluid [70]. The same group used the cellulosic (cellu-
losic filter paper) and nanocellulosic (nanocellulosic aerogels and cel-
lulose nanocrystals) materials as transducer surfaces of biosensors for
protease detecting and sequestration at the concentrations present in
chronic wound fluid. Besides, the conjugation of a tri-peptide substrate
to the materials was examined to improve the sensor selectivity and
sensitivity. The results derived from this study suggested that 3D
structure of cotton-based nanocellulose aerogel was more suitable for a
biosensor layer showing the potential ability for detecting HNE, at the
levels found in wound fluid with a limited sensitivity concentration of
0.13 U/mL, relative to two other materials [71]. Chitosan has been
reported as a promising biomaterial for the development of biosensors
due to its excellent bioadhesivity, film forming ability, 3D scaffolds
properties, and accessibility of the functional groups to link biomole-
cules. However, the weak electrical conductivity and electrochemical
performance of chitosan make it difficult to be used as an independent
material in biosensing applications. Therefore, the combination of
chitosan with conducting polymers or metal nanoparticles is necessary
for improving its biosensing performance [72]. For instance, a flexible
aerogel-based biosensor was fabricated by the assembly of carbon na-
notubes into chitosan 3D frame. Good mechanical stability and superior
electrical conductivity of carbon nanotube made it appropriate to re-
medy the shortcoming of chitosan aerogel [73]. Some of the recent
biomedical applications of bioaerogels are summarized in Table 2.
Table 2
Some of the biomedical applications of bioaerogels.
Application Aerogel type
Drug Delivery Alginate aerogel
Alginate aerogel microspheres
pH-responsive chitosan aerogels
Cellulose nanofiber aerogel
Polyethylenimine-grafted cellulose nanofibril aerogel
Hybrid aerogel of chitosan, carboxymethyl cellulose and
graphene oxide
Tissue engineering scaffold Nanocellulose-based aerogel
Dialdehyde nanocellulose/collagen compositw aerogel
Bio-sensing Cellulosic and nanocellulosic aerogel
Cotton-based peptide-cellulose aerogel
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Biomedicine & Pharmacotherapy 111 (2019) 964–975
4. Biocompatibility, toxicity, biodegradability, and intracellular
uptake
For any substances to be used in biological applications, bio-
compatibility is a prerequisite characterization that should be de-
termined. Various in vivo and in vitro methods are utilized for bio-
compatibility testing of a large range of materials including different
polymers and biopolymers [49]. In a research by Fernández-Cossío
et al., bioactivity and biocompatibility of agarose gel was investigated
by an in vivo method for the purpose of using it as a tissue filler in a
subcutaneous implant. The implant showed some biodegradation by
macrophages, and there were no observable histopathologic indications
of necrosis, calcification, tumorigenesis, gel migration in tissues, or
infection over the evaluation period (8 months) [50]. Chitosan, as one
of the most commonly used carriers in drug delivery systems, has been
widely investigated from various aspects, such as their biodegradation
and metabolic fate in the body [46]. The most commonly applied assays
for evaluating biocompatibility of chitosan carriers are in vitro cyto-
toxicity analysis, which measure the effects on cells after exposure to
toxic substances and are usually performed in less than 96 h [74].
Onishi et al. studied biodegradability and body distribution of 50%
deacetylated chitin. Biodegradation characteristics were investigated
via an in vitro method by incubation with lysozyme which was found to
efficiently degrade chitosan. Body distribution was assessed using ip
injection to mice, and the results showed no accumulation in the body
and easy urinary excretion [75]. Chitosan toxicity was studied by Rao
et al., and it was reported that no significant toxic impacts were ob-
served in in vivo acute toxicity tests in mice, indicating that chitosan
was nontoxic. Besides, no eyes or skin irritation was reported in rabbits
and pigs, respectively, and the sterilized films were not pyrogenic [76].
In another research, Orive et al. assessed biocompatibility of alginate
and alginate-based microcapsules through various in vitro techniques.
Polyphenol and protein content of different compositions, purities, and
viscosities of alginate were determined and found to be sensitive and
valid techniques for assessment of biocompatibility. It was concluded
that alginates could be utilized as carriers for implantation and cell
immobilization [64]; however, elemental composition and molecular
details of the utilized alginates and their gels, such as proportion of
mannuronate (M) and guluronate (G), viscosity, counterion amounts,
and wetability were observed to affect biocompatibility of the samples.
As reported by Tam et al., the alginate with higher viscosity and in-
termediate G content showed more biocompatibility than samples with
contrary properties [53]. Similar research were performed on cellulose,
as a natural polymer with a wide variety of derivatives. Miyamoto et al.
applied in vivo methods for appraising the absorbance by living tissue
and foreign body reaction for cellulose and some derivatives, i.e., me-
thylcellulose, ethyl cellulose, hydroxyethyl cellulose, aminoethyl cel-
lulose, and cellulosic polyion complexes. It was observed that absor-
bance by living tissues depended on the crystallinity and chemical
structure of polymers, while foreign body reaction was mild and almost
the same for all the tested samples showing that cellulose could be
Status Ref.
Carrier for the fast delivery of nonsteroidal anti-inflammatory drugs and [56,65]
improve the bioavaiability of nicotinic acid [64]
In vitro delivering of ketoprofen and benzoic acid [57]
For the PH-controlled delivery of 5-fluorouracil [59]
Carrier for oral controlled delivery of bendamustine hydrochloride [66]
pH- and temperature-responsive drug delivery carrier [58]
For the pH-controlled delivery of 5-fluorouracil
Scaffold for supporting cell growth and proliferation/In vitro [60]
For biological wound dressings and to promote cell activity and proliferation [63]
For wound-dressing and protease sensor design/In vitro [61]
Biosensor for detecting human neutrophil elastase/In vitro [62]
F.P. Soorbaghi et al. Biomedicine & Pharmacotherapy 111 (2019) 964–975

Fig. 12. Confocal fluorescence microscopic images of in vitro cell internalization of CNPs (25 μg/mL) in SCC7, U87, HT29, PC3, and A549 cells at various pH
conditions (A). In vivo NIRF images regarding distribution of CNPs (200 μg/μL head) in the mice transplanted SCC7, U87, HT29, PC3, A549 tumors.
Reprinted from [82]. Copyright (2017), with permission from Elsevier.

considered as a biocompatible material by some physical and/or che-
mical transformations [77].
Although native chitosan has not been investigated, the intracellular
uptake and distribution of chitosan/DNA complexes have been studied
in vitro [78]. Chitosan polyplex uptake at 37 °C was 3-fold higher than
that at 4 °C, yet this could be due to the increased interaction but not an
ATP dependent endocytic mechanism. So, the authors suggested nu-
clear localization and also little dissociation of the DNA from the
chitosan [79]. In a more comprehensive study, Leong et al. stained
lysosomes and found some co-localization with chitosan DNA nano-
particles. However, the majority of the polyplexes were found in the
cytosol [80]. A complex of doxorubicin with chitosan has also been
studied; complexes entered cells through an endocytic mechanism
which was not further elucidated [81]. Hydrophobic (5-β-cholanic
acid) modified glycol chitosan nanoparticles (CNPs) were internalized
into cancerous cells through all the endocytic mechanisms studied, i.e.,
clathrin coated vesicles, caveolae, and macropinocytosis (Fig. 12). This
study agreed with that of Leong et al. over the fact that some particles
were lysosomal, but most were not [82]. Unfortunately, these studies
all involve nanoparticle uptake of relatively large (> 100 nm) nano-
particles or aggregates of complexes and not just labeled chitosan.
Dodane and Vilivalem reported that chitosan had membrane perturbing
properties that did not decrease cell viability [83]. It is likely that
chitosan and chitosan nanoparticles enter the cell via cell membrane

973
F.P. Soorbaghi et al.
perturbation due to the cationic charge associated with them [46].
5. Conclusion
This review summarized the recent articles on bioaerogel structures
based on biomaterials, i.e., chitosan, chitin, agar, alginate and cellulose,
focusing on material characteristics, synthesis methods, and their po-
tential biomedical applications. It was demonstrated that bioaerogels
represented outstanding characteristics, such as low density, high por-
osity, low thermal conductivity, high specific surface area, ultralight
weight, etc. Also, owing to their natural origin, they have attracted
tremendous interest of the researchers due to their biocompatibility,
biodegradability, and abundance. As shown, the general synthesis
procedure for fabrication of aerogel structures is almost similar to the
conventional sol-gel method used for preparation of silica aerogels. The
process starts with mixing of the precursors to form a sol. After that, the
hydrolysis/polycondensation reactions take place leading to the for-
mation of a gel structure, called “hydrogel”. The next step after for-
mation of the hydrogel is usually a solvent-exchange step leading to
formation of an alcogel. The final and key step to change hydrogel/
alcogel into aerogel is the drying step which is implemented via various
methods, such as supercritical drying, freeze-drying, and ambient-
condition evaporation. It was indicated that this step had a profound
effect on the final structure of the prepared aerogels, and supercritical
drying and freeze-drying were introduced as the most applied methods.
Diverse biomedical applications of bioaerogels in drug delivery, tissue
engineering scaffolds, and biosensing were introduced, and it was re-
vealed that they had a strong ability to be utilized in each of the
mentioned fields, considering their unique above-mentioned virtues.
Moreover, from biological aspects, it was shown that several assays
have been done on bioaerogels or their biomaterial precursors which
have confirmed their biosafety, although more research needed to be
carried out to appraise their behavior in biological media meticulously.
In sum, bioaerogels are recognized as promising biomaterials prone to
be further studied and developed for novel biomedical applications
which are of paramount importance in the current century.
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