Biomedical applications of silica-based aerogels: a comprehensive review

Abstract

Silica-based aerogels are the appropriate and well-known porous materials that have become interesting in science and technology, especially in the biomedical community. Silica-based aerogels are prepared from silica gels where the liquid is drawn out of the network structure so that its three-dimensional structure is not disturbed. From a nanotechnologist's perspective, silica aerogels will have a special place in nanotechnology because they have low density, large surface area and nanometer pores, and the size of their pores can be adjusted in different ways. In addition to their prominent features, these materials are very attractive despite the possibility of changing their chemical composition according to the desired applications. Recent advances in silica-based aerogels as well-known porous materials have had a great impact on extensive application in various fields mostly in high-tech science and engineering, and biomedical usages, including environmental control, tissue engineering, cancer diagnosis, cancer therapy, biomarking, and drug delivery. Many vital and key issues in the field of (nano) material applications, especially their usages in biomedicine, should be investigated before clinical applications. Some of these important issues include toxicity, bioactivity, compatibility, and so on. Minimal toxicity and maximum biodegradability are two important future challenging issues related to the interaction of (nano) materials and biological systems. So, it is essential to know how to design and synthesize nanoscale structures for medical and biological applications. Engaging with materials whose characteristics can be customized is very important in the medical field. In this review, we intend to provide up-to-date information on silica-based aerogels and applications in biomedicine. Hence, this review summarizes biomedical applications of silica-based aerogels and discusses the potential toxicity induced by them. The present study focuses on the basic concepts and recent advances in silica-based aerogels in the biomedical field. Biomedical applications of silica-based aerogels

Full text

Vol.:(0123456789)
1 3
Macromolecular Research
https://doi.org/10.1007/s13233-023-00142-9
REVIEW
Online ISSN 2092-7673
Print ISSN 1598-5032
Biomedical applications ofsilica‑based aerogels: acomprehensive
review
FatemehSoghraJahed1· SaminHamidi1,2· MonirehZamani‑Kalajahi1· MohammadrezaSiahi‑Shadbad2,3
Received: 16 December 2022 / Revised: 7 February 2023 / Accepted: 14 February 2023
© The Author(s), under exclusive licence to The Polymer Society of Korea 2023
Abstract
Silica-based aerogels are the appropriate and well-known porous materials that have become interesting in science and tech-
nology, especially in the biomedical community. Silica-based aerogels are prepared from silica gels where the liquid is drawn
out of the network structure so that its three-dimensional structure is not disturbed. From a nanotechnologist's perspective,
silica aerogels will have a special place in nanotechnology because they have low density, large surface area and nanometer
pores, and the size of their pores can be adjusted in different ways. In addition to their prominent features, these materials
are very attractive despite the possibility of changing their chemical composition according to the desired applications.
Recent advances in silica-based aerogels as well-known porous materials have had a great impact on extensive application
in various fields mostly in high-tech science and engineering, and biomedical usages, including environmental control, tissue
engineering, cancer diagnosis, cancer therapy, biomarking, and drug delivery. Many vital and key issues in the field of (nano)
material applications, especially their usages in biomedicine, should be investigated before clinical applications. Some of
these important issues include toxicity, bioactivity, compatibility, and so on. Minimal toxicity and maximum biodegradabil-
ity are two important future challenging issues related to the interaction of (nano) materials and biological systems. So, it is
essential to know how to design and synthesize nanoscale structures for medical and biological applications. Engaging with
materials whose characteristics can be customized is very important in the medical field. In this review, we intend to provide
up-to-date information on silica-based aerogels and applications in biomedicine. Hence, this review summarizes biomedical
applications of silica-based aerogels and discusses the potential toxicity induced by them. The present study focuses on the
basic concepts and recent advances in silica-based aerogels in the biomedical field.
Extended author information available on the last page of the article

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Graphical abstract
Biomedical applications of silica-based aerogels
Keywords Antimicrobial properties· Drug delivery· Silica-based aerogels· Tissue regeneration· Toxicology
1 Introduction
1.1 Aerogels structure
Aerogels are solid gels with nanometer pores, light den-
sity (0.003–0.5g cm−3), porosity, wide surface area
(500–1500 m2 g
−1), sizeable internal size and tight
mechanical strength, which have gas in pores that have
replaced the liquid [1]. Aerogels are more famous due
to their internal structure and architecture, and the type
of their constituent materials is usually the next priority.
These structures are made using many primary raw mate-
rials such as minerals, organic and hybrid [2]. For the first
time, Kistler in 1931 introduced aerogels prepared using
silica, cellulose, agar, gelatin and albumin [3]. Primary
aerogels were produced from inorganic compounds.
Mineral aerogels constitute the largest number of aero-
gels. These are set up from alkoxides and incorporate
aerogels from different metal oxides, e.g., silicon—(SiO2),
alumina—(Al2O3), titania—(TiO2), zirconia—(ZrO2)
and different oxides. Among inorganic aerogels, aerogels
synthesized based on silica are widely used [4, 5]. Nor-
mally, silica-based aerogels display holes in the scope of
5–100nm and a normal pore measurement somewhere
between 20 and 40nm. A substantial trait of silica-based
aerogels is their mesoporosity which is governed by modi-
fying the sol–gel preparation method [6].
Multifunctional organic monomers used to prepare
primary emerging organic aerogels (in 1987) contin-
ued by supercritical drying [7]. Resorcinol–formalde-
hyde and melamine–formaldehyde aerogels are the most
broadly contemplated organic-based aerogels [8–10].
Organic aerogels possess some normal factors regard-
less of the dissimilarities beginning from the utilized
synthesis routes. In particular, they have a small pore
size (≤ 50nm), have high explicit surfaces (400–1000
m2 g−1) and are available as a solid platform, which is
prepared from either associated colloidal particles or
polymeric chains of around 10nm [11]. Recently aero-
gels have attracted a lot of attention from researchers and
governments due to their potential of being eco-friendly,
which has led to the expansion of their applications.
These applications include; the utilization of aerogels as
micropollutant scavengers [12], for thermal insulation
and sound absorption [13], for high energy harvesting
efficiency [14, 15], for high-performance supercapacitor
[16, 17], biomedical applications [18] etc.

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1.2 Synthesis ofaerogels
Forming a gel in an aqueous solution using compounds that
create chemical or physical crosslinks is the first pave in the
aerogel preparation. At the next stage, the liquid in the gel
is displaced with a solvent, which will eventually solvent
penetrate the gel. Finally, the solvent is removed or dried
using different methods [19].
According to the drying method, three categories; aero-
gels, xerogels and cryogels can be synthesized resulting
from supercritical drying, ambient-pressure drying, and
freeze-drying, respectively. Sol–gel process is the standard
way to synthesize aerogels [20]. Different processing steps
(i.e., gel formation, aging, and drying steps) are shown in
Fig.1.
In the sol–gel method, first, a colloidal matrix in a liquid
(sol) is prepared from its precursor and then a porous solid
phase (gel) is formed by adjusting different parameters such
as pH, temperature, and the chemical composition of the
precursors, etc. [22].
In the aging stage, the formed gel is immersed in solu-
tions such as alcohol or a combination of water and alcohol
for greater strength [23, 24].
In the aging process, two events occur at the same time
but at explicit velocities: (1) deposition of smaller dissolved
particles on larger particles (2) neck growth between depos-
ited silica particles and re-particles [25].
Several parameters, such as the solvent type, solvent
amount, time duration, temperature and pH, affect this
step's gel architecture. The nature of the exchange solvent is
very important in the aging process because unappropriated
solvents with high vapor pressure may cause gel shrinkage.
For instance, the pore size of the material ascends in the
sequence isopropanol > methanol > ethanol > propanol
> isobutanol > butanol > hexanol when utilized as aging
solvents [26]. After the aging process, water was removed
by washing the gel with alcohol or heptane.
Drying is important in aerogels preparation. In this step,
the solvent is removed from the gel, and the drying route
highly influences the gel's texture, porosity, and structural
properties. The resultant gels are called xerogels, cryogels,
and aerogels, depending on the way of dying [27].
If the solvent is removed by evaporation, the “ambi-
ent-pressure drying process” is called the drying method.
During evaporation, the liquid–gas surface tension leads
to capillary tension, which collapses as the gel contracts
[28]. Despite the gel shrinkage risk, the ambient-pressure
drying method is safer and cheaper than the other methods
[29]. The materials obtained from this drying method are
named xerogel.
In a freeze-drying way, the shirking possibility is
reached to a minimum as a prevention liquid–gas inter-
face [30]. Crystal formation, through the process, leaves
large voids in the gel structure that make the structure
more fragile. Modifying the gel surface before drying his
limitation may bypass [31, 32]. Furthermore, the freez-
ing rate affects the size of pores, as fast freezing makes
pores smaller [33]. Although freeze-drying is a green and
straightforward drying route, setup requirements, i.e., very
low temperature and pressure, are limiting parameters [4,
34]. Cryogels are obtained from the freeze-drying method.
Fig. 1 Gel formation, aging
and drying steps in the sol–gel
method [21]

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A supercritical fluid is used in the drying process in
aerogel formation. Supercritical drying avoids pore col-
lapse using low surface tension solvents [35]. CO2 is one
of the well-known supercritical fluids to prevent the struc-
ture damage. However, this drying method's high energy
consumption and time-wasting are limitations of this dry-
ing method [36].
1.3 Silica‑based aerogels
Silicon alkoxides are used to synthesize silica-based aero-
gels, including tetraethoxysilane (TEOS), tetramethox-
ysilane (TMOS), methyltrimethoxysilane (MTMS) and
polyethoxydisiloxane (PEDS) [37]. First, the material from
which silica-based aerogel is synthesized and hydrolyzed
by acid or base catalysis using water or a mixture of water
with various solvents, usually alcohols, acetone, dioxane,
tetrahydrofuran, etc. The alkoxide groups are then replaced
by hydroxyl groups in the precursor, which eventually lead
to the form of silanol groups. During the condensation reac-
tion, which begins at the same time as hydrolysis, water or
alcohol is eliminated and siloxane bonds are formed [38].
Several parameters, such as the molar ratio of precursors,
temperature, pH, type of catalyst and time, influence the
crosslinking of the final product. Silica precursors for aero-
gel synthesis can be made using less expensive materials
such as water glass instead of expensive silicon alkoxides.
Using cheap inorganic, organic, and agricultural wastes like
kaolin, bagasse ash, and rice husk also are reported [39–42].
Sodium silicate (Na2SiO3) is obtained by alkaline extrac-
tion and then formed by adding silica gel. In these cases, pH
is crucial in the particle dimension and silica lattice porosity.
Generally, a highly porous silica structure with very small
particle sizes is synthesized using low pH [18]. In this kind
of synthesis Na+ specious eliminate from the gel structure
to neutralize the material. Replacing Na+ with H+ ions is
performed by washing or using ion exchange resins [26].
Silica-based aerogels owing to unique physical and chem-
ical features promise a new era of technologies. During past
decades, the application of silica aerogels has been extended
in many research areas. For example, the use of silica-based
aerogel as a corrosion protective additive was indicated to be
a promising approach in real-life corrosion protection appli-
cations [43]. Other applications of silica aerogels include;
the optimization of the thermal conductivity of materials
[44], adsorption [45], catalyst carriers [46], optical fibers
[47] etc. One of the important applications of silica-based
aerogels is their biomedical applications, which will be dis-
cussed in the following sections.
2 Biomedical applications ofsilica‑based
aerogels
Table1 shows the important biomedical usages of silica-
based aerogels and their benefits versus conventional
approaches.
2.1 Silica‑based aerogels asantibacterial agents
Bacteria are classified into two main groups, including
gram-positive and gram-negative indicating their cell wall
design that affects bacterial susceptibility. The cell wall of
gram-positive groups is composed of a dense peptidoglycan
section attached to teichoic acids. The peptidoglycan layer of
Gram-negative bacteria is thinner with an outer membrane,
making them more potent against antibacterial agents [48].
Bacterial infections, especially resistant bacteria, are
spreading around the world. This way, drugs such as antibi-
otics or anti-viruses are resistant to germs that can be bacte-
ria, viruses and some parasites called antimicrobial resist-
ance. Antimicrobial resistance prevents conventional drugs
from being harmed and not only stays in the patient but also
spreads to others. Improper use of antibiotics by a doctor or
inappropriate use by both people are essential factors in this
phenomenon. According to reports from the World Health
Organization (WHO) in 2019, more than 2.8 million folks
were infected with drug-resistant bacterial diseases, which
resulted in the death of approximately 35,000 people in the
United States. In addition, around 33,000 people die each
year in Europe from refractory bacterial infections [49, 50].
Given these figures, however, drug-resistant bacteria appear
to have become severe challenges in hospital instruments,
Table 1 Important biomedical usages of silica-based aerogels and their benefits versus conventional approaches
Biomedical application Advantages
Antimicrobial activity Carriers for efficient loading of bioactive materials or antibacterial agents
Bone regeneration Platforms with large surface area and interconnected networks for bone scaffold material and tissue engi-
neering
Nerve regeneration and prosthetics Silica-based aerogels tolerate chemical modification versus other biomaterials, be as an intelligent neuronal
implant to incorporate an electrically-active interface
Drug delivery Delivery of drugs with different physicochemical properties. Managing the release of drugs by loading the
drugs through the silica-aerogel synthesis

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food preservation and the health community worldwide [51,
52].
There are various mechanisms for interpreting antibi-
otic resistance, including changing the antibiotic's target
site or changing the drug's metabolic pathway, reducing the
drug's accumulation in the cell, or inactivating it. To com-
bat microbial resistance, an urgent approach is needed for
new approaches and the development of newer antimicro-
bials [53]. These mechanisms can be intrinsic or acquired
resistance. Intrinsic resistance to bactericidal agents is attrib-
uted to chromosome encoding. It happens automatically via
a low tendency to target, reduced bactericidal permeability,
secretion of antibacterial components out of bacteria, and
removal of antibacterial materials by enzymes [54, 55].
In acquired resistance, the resistance strategy results from
horizontal gene transfer between different or identical bacte-
rial species [56]. Different techniques using new materials
are developed to bypass the antibiotic resistance mechanism,
Fig. 2 The potential antimicro-
bial mechanisms of nano-
structured systems containing
metals [60] (ROS: reactive
oxygen species; ATP: adenosine
triphosphate)

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but they also have some limitations. For example, the accu-
mulation of metal oxide/metal nanoparticles reduces their
antimicrobial activity [57]. Carbon-based and metal/metal
oxide components can also be very toxic at high levels [58].
Nanoparticles composed of lipids have disadvantages such
as low capacity, the release of harmful byproducts, and low
stability as antibacterial agents [59]. The potential antimi-
crobial mechanisms of nanostructured systems containing
metals are detailed in Fig.2 [60].
In this regard, aerogels, especially silica-based aerogels,
have fascinated scientist’s considerations due to their specific
properties. Silica is known as a biocompatible material and
was accepted as "Generally Recognized As Safe (GRAS)”
by the U. S. Food and Drug Administration (FDA) in 2010
[61]. Since then, different silica-based materials have been
applied as carriers, medical and dental applications, clinical
imaging, cancer diagnosis and therapy, cosmetic and food
additives, etc. [61]. Inherently, silica aerogels have no anti-
bacterial activity, but by functionalization or modifying their
surfaces and antibiotic loading [62, 63], they can release
antibacterial activity.
2.2 Antibacterial agent doped silica‑based aerogels
Transforming the surface charge of aerogels from nega-
tive to more positive by adding cationic groups and amino
acids makes them powerful antibacterial agents with contact
mechanisms. Negative charges are distributed in the cell wall
of bacteria, which exposes them to interact with positively
charged bactericidal materials, conducting them cell death
by electrostatic interaction [64].
Antimicrobials either kill bacteria or slow down their
growth process. The bactericidal mechanism of these sub-
stances is usually interpreted in four ways. 1—prevent cell
wall formation, 2—disruption in DNA construction, 3—
inhibition of protein proration, 4—cell wall destruction [60].
Several parameters affect the electrostatic interaction
between bacteria and aerogels, such as the hydrophobic-
ity and roughness of aerogel surfaces. Moreover, in this
strategy, the bacteria adhesion to the surface of aerogel
is minimized by a hydrophobic surface. It is reported that
bacteria usually colonize on hydrophilic surfaces. Bactria
adherence minimizes with modification of aerogel surface
with silylating agents [65]. For example, hydrophobization
of silica aerogel via methylation reaction using trimethylsilyl
chloride (TMCS) (Fig.3 [65]) provides a high inhibition
efficiency of hydrophobic silica aerogel against bacterial
adhesion. Moreover, silica aerogels can act as an antibacte-
rial agent by functionalization or modifying their surface and
antibiotic loading [62, 63].
In one study, nanoparticles of copper oxide and copper
as antibacterial materials were located on silica thin films.
Antibacterial activity investigation indicated that copper
nanoparticles have a remarkably improved effect on bacteria
killing than copper oxide nanoparticles due to further elec-
tron transfer between copper nanoparticles and bacteria [66].
Oh etal. reported a hydrophobic nanoporous silica aero-
gel (HNSA) that has potential in healthcare applications.
The hydrophobic nanoporous silica aerogel was produced
Fig. 3 a Schematic of hydrophobization of silica aerogel via meth-
ylation reaction using TMCS, b static water contact angle measure-
ments of TMCS-functionalized silica aerogel (hydrophobic), and c
panel relates the number of S. typhimurium LT2 bacteria per unit area
(mm2) remaining on surfaces [65]

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through sol–gel method by tetraethyl orthosilicate and tri-
methylsilyl chloride polymerization. The antiadhesive prop-
erties were investigated through dip-inoculation in a mixture
of gram-positive Staphylococcus aureus and gram-negative
Escherichia coli O157:H7. The success of HNSA synthesis
was verified using AFM, SEM, AFT-FT-IR and XPS stud-
ies. The results showed the excellent antiadhesive properties
of HNAS against E. coli and S. aureus. This behavior is
ascribed to the air bubbles formation that prevents bacteria
from reaching the surface and the decrease of van der Waals
interactions between the HNAS and bacteria due to the pres-
ence of pores throughout the HNAS [67].
Similarly, the same group in another work studied the
bacterial anti-adhesion properties of hydrophobic silica
aerogel against Salmonella Typhimurium and Listeria
innocua. The authors found that the smaller size of HNAS
pores from bacteria length prevents the bacteria penetra-
tion into the aerogel. This property makes HNAS a more
effective food-contact surface material than common food-
contact materials [65].
2.3 Silica aerogels intissue engineering; bone
regeneration
Aerogels are suitable materials for tissue engineering due
to specific physical characteristics in general biocompatibil-
ity, high and tailorable porosity, and mechanical strength
[68–70]. Furthermore, silica-based nanomaterials have tun-
able pore size and active surface functionalities, so they
are significant in tissue engineering [71]. According to the
synthesis conditions, silica-based aerogels surface has many
silanol groups, which could improve their bioactivity, pro-
mote cell attachment, proliferation and differentiation and
also exhibit controlled biodegradation or resorption rate
simultaneous with the new tissue formation [72]. In this
direction, Sani etal. [73] synthesized silica aerogel from
rice husk ash (RHA) via the simple sol–gel ambient-pressure
drying (APD) technique and applied it as a potential alterna-
tive material for tissue engineering applications. Figure4
represents images of human dermal fibroblast cells (HSF
1184) after I 24 and II 48h culturing before and after expo-
sure to calcined silica aerogel.
The aerogel composite of silica/poly-ε-caprolactone was
investigated by Ge etal. as a bone scaffold material in bone
tissue engineering [74]. They showed that adding alkaline
silica aerogel could neutralize the acidic condition of cell
growth during polycaprolactone (PCL) degradation. It was
found that by the wt/wt ratio of 0.5:1 of silica aerogel to
PCL, the environment remained constant for up to 4weeks,
giving a good atmosphere for cell survival and growth.
Mallepaly etal. [75] prepared a silk fibroin silica aero-
gel scaffold as a biomaterial. The study on the invitro cell
culture with human foreskin fibroblast cells showed the
silk fibroin aerogel scaffold is cytocompatible and cells are
present within the scaffold. The silica aerogel network can
transfer nutrients and metabolic wastes to increase cell pro-
liferation. This scaffold with tailorable properties has the
potential for tissue engineering application.
Fig. 4 Images of human dermal
fibroblast cells (HSF 1184) after
I 24 and II 48h culturing. a
Untreated and b exposed to 1.0
wt% of calcined silica aerogel
[73]

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Ding [76] fabricated a chitin silica aerogel that can absorb
an aqueous solution similar to extracellular matrices. To test
the potential application of this aerogel as a biomaterial, the
cell studies were performed on fibroblast cell attachment
on chitin gels that it was well and the typical morphologies
were maintained compared with the control sample.
Chitosan-silica mesoporous aerogels based on chitosan
and tetraethoxysilane (TEOS) as inorganic silica precur-
sor and 3-glycidoxypropyl trimethoxysilane (GPTMS) as
crosslinker agent was synthesized by Reyes-Peces etal. [77]
for tissue engineering applications. These biomaterials have
osteoregenerative properties. The result indicated that the
aerogels are biocompatible and bioactive without cytotoxic
effects. In addition, the control of bioactive hydroxyapatite
spherulite layer formation in simulated body fluid (SBF)
induces the adhesion and proliferation promotion of osteo-
blasts. The study results indicate the potential application of
the proposed chitosan-silica hybrid aerogels in bone regen-
eration and maturation.
Maleki etal. synthesized a silica-silk fibroin bioaerogel
through the one-pot aqueous sol–gel process using tetra-
ethylorthosilicate and silk fibroin (SF) biopolymer [78].
The 14-day treatment invitro showed the silica-SF hybrid
aerogels of this study are cytocompatible and non-hemo-
lytic. Also, their surfaces are amenable to the osteoblast's
attachment, growth, growth, and proliferation. The authors
used the Spague-Dawley rats with bone defects for invivo
experiments. The evaluation based on X-ray radiology and
micro-CT showed new bone tissue formation after 25days
of implantation. Furthermore, toxicology studies on blood
samples confirmed silica-SF aerogel has no toxicity. Finally,
this bioaerogel can be used as a bone regeneration promoter.
All the synthesis process is represented in Fig.5.
Hegedus etal. combined the β-tricalcium phosphate
(β-TCP) with silica aerogel composite through sol–gel
technique [79]. The study on the release rate effect of
calcium, phosphate and orthosilicate ion on the activity
of osteogenic and bone healing at different temperatures
showed that the released calcium and phosphate ion is
optimum to assist bone rebuilding; the dynamic of silica
dissolution is dependent on sintering temperature. The
results indicated that the β-TCP-silica aerogel composite
treated at or less than 1000 °C positively affects the osteo-
blastic activity of MG63 cells. This aerogel can be used in
bone-substitute bioactive material.
The hydroxyapatite (HA) was incorporated in silica
aerogel through sol–gel technique and then the ambient
temperature drying method. The invitro studies indicated
that the cell viability affiliates on the HA/SiO2 weight pro-
portion and silica-rich aerogels in the ratio of 0.5 have
the highest cytocompatibility and enhance the viability
and growth of normal human’s fibroblast cells. So this
HA incorporated silica aerogel can be used as soft tissue
engineering biomaterial [80].
Reséndiz-Hernández etal. [81] synthesized a silica
aerogel with pseudowollastonite particles by two-step
sol–gel route and then ambient-pressure drying. The
invitro cytotoxicity study using rat osteoblast cultures
showed high cell viability and proliferation on silica/
pseudowollastonite aerogel, making it a biocompatible
Fig. 5 The scheme of silica-SF
aerogel hybrid scaffold prepara-
tion using sol − gel reaction,
unidirectional freeze casting,
and supercritical drying method
[78]

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material. The results indicated that this aerogel has a high
potential for bone tissue regeneration.
Firuzeh Sabri etal. evaluated the polyurea-crosslinked
silica aerogel as a biomaterial [82]. The biocompatibil-
ity of this aerogel was indicated using invivo studies on
Sprague–Dawley rats. It is reported that the synthesized
chitosan-silica hybrid aerogels, which show high hemoly-
sis and low cytotoxicity, may be applied as a biomaterial
for tissue engineering [83].
Lazar etal. [84] presented a polymethylmethacrylate sil-
ica aerogel-based composites containing hydroxyapatite par-
ticles and calcium phosphate for artificial bone replacement.
2.4 Nerve regeneration andprosthetics
Since the aerogel surface is amorphous, it can be a suitable
platform for cell adhesion and proliferation. This feature
seems vital for cells that must be attached and anchored to
the substrate before proliferation. In general, neurons are
non-migratory cells, and recent research has focused on
using aerogels as neural prosthetics. Recent research shows
that aerogels have very interesting surface and bulk proper-
ties for use as nerve scaffolds [85–87]. Investigations have
revealed that PC12 cells grow very fast on aerogels in com-
parison to polystyrene Petri dishes. A schematic illustration
of the interaction between the electric field, aerogel and
PC12 cells at the microscopic level is given in Fig.6.
Using silica-based aerogels for nerve conduits prom-
ises good news [86, 87]. Lynch etal. [87] examined the
extension of neurites by PC12 cells plated on matrigel-
coated and collagen-coated mesoporous aerogel surfaces.
They have successfully established the methodology
for the adhesion and growth of PC12 cells on polyurea-
crosslinked silica aerogels. In addition, they quantified
neurite behaviors and compared their response on aerogel
substrates with their behavior on tissue culture (TC) plas-
tic and polydimethylsiloxane (PDMS). They found that, on
average, PC12 cells extend longer neurites on crosslinked
silica aerogels than on tissue-culture plastic and, that the
average number of neurites per cluster is lower on aerogels
than on tissue-culture plastic.
In addition, some aerogel systems bare chemical reac-
tions very well compared to many biomaterials such as
collagen, so they are used as a platform for inserting elec-
trical interface used as aerogel neural scaffold.
A customized direct current (DC) electrical stimulation
chamber was introduced as a smart aerogel to generate
a consistent electrical field across interconnected silica
aerogel coupons (Fig.7) [88].
This investigation revealed that interconnected sil-
ica aerogel surfaces conducive to longer PC12 neurite
Fig. 6 a Schematic of the aero-
gel structure at the microscopic
level with the orientation of the
external electric field. In white
is the ARF-CA structure formed
by chains of beads and in black,
the pores within the structure. b
In the presence of an electrical
field, the structure of the aero-
gel generates a current (blue
arrows) owing to the electrically
conductive nature of ARF-CA.
c Influence of pores and ARF-
CA bulk structure on the current
induced by an external field.
Due to the conductive nature of
the ARF-CA and the dielectric
nature of the pores, a positively
charged layer is formed in the
pores surrounding the ARF-CA
structure. d PC12 cells sense
the induced electric current
from the outermost layer of the
pores and the CA-ARF structure
in every direction, which may
explain why they extend neur-
ites in all directions. (ARF-CA:
acetic acid-catalyzed resorcinol
formaldehyde aerogels) [85]

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extension. Furthermore, by the addition of externally-
applied DC bias (of 200mV mm−1) the growth rate of
PC12 neuritis is increased to the anode. This work shows
that aerogels were used as a substrate for smart implants,
which can establish an integrated connection with the
body environment in the conditions of this view.
Analyzing aerogels' biological stability and biocompat-
ibility in invivo as a necessary evaluation indicates that
this material can be used in neuronal prosthetics.
A comparison of a polyurea porous silica aerogel plat-
form with suture repair ofthe sciatic nervewas reported
in 2014 [89]. In this study, multi-channel aerogelswere
designed to repair sciatic nerve connections in the rat model
(Fig.8).
This repair method by aerogels provides a non-invasive
method for nerve repair, which is a very suitable alternative
to allograft/autograft methods, which saves time and does
not require expert personnel. As it was concluded in this
study, the surface features of the aerogel scaffold play a very
important role in nerve transmission. A very small amount
of friction is enough to prevent the nerve from slipping, and
sutures are no longer needed. In addition, the morphology
and topology of the synthesized aerogel surface played a
very important role in keeping the nerve stable without
suturing. Using this aerogel scaffold, the required time was
less than 5min, much less than the 18min required during
suturing, which is a very important improvement in surgical
interventions.
Fig. 7 Electrical stimulation chamber: a schematic diagram of
custom-built electrical stimulation chamber used for polyurea-
crosslinked silica aerogel (PCSA) and tissue-culture polystyrene
(TCPS) substrates. b Image of insulated electrodes and connecting
leads affixed to a petri-dish lid. c PCSA substrate adhered to the bot-
tom of a petri-dish. d A complete device with a petri-dish lid placed
over the bottom, so the electrodes fit snugly on opposite sides of the
chosen substrate [88]
Fig. 8 a Aerogel scaffold for
nerve support, b invivo optical
image of the multi-channel X-Si
aerogel scaffold before insertion
at the sciatic nerve surgical site,
c optical image of the single
channel X-Si aerogel scaffold
before insertion a the facial
nerve surgical site in a freshly
euthanized cadaver rat [89]

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2.5 Silica‑based aerogels indrug delivery
Recently, researchers have shown tremendous interest in
using aerogels as drug delivery systems. This attention
comes from the unparalleled characteristics of these three-
dimensional (3D) aerogels, including significant poros-
ity, amorphous network, and wide area. In the meantime,
silica-based aerogels have fascinated the consideration of
many researchers because of their extraordinary features,
such as great stability, porous structure, huge specific sur-
face area, ease of surface functionalization, and adsorption
properties. These properties make them a great option for
the high-performance drug vehicle with proper biodegra-
dability, biocompatibility, and innocuous to individuals
[90]. The relationship between the medical application of
silica aerogels and their physical properties is one of the
investigated cases in this field. In a study, a novel drug-
aerogel formulation was developed and characterized for
the bioavailability increase of ketoprofen, a drug with
low water-solublity. The amount of ketoprofen loaded on
a silica aerogel was investigated under density variation.
Results showed that aerogel density could control ketopro-
fen loading on silica aerogels. The drug-loading amount
increased by increasing the aerogel density to a certain
amount. Accordingly, the demanded thickness could be
chosen based on drug type and dose and drug delivery
purposes [91]. In the mentioned study, the supercritical
CO2 technique was applied for drug loading, which pro-
vided a homogeneous and uniform drug absorption into
the pores of the aerogel. As a result, ketoprofen and similar
drugs, which are in their usual crystalline forms, could
retain their amorphous structure after being applied to the
aerogel. Therefore, drug solubility and release could be
achieved faster compared to drugs in the crystalline form.
In 2003, Smirnova and her scientific group [92] investi-
gated the adsorption of ketoprofen and miconazole on silica
aerogels. Adsorption was performed by introducing of drug
solution in supercritical CO2. The experimental results
showed that silica aerogel could adsorb both drugs with high
affinity allowing it to be utilized as a drug carrier. Also, in
the presented study, the effect of carrier hydrophobicity was
investigated on the absorption process. It was revealed that
the carrier could be chosen from hydrophilic or hydropho-
bic aerogels. In ketoprofen- hydrophilic aerogel interactions,
plenty of hydrogen bonding places enabled higher adsorp-
tion capacity than hydrophobic aerogels.
Guenther etal. [93] applied dithranol-silica aerogel as
a dermal drug delivery system. Dithranol is unstable and
almost insoluble in water, showing weak penetration, so
there was a need to increase its dermal availability. They
used hydrophilic and hydrophobic membranes, tested several
formulations, and the prominent one was utilized to investi-
gate dithranol penetration into the human stratum corneum.
Dithranol-hydrophilic silica aerogel drug delivery system
presented higher permeation behavior than the standard oint-
ment and was reproducible for months after production.
In other research [94], a supercritical drying process was
used for the synthesis of silica-based aerogel microparti-
cles. The surface area of 567.62 m2 g−1 was reported for the
prepared aerogels. Artemisinin, dihydroquercetin, rifabutin,
loratadine, and ibuprofen were used for adsorption experi-
ments. The analysis of adsorbed drugs was performed by the
HPLC method. Analytical experiments indicated an increase
in the release rate of 50% of the drug, higher bioavailability
values for drug-loaded samples, and a significant increase in
dissolution rate, compared to active pure medicines values.
In a research reported by Murillo-Cremaes etal. [95]
supercritical fluids used for the matrix synthesis and drug
impregnation process. Triflusal was chosen as a hydrophobic
and moisture-sensitive material model system and inserted
in various aerogel and polymeric platforms via supercriti-
cal CO2. SiO2 aerogels as drug carriers loaded with trif-
lusal and invitro release, profiles were investigated over the
common polymeric platform. In comparison with polymeric
Fig. 9 Comparison of drug
release rates of silica and silica-
gelatin aerogels [96]

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matrix, SiO2 aerogels provided much faster release kinet-
ics and prevented the hydrolyzation of the active ingredient
more efficiently. In addition, the triflusal was distributed in
a molecular form inside the SiO2 aerogels, enhancing the
bioavailability of partially soluble drugs.
Hybrid aerogels, which can be gained from organic and
inorganic sources, exhibit a promising research area. Fur-
thermore, they are excellent candidates for controlled drug
delivery. For example, due to the biocompatibility of silica-
gelatin aerogels, they are considered a good choice for drug
delivery systems in living organisms. Figure9 schemati-
cally represents drug release rates of silica and silica-gelatin
aerogels [96].
Accordingly, in a study by Nagy etal. [97], this type of
hybrid material was synthesized and functionalized with
methotrexate, a (drug with the most application in treating
autoimmune diseases and cancer). They also investigated its
cytotoxicity effects. The usefulness of the hybrid aerogel was
proved by the fact that the methotrexate-free hybrid aerogel
was biocompatible, and the release of methotrexate was trig-
gered by the collagenase activity of tumor cells. Therefore,
a functional drug release system was developed. Moreover,
the growth inhibitory effect of the methotrexate-modified
hybrid aerogel particles was as similar as free methotrexate,
indicating the methotrexate activity remained unbroken after
functionalization. Thus a high mass specific activity, the
main necessity for the successful therapeutic implementa-
tion of methotrexate-modified silica-gelatin hybrid aerogel,
was provided. In addition, the same local therapeutic effect
as free methotrexate could be achieved by the functionalized
aerogel, but without affecting the whole body.
Caputo etal. [98] investigated the effect of experimental
factors such as pressure, temperature, and concentration on
nimesulide adsorption as an anti-inflammatory drug. The
method was created to create a new drug delivery system
using supercritical CO2 to treat drugs with poor water solu-
bility. Adsorption isotherms and kinetics were investigated
and explained by pseudo-second-order and Freundlich iso-
therm models, respectively. The obtained results include
the uniform dispersion of nimesulide into the silica aerogel,
and faster nimesulide release from the drug/silica aerogel
composite compared to a crystalline drug, which may be
related to non-crystalline structure of the drug, and enhanced
specific surface area of the drug/silica aerogel composite.
According to the results, the release rate of anti-inflamma-
tory drugs was increased by the correctly generating drug/
silica aerogel composite with a supercritical adsorption pro-
cess. The only drawback of the proposed approach was the
slow adsorption kinetics. Because the adsorption process
had relatively high activation energy and nimesulide repre-
sented low solubility in supercritical CO2. The first problem
was solved by adding a co-solvent, such as acetone, to the
supercritical CO2, in which nimesulide is freely soluble. In
addition, a column packed with the silica aerogel was used
to deliver the ternary fluid phase on it, and thus a continuous
plant was set up.
Among the various developments in silica aerogel prepa-
ration with the aim of wide application in pharmaceutical
science [99], hybridization [100, 101], coating [102, 103],
and functionalization [104], surface modification can make
considerable usefulness possible. For example, the possi-
bility of unique interactions in the modified carrier enables
the developed drug release. The surface of silica aerogel
consists of silanol groups, which do not tend to interact with
various functional groups on the drug structures. There-
fore, appropriate functionalization will be useful. It has
been made clear that drug-loading amount and its release
rate are significantly influenced by electrostatic interaction
between silanol groups in silica aerogel surface and drug
molecule [105]. Afrashi etal. [106] developed the fabrica-
tion of a polyvinyl alcohol (PVA) nano fibers coated silica
aerogel, multi-layer composite (MLC), as a drug delivery
system (Fig.10(I), (II)). The applicability of the synthesized
hydrophobic and hydrophilic silica aerogels was assessed
by fluconazole, as an anti-fungal drug. Thus, an appropriate
controlled drug delivery system was designed. Silica aero-
gels represented an increased release rate compared to pure
fluconazole despite having a wide area and plenty of pores.
Moreover, the fluconazole release rate was controlled with
the help of PVA nano fibers. Moreover, the stronger con-
trolled drug release was obtained by the hydrophilic silica
aerogel composite than the hydrophobic one (Fig.10(III)).
Only a few types of research have been performed on
silica aerogel modification for drug delivery carriers [104,
107, 108]. Alnaief etal. [107] investigated how to modify
the surface of the aerogel without disturbing its structure.
The reinforced aerogels presented better adsorption capacity,
indicating special interactions with amino groups. Various
routes of silica aerogels functionalization with amino moiety
(liquid and gas phase functionalization) were compared. It
was found that transparent silica aerogels were prepared with
a surface area of 800–1040 m2 g−1 and up to 7 wt% of amino
groups for the first time. Moreover, the drug-loading capac-
ity increased in the case of ketoprofen due to the functional
interaction with carboxylic acid groups in this drug. Mean-
while, drug release rates were not considerably changed by
the functionalization.
Veres etal. [108] described the modification of hybrid
aerogels composed of silica and gelatin through supercritical
fluid technology with hydrophobic groups of phenyl, methyl
moiety, and a long hydrocarbon chain. Ketoprofen, ibupro-
fen, and triflusal, weakly acidic drugs (pKa < 5.5) were
chosen as model systems to impregnate the functionalized
hybrid silica-gelatin aerogels. The resulting matrices, which
dispersed in a molecular form inside the hybrid aerogels, i.e.,
not crystallized, were loaded with a high amount of drugs

Macromolecular Research
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(ca. 15–25, 10–15, and 20–30 wt% for ibuprofen, ketoprofen,
and triflusal, respectively). Both semi-retarded and immedi-
ate release could be obtained for the studied drugs based on
surface hydrophobicity and matrix composition.
In another study, the synthesis of inorganic/organic
hybrid nanoparticles was announced by Tiryaki etal.
[109]. In the presented research, organic polymers, includ-
ing dextran (Dex) and dextran aldehyde (Dex-CHO) coated
inorganic silica aerogels. The obtained composites were
applied as colon-targeted and enzyme-triggered 5-fluoro-
uracil delivery systems. Surface modification of the silica
aerogel with 3-(aminopropyl)triethoxysilane (APTES) was
performed to enhance the organic polymer coating and
drug-loading efficiency. Dex and Dex-CHO/silica aerogels
represented 5-FU release of 1.7% and 3.4%, respectively,
compared to 86.4% for 5-FU released from bare silica
aerogels in simulated intestinal and gastric fluids. Among
the advantages of the resulting inorganic and organic
nanohybrid it could be mentioned its biocompatibility that,
is not influenced by the upper gastrointestinal regions and
the strength of enzyme-triggered drug delivery systems for
drug targeting the colon area (Fig.11).
Fig. 10 I Image of the MLC with (a) hydrophilic silica aerogel, (b)
hydrophobic silica aerogel, (c) Schematic of the MLC, II FE-SEM
cross-sectional view of the MLC, III the anti-fungal test of (a) the
composites contain hydrophilic and hydrophobic drug-loaded silica
aerogels and (b) silica aerogels (contain and without drug) and flu-
conazole powder [106]

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1 3
Jabbari-Gargari etal. [104] modified the surface of silica
aerogel using carboxylic acid and investigated its effect
on the capacity of loaded drug and the rate of drug dis-
solution as a celecoxib (CCB) delivery carrier. The CCB,
a nonsteroidal anti-inflammatory drug with low solubil-
ity (6.2 ± 0.2μg mL−1) has uncontrolled absorption when
taken orally. N-(2-Aminoethyl)-3-aminopropyltrimethox-
ysilane (AEAPTES) and subsequently succinic anhydride
was successfully utilized for the modification of calcined
silica aerogel (SA-OH). According to the obtained results,
the terminal –COOH groups were successfully grafted on
the SA-OH. In addition, the modified aerogels provided a
smaller mean pore size and the same mesoporous structure
as the pristine samples. Furthermore, after drug loading
on the SA–OH and SA–COOH carriers, their crystallinity
state became non-crystalline and amorphous, respectively.
In addition, COO−–NH3+ bonding between the functional
groups of the CCB and the carrier was seen in the case of
loading on SA–COOH (Fig.12).
In addition to the smaller pore size in SA-COOH carrier,
this advantage caused the drug release rate to be controlled
compared to the SA-OH/CCB. It was also found that drug
dissolution rates were increased in the case of both carri-
ers than the pure CCB. Drug release experiments confirmed
these findings.
In another work reported by the same group of research
[110], the incorporation of aspirin on hydrophobic trimeth-
ylchlorosilane silylated silica aerogel (TS-SA) nanostruc-
ture was successfully conducted using the ambient-pressure
loading and drying routes. Thus, uniform drug adsorption
on the aerogel surface was achieved. The loading process
was not related to the drug's chemical degradation, and the
carrier's morphology was not changed after drug loading,
as FT-IR and UV analyses and SEM results demonstrated.
Compared to pure aspirin, which dissolves faster, its dis-
solution in the form of aspirin- TS-SA was controlled over
time. A more gradual drug release was another advantage
from the structural stability of hydrophobic TS-SA in water.
Besides, drug loading on TS-SA in ambient pressure could
provide attractive applicability in controlled drug delivery
systems. Figure13 shows the preparation of silica aerogel
and drug-loading steps.
Another work [111] describes the modification of sil-
ica aerogel with trimethylchlorosilane vapor, resulting in
Fig. 11 Schematic illustration
of the preparation of organic/
inorganic hybrid aerogel as
5-fluorouracil delivery system
[109]

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gradual hydrophobicity. Described approach for synthesis
had minimum effect on their transparency and porosity, pro-
viding its application to a variety of aerogels. The applica-
bility of modified silica aerogel was investigated using two
soluble and insoluble antiseptic agents that were entrapped
in silica aerogel, and subsequent hydrophobization to vary-
ing degrees. Results indicated that release kinetics could be
increased or decreased depending on the hydrophobization
degree compared with unmodified aerogel. This is due to
the influence of the degree of hydrophobicity on diffusional
rates, pore structure, and wetting of the aerogel. The pre-
sented work suggested using the gradual hydrophobization
approach for other drug-aerogel systems and other aerogel
applications, such as contaminated sorbents, transparent
insulation panels, or catalysis supports.
3 Potential toxicity induced bysilica
aerogels
The cytotoxicity of silica aerogels that are designed for drug
delivery at concentrations above (≥ 10mg mL−1) is studied
by Tiryaki etal. in Caco-2 (epithelial colon) cells [109].
Although APTES-modified silica shows toxicity, it was abol-
ished after modification withdextran. The induced toxicity
by the silanol groups could be bypassed by reinforcing the
silica with biodegradable polymers. However, referring to
the low degradability ofmesoporous silicaNPs, the potential
risk for silica aerogels should be considered [112].
Yet, low degradability is used in designing biocompat-
ible implants. A study of polyurea crosslinked silica aero-
gel implants inserted subcutaneously intramuscularly in
rats showed no toxic effect surrounding tissues and distant
organs [82].
Compared to other materials used for biomedical pur-
poses, such as nanofibers in biomedical applications
[113–115], it can be mentioned that the use of silica-based
materials has received a unique place.
4 Conclusion
The application of silica-based aerogels in biomedicine is
highly appreciated owing to their customized structure and
surprising parameters that could provide applied methods
and solutions in different areas. This paper reviews the
applications of silica-based aerogels in drug delivery, tissue
regeneration, and bactericidal properties. Silica-based aero-
gels have increasingly attracted scientists' consideration as
a multi-application biomaterial to benefit healthy life. They
are considered as an attractive candidate for future devel-
opment of smart neural implants. Silica-based aerogels are
superior to the othernanomaterialsowing to their cavities,
low mass and tailorable structure, which turns them into
a delivery platform for drug and bioactive materials and a
platform for implants and antibacterial agents. Although
silica aerogels generally have no antibacterial activity, they
can be utilized as carriers or supports antimicrobial agents.
As a result, these functionalized or loaded silica aerogels
Fig. 12 Schematic of modification procedure of silica aerogel nanostructure and drug-career interaction [104]

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effectively inhibit bacterial growth or kill them even at low
concentrations. It is assumed that drugs' stability, pharma-
cokinetic and dissolution rate could be affected through
adsorption onto aerogels. Also, it was found that silica-based
hybrid aerogel structures, present tunable chemical and
mechanical properties, may also improve biomaterials' pri-
mary characteristics, including biodegradability, bioactivity,
biocompatibility, non-cytoxicity, etc. The suitable chemical
composition, highly porous network and great mechanical
properties of silica-based aerogels have met the functional
needs of tissue engineering that cannot be, as other porous
biomaterials cannot easily obtain. In addition, as a result of
much research, it is clear that silica-based aerogels are very
promising options as drug delivery vehicles because of their
unique properties such as high drug-loading capacity, ability
for controlled/sustained and tunable drug release, capability
to increase the oral bioavailability of poorly soluble drugs,
and to improve drug stability. It is undoubtedly an advantage
since developing a new formulation needs much time and
wastes more financial sources. Therefore, it is necessary to
continue research in this direction.
While tremendous advances in silica-based aerogels have
been made, more investigations are needed to handle the dif-
ficulties associated with these materials' commercialization
and medical applications. However, the preclinical and clinical
stages must be thoroughly tested to accept silica aerogels in
the market. Furthermore, affordable product cost and improved
biological characteristics of silica aerogels will also determine
the speed of commercialization in this journey. Thus, silica
aerogels with invivo and invitro investigations provide alter-
native platforms for new therapeutic applications. The future
of silica-based aerogel may very well lie in already-developed
technologies. It is hoped this review will stimulate ongoing
and future studies to provide a variety of perspectives for sil-
ica-based aerogel applications in biomedicine.
Fig. 13 Preparation of silica aerogel and drug-loading steps [110]

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Author contributions FSJ and MZK wrote the main manuscript text
and SH and MRS prepared all documents. All authors reviewed the
manuscript.
Declarations
Conflict of interest Declared none.
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Authors and Aliations
FatemehSoghraJahed1· SaminHamidi1,2· MonirehZamani‑Kalajahi1· MohammadrezaSiahi‑Shadbad2,3
* Samin Hamidi
hamidisamin@gmail.com
* Monireh Zamani-Kalajahi
mzamanik86@gmail.com
1 Food andDrug Safety Research Center, Tabriz University
ofMedical Sciences, Tabriz, Iran
2 Pharmaceutical Analysis Research Center, Tabriz University
ofMedical Sciences, Tabriz, Iran
3 Pharmaceutical andFood Control Department, Faculty
ofPharmacy, Tabriz University ofMedical Sciences, Tabriz,
Iran