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Zeolites are microporous tectosilicates of natural or synthetic origin, which have been extensively used in
various technological applications, e.g. as catalysts and as molecular sieves, for separating and sorting
various molecules, for water and air purification, including removal of radioactive contaminants, for har-
vesting waste heat and solar heat energy, for adsorption refrigeration, as detergents, etc. These appli-
cations of zeolites were typically related with their porous character, their high adsorption capacity, and
their ion exchange properties. This review is focused on potential or already practically implemented
applications of zeolites in biotechnology and medicine. Zeolites are promising for environment protec-
tion, detoxication of animal and human organisms, improvement of the nutrition status and immunity of
farm animals, separation of various biomolecules and cells, construction of biosensors and detection of
biomarkers of various diseases, controlled drug and gene delivery, radical scavenging, and particularly
tissue engineering and biomaterial coating. As components of scaffolds for bone tissue engineering, zeo-
lites can deliver oxygen to cells, can stimulate osteogenic cell differentiation, and can inhibit bone resorp-
tion. Zeolites can also act as oxygen reservoirs, and can improve cell performance in vascular and skin
tissue engineering and wound healing. When deposited on metallic materials for bone implantation,
zeolite films showed anticorrosion effects, and improved the osseointegration of these implants. In our
studies, silicalite-1 films deposited on silicon or stainless steel substrates improved the adhesion, growth,
viability and osteogenic differentiation of human osteoblast-like Saos-2 cells. Zeolites have been clinically
Received 8th January 2018, used as components of haemostatics, e.g. in the Advanced Clotting Sponge, as gastroprotective drugs,
Accepted 25th March 2018
e.g. Absorbatox® 2.4D, or as antioxidative agents (Klinobind®). Some zeolites are highly cytotoxic and
DOI: 10.1039/c8bm00028j carcinogenic, e.g. erionite. However, in other zeolites, the antiproliferative and pro-apoptotic effects can
rsc.li/biomaterials-science be used for tumor therapy.
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976 | Biomater. Sci., 2018, 6, 974–989 This journal is © The Royal Society of Chemistry 2018
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contaminated waters.21 Zeolites are also promising agents for porous nanoparticles is also promising for the treatment of
water softening. Disk membranes generated from high-purity children with attention deficit hyperactivity disorder (ADHD)
natural clinoptilolite mineral rock have shown promising by trapping Pb in their organism, and also by delivering DOPA
water desalination and de-oiling performance.68 (i.e., L-3,4-dihydroxyphenylalanine, a precursor of dopamine)
Zeolites are also potent agents for soil purification. For into their central nervous system after injection of the zeolite
example, together with other natural minerals, i.e. bentonite clinoptilolite in suspension into the blood. However, this treat-
and goethite, clinoptilolite was found to be a promising adsor- ment has not yet been clinically approved.51,71 Consumption
bent that can be utilized for removing toxic Cr3+ and Cr6+ from of ethanol together with clinoptilolite decreased the
contaminated soil.22 absorption of ethanol and its blood level in healthy alcohol
In air purification, clinoptilolite as an adsorbent bed, com- drinkers. This effect was more pronounced in males.72
bined with Fe(0) and Cu2O nanoparticles as catalysts, was used Microencapsulated urease-zeolite W oral sorbent was proposed
for removing benzene, toluene and xylene from polluted air.23 for the removal of urea from the organism during uremia.73
In the decontamination of environments from radioactivity, It is problematic to eliminate toxins from the blood in
clinoptilolite was evaluated as sorbents for remediating land patients suffering from the final stages of uremia. Small
contaminated with radiocaesium and radiostrontium in order uremic toxin molecules can be removed using zeolites.
to return it to farming use.24 In decontaminating water from Elimination of urea, uremic acid, creatinine, p-cresol and
radionuclides, e.g. 134Cs, 137Cs and 90Sr, the cation-exchange indoxyl sulphate was investigated in a study by Wernert et al.74
capacity of a clinoptilolite was substantially enhanced by 75% of creatinine can be eliminated by adsorption onto acidic
exposing it to high-energy (8 MeV) electrons.69 Clinoptilolite mordenite, and 60% of p-cresol can be eliminated by adsorp-
was also used for alimentary decontamination, e.g. for remov- tion onto a silicalite-1. The efficiency of this elimination pro-
ing radioactive caesium (137Cs) from the meat of broilers and cedure is similar to or even higher than the conventional dialy-
pheasants.70 sis system.74 These results were further confirmed by another
study by the same group,75 performed on pure silica MFI zeo-
lites and alumino-silicate MFI zeolites (Si/Al = 30), with H+,
Na+, K+ and Mg2+ as charge compensating cations. When
3. Organism detoxification using exposed to aqueous solutions of p-cresol at 37 °C, all tested
zeolites types of MFI zeolites showed high adsorption capacity for
p-cresol, but this capacity was highest for pure silica MFI.75
In addition to environmental decontamination, animal and
human organisms can also be decontaminated from toxic
agents. For example, mice exposed to Pb and supplemented
with clinoptilolite exhibited 2.3-fold lower frequency of 4. Use of zeolites in veterinary
chromosome aberrations, a 2.5-fold higher mitotic index, a medicine and zootechnology
1.5-fold higher percentage of normal erythrocytes, and a 1.3-
fold higher body weight in comparison with Pb-exposed and Zeolites can improve animal health via several mechanisms,
unsupplemented animals.49,50 Clinoptilolite in the form of including direct positive effects on the morphology, function
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and microbial flora of the digestive tract, delivery of metaboli- larly the surface charge governed by pH. With the use of Na-
cally important ions, improving the nutrition status, strength- BEA and H–Y zeolites, three representative microbes,
ening immunity, decontamination of food and drinking water Escherichia coli, Bacillus subtilis and Staphylococcus aureus,
from toxins. For these applications, mainly natural zeolite clin- were separated from their mixture.90 The separation of mam-
optilolite is used, and it is the most widespread compound in malian cells, e.g., cell lines and cells in primary cultures, was
the medical market. based on the different adhesion behavior of these cells on
Adding clinoptilolite into the diet of poultry improved the zeolite L substrates functionalized with two enantiomers of
morphology of the gut (e.g., induced a greater height of villi) penicillamine (PEN) – L-PEN and D-PEN.37 Disk-shaped zeolite
and the composition of physiological microbial flora in the L particles, coated with the cyclic integrin ligand c[RGDfK] via
gut,52 reduced intestinal mucosa damage and the inflamma- an isocyanate linker, were used for rapid detection of cancer
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tory response to bacterial lipopolysacharide,53 increased the cells, based on the fast adhesion ability of these cells.38
antioxidant capacity of the organism,54 and increased the
content of omega-3-polyunsaturated fatty acid in the body and
in the eggs.76,77 These positive effects of dietary clinoptilolite
were further enhanced by ion exchange with Zn. In poultry, Zn 6. Zeolites as promising carriers for
deficiency can cause reduced weight gain, skeletal malfor- drug and gene delivery
mations, poor bone mineralization and immunological dys-
functions. Zn delivered through clinoptilolite reached higher Zeolites are promising for therapeutical delivery of various
bioavailability than ZnSO4, as evidenced by enhanced tissue drugs, e.g. anti-inflammatory, anticancer and antimicrobial
Zn accumulation and the expression of Zn transporter genes drugs, and also for delivery of nucleic acids. Clinoptilolite was
in laying hens78 and in broilers.79 Zinc-bearing clinoptilolite proposed as a microporous carrier for pH-controlled oral deliv-
also showed protective effects against Salmonella pullorum ery of aspirin (acetylsalicylic acid), i.e. a non-steroidal anti-
infection in chicken.80 The health of farm animals ( poultry, inflammatory drug with an anticoagulant property, in order to
cattle) can also be improved significantly by removing nitrates prevent gastric irritation due to inhibition of cyclooxygenase I
and mycotoxins (aflatoxin, ochratoxin) from their food and located in the gastric mucosa.91 Similar problems are associ-
drinking water with the use of clinoptilolite;81–83 for a review, ated with the oral delivery of other non-steriodal anti-inflam-
see ref. 3. matory drugs, namely diclofenac and piroxicam, and these
The positive effects of zeolites on the digestive tract, problems too can be solved with the use of zeolitic carriers,
observed in domestic animals, can also be projected to human e.g. clinoptilolite56 or zeolites X and Y.92 Microporous zeolites
medicine. A clinoptilolite-based drug, Absorbatox® 2.4D, of distinct framework types, textural properties and crystal
reduced the severity of clinical symptoms and signs associated morphologies (BEA, ZSM and NaX) are promising for oral
with endoscopically negative gastroesophageal reflux disease delivery of indomethacin, another poorly water-soluble non-
and non-steroidal anti-inflammatory drug medication. This steroidal anti-inflammatory drug, as demonstrated in cultures
gastroprotective effect of clinoptilolite is probably due to its of the Caco-2 human colorectal adenocarcinoma cell line.93
binding to hydrogen ions and biologically active amines and Zeolites and their composites were also proved to be suit-
nitrates.55 able carriers for anticancer drugs, such as 5-fluorouracil, doxo-
rubicin and mitoxantrone. Faujasite (NaY) or zeolite L nano-
particles, loaded with 5-flourouracil, were internalized by cells
5. Use of zeolites for separating of two human colorectal carcinoma cell lines, i.e. HCT-15 and
biomolecules and cells RKO cells, where the drug was released and markedly
decreased the cell viability. At the same time, control unloaded
Zeolites are promising for the development of new chromato- zeolite particles presented no toxicity to both cancer cell
graphic carriers for purification of proteins and fractionation lines.40 Similar effects on human colon adenocarcinoma Caco-
of cellular components such as proteins and nucleic acids.84,85 2 cells were observed when 5-fluorouracil was encapsulated
Various proteins can also be immobilized on the surface of into porous NaX or BEA zeolitic particles. This effect was more
zeolite L crystals using mild radical nitroxide exchange reac- pronounced in NaX particles.94 In another in vitro study, mag-
tions. Exposure of these crystals to aqueous protein solutions netite-zeolite 4A composite nanoparticles loaded with 5-flouro-
leads to site-selective immobilization of proteins onto the crys- uracil efficiently inhibited the proliferation of human gastric
tals.86 In addition, zeolites can be used for refolding various carcinoma AGS cells through apoptotic mechanisms.95 A
proteins from their inactive form to their active form, which is smart system for the delivery of doxorubicin was recently devel-
important e.g. in preparing recombinant proteins.87–89 oped, consisting of zeolitic imidazole framework nanospheres.
Another interesting application is for separating various This system enabled easy encapsulation and controlled release
types of microbial and mammalian cells. Specific microbial of the drug.96 The Zn2+-loaded clinoptilolite/graphene oxide
cells were shown to absorb selectively to certain zeolites. This nanocomposite is also a promising carrier for doxorubicin.57
selectivity depends on the physical and chemical properties of Another cytostatic, i.e. mitoxantrone, was loaded into the pores
the outer surface of the zeolite, e.g. its wettability and particu- of zeolite beta polymorph disordered framework (BEA) nano-
978 | Biomater. Sci., 2018, 6, 974–989 This journal is © The Royal Society of Chemistry 2018
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particles, and showed considerable cytotoxicity when applied sensitive field-effect transistors.58 A citrate-selective sensor was
to cancer cells.97 prepared by modifying a polyvinyl chloride membrane with
Zeolites have been tested for delivering various anti- modified nano-clinoptilolite particles by a hexadecyltrimethyl
microbial drugs, such as antibiotics, chemotherapeutics, ammonium surfactant.59 A Cu-A zeolite/graphene-modified
metallic ions and nitric oxide (NO). ZSM-5 nanoparticles glassy carbon electrode was constructed for simultaneous
showed high loading efficiency and sustained release of genta- electrochemical determination of dopamine and ascorbic
micin, which significantly reduced the adhesion of acid.104 Ascorbic acid and Acetaminophen A were also deter-
Staphylococcus epidermidis and prevented biofilm formation. mined voltammetrically by a novel carbon paste electrode
These particles are therefore promising for preventing infec- modified with Fe3+-exchanged clinoptilolite nano-particles.105
tion of bone implants.63 Porous zeolite/chitosan composites ZSM-5 zeolite was applied for in situ real-time determi-
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proved to be promising for the delivery of cephalexin.98 Zeolite nation of superoxide anion, based on direct electron transfer
Y was used for sustained release of sulfadiazine for the prepa- of Mn2+ phosphate (Mn3(PO4)2), which acted as a superoxide
ration of topical antibacterial formulations, and the antibacter- dismutase. Mn2+ was ion-exchanged into
ial effect was further enhanced by encapsulation of Ag nano- ZSM-5 microstructures, and was further coated with poly
particles.99 Other metallic ions, such as Zn2+ and Cu2+, have (diallyldimethylammonium chloride).106 Recently, zeolite NaX
also been loaded into zeolites (types X and A) in order to incor- synthesized at various temperatures (from 60 to 100 °C)
porate their antibacterial, anticandidal and antifungal pro- immobilized with urease was tested for the potential construc-
perties.100 NO is important for the regulation of various bio- tion of a urea biosensor.32
logical processes, such as vascular tone, neurotransmission, In addition, a strategy for harvesting and detecting tumor
inflammatory cell responsiveness, and also for defence against secretory proteins was developed using zeolites. Proteins
invading pathogens and wound healing. Composites of secreted from the human hepatocellular carcinoma cell line
polytetrafluoroethylene and NO-storing Zn2+-exchanged zeolite were enriched by zeolite L nanocrystals, followed by 1-D
A significantly reduced the growth of clinically relevant strains sodium dodecyl sulfate-polyacrylamide gel electrophoresis
of bacteria, namely Gram-negative Pseudomonas aeruginosa (SDS-PAGE) for protein fractionation, and then by liquid
and Gram-positive methicillin-sensitive and methicillin-resist- chromatography-electrospray ionization mass spectrometry
ant Staphylococcus aureus and Clostridium difficile.101 coupled with tandem mass spectrometry (LC-ESI-MS/MS) for
For potential gene delivery into cells, zeolite L crystals have protein identification and further proteomic and secretomic
been developed as multifunctional nanocontainers to deliver analysis.107
simultaneously DNA oligonucleotides and other organic mole-
cules into living cells. Multifunctional zeolite L was prepared
by filling the pore system with guest molecules, whilst DNA 8. Antioxidative, antiapoptotic and
was adsorbed electrostatically on their surface.39,102 The anti-inflammatory effects of zeolites
efficiency of cell transfection can also be enhanced by zeolites.
Zeolite-based silicalite nanoparticles markedly enhanced (by Zeolites have significant antioxidant activity, which can be uti-
over 150%) the transfection efficiency of poly(ethylene imine)- lized in human and veterinary medicine. Clinoptilolite showed
plasmid DNA complexes applied to human embryonic kidney positive effects on hepatocytes after partial hepatectomy in rats
HEK-293 cells.103 on the basis of the antioxidative effects of this zeolite. After
Zeolite nanoparticles carrying drugs, DNA and other bio- oral administration, clinoptilolite decreased the level of malon-
active molecules are usually internalized into cells by endo- dialdehyde, a marker of oxidative stress, in the liver tissue. At
cytosis. Zeolite nanoparticles can therefore be used as tools for the same time, the activity of superoxide dismutase and the
studying the endocytosing mechanisms and pathways in cells. level of glutathione, i.e. antioxidant molecules, significantly
For example, de-aluminated zeolite Y nanoparticles were used increased in this tissue.60
for studying endocytosis in human peripheral dendritic cells, Zeolites also have a protective effect on hepatocytes during
i.e. important cells of the immune system, in correlation with anticancer therapy using Adriamycin (doxorubicin). In primary
the maturation status of these cells.44 cultures of liver cells derived from rats treated with
Adriamycin, subsequent treatment with clinoptilolite signifi-
cantly reduced the production of imflammatory cytokines, i.e.
7. Construction of biosensors and tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) by
detection of biomarkers using zeolites hepatocytes. In addition, this treatment led to reduced apoptosis
of hepatocytes, which was detected using the TdT-dUTP
Zeolites are promising materials for creating biosensors, and Terminal Nick-End Labeling (TUNEL) method. These results
also systems for harvesting and detecting biomarkers of were attributed to the antioxidant effects of clinoptilolite.61 In
serious diseases, particularly tumors. tumor-bearing animals (mice and dogs) treated with doxorubi-
In biosensing, clinoptilolite and zeolite beta are promising cine, too, clinoptilolite decreased the lipid peroxidation and
for developing potentiometric biosensors based on co-immo- enhanced the effect of doxorubicine. This was manifested by a
bilization of enzymes with various types of zeolite on pH-ion- strong reduction in the pulmonary metastasis count.108
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Other natural zeolites, such as chabazite, phillipsite and Accordingly, zeolite-based haemostat QuickClot® (i.e., a com-
analcime, administered perorally, also increased the blood mercial material composed of zeolite beads) accelerated blood
levels of antioxidant enzymes, namely gluthatione peroxidase, coagulation and shortened the clot formation time, when added
superoxide dismutase and gluthatione reductase, and reduced to blood taken from human volunteers and from sheep in
the lipid peroxidation in clinically healthy men, both non- vitro.115 Another zeolite-based haemostat is Advanced Clotting
smokers and smokers.36 Faujasite and ferrierite zeolites Sponge (ACS), which is similar to QuickClot®, but consists of
limited the effects of reactive oxygen species (ROS) on human larger beads of the zeolite, which are packaged in a gauze.114,116
albumin under in vitro conditions. This was attributed to the However, the haemostatic effect of zeolites is associated
conversion of ROS to water molecules within the zeolite void with an exothermic reaction, which can increase the temperature
system, which generates H+ ion transport.45 of zeolites to as much as 90 °C, and can cause severe damage
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The antioxidative properties of zeolites could also be utilized (i.e., burns) to the adjacent tissues. This problem was addressed
in the treatment of Alzheimer’s disease. Studies on neuronal- by pre-hydrating the zeolites, so that they could absorb water less
like SH-SY5Y cells in vitro, and on APPswePS1dE9 transgenic exothermically. This modified zeolite formulation was commer-
mice in vivo (i.e. an animal model of ageing-related neurodegen- cialized as Advanced Clotting Sponge plus (ACS+®).114,116
eration), revealed that dietary zeolites (i.e. tribomechanically Another possible way to reduce the exothermic reaction of zeo-
micronized clinoptilolite tuff) reduced the production of mito- lites and the temperature at the wound site is by adding another
chondrial ROS, increased the activity of superoxide dismutase mineral, bentonite, to the zeolite (in a bentonite : zeolite weight
in the hippocampus, and reduced the amyloid levels and the ratio of 2 : 1). This formulation, commercialized as CoolClot®,
plaque load in mouse brain.109 In an ex vivo study performed significantly reduced the bleeding time in dogs and the clotting
on homogenized brains, taken from mice after feeding with a time in human blood samples in vitro,117 and supported the
diet containing clinoptilolite, this zeolite showed a beneficial healing of experimental wounds in rats in vivo, without a signifi-
effect on the ligand binding to serotonergic receptors.110 cant increase in the wound surface temperature.118
The antioxidative effect of zeolites can also protect the skin Other minerals applied as haemostatic agents were phyllo-
from damage caused by UV irradiation. For example, NaY zeolites silicates like smectite (WoundStat119,120), kaolin (e.g. QuikClot
decreased the photocatalytic activity of TiO2, a component of Combat Gauze® 114) and halloysite.121 The effect of phyllosili-
some sunscreens, and thus prevented damage to cultured human cate smectite on haemostasis was reported to be even better
skin fibroblasts by ROS generated by UV-irradiated TiO2.111 than the effect of zeolites.119,120 However, practical application
Zeolites could therefore be used for creating novel sunscreens. of zeolites in haemostasis is desirable, as phyllosilicates are
As was mentioned above, the antioxidant properties of clin- nano-materials which could get into the blood circuit.
optilolite can also be used in veterinary medicine, e.g. for
improving the antioxidative capacity of broiler chicken, mani-
fested by an increase in glutathione peroxidase, catalase and 10. Zeolites in tissue engineering,
superoxide dismutase, and by a decrease in malondialdehyde.54 implant coating and wound healing
Antioxidant properties of zeolites have also been utilized in
human medicine. In a randomized double-blind, controlled Zeolite-based materials can be considered as a kind of bio-
clinical trial, a natural zeolite, Klinobind®, especially when active ceramics, and thus they can be used effectively in the
treated with mechanical micronization and with tribochemical construction of scaffolds for bone tissue engineering, in which
and thermal activation, suspended in water and administered zeolites can mimic the mineral component of the natural bone
perorally, increased antioxidant enzymes (catalase) and matrix. For example, zeolites (specifically zeolite NaY) were com-
decreased ROS (H2O2) in blood plasma taken from smokers.112 bined with poly(vinylidene fluoride), an electroactive material
Tribomechanically-activated clinoptilolite also proved to be ben- showing a piezoelectric effect and considered to be suitable for
eficial for the treatment of dyslipidemia. In a phase I/IIa pro- bone tissue engineering. The resulting composites promoted
spective, open-label, uncontrolled, dose/granule size-ranging the proliferation of human foreskin fibroblasts and mesenchy-
study, this mineral significantly improved the lipid profiles in mal stem cells (MSCs), and also the differentiation of MSCs
the blood of dyslipidemic patients, evaluated by the concen- towards osteoblasts. In addition, these composites did not
trations of total cholesterol, low-density lipoprotein cholesterol, evoke any inflammatory reaction after subcutaneous implan-
high-density lipoprotein cholesterol and triglycerides.113 tation in C57Bl/6 mice in vivo, as indicated by N-acetyl-β-D-gluco-
saminidase and NO assays performed in blood plasma.122
Other important zeolite-containing biomaterials are zeolite-
9. Zeolites in haemostasis A/chitosan hybrid composites with zeolite contents of
20–55 wt%, prepared by in situ transformation of silica/chito-
Due to their adsorption capacity, zeolites can be used as san mixtures in a sodium aluminate alkaline solution through
potent haemostatics. Zeolites can entrap exothermically large impregnation–gelation–hydrothermal synthesis. These compo-
volumes of water in the open porous internal space of zeolites. sites were prepared in various shapes, including cylinders,
At the same time, zeolites concentrate coagulation factors and plates and thin films. They contained macropores ranging in
platelets in haemorrhaging blood (for a review, see ref. 114). size from 100 μm to 300 μm, and showed suitable mechanical
980 | Biomater. Sci., 2018, 6, 974–989 This journal is © The Royal Society of Chemistry 2018
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properties for bone tissue engineering. In addition, when coating.34,35,125,126 Moreover, the SF has been shown to be
immersed in simulated body fluid (SBF), they acted as bio- osteoconductive, i.e. to promote the proliferation of human
active, i.e. they promoted the formation of hydroxyapatite fetal osteoblasts (hFOBs), in comparison with the bare titanium
(HAp) by their ion exchanging properties, and, when enriched alloy, Ti6Al4V. In addition, SF promoted the differentiation of
with Ag+, they showed antimicrobial activity.123 hFOBs into mature osteoblasts, which was manifested by the
Similar antimicrobial and HAp-forming activity in SBF was expression of the BMP-2 gene, and by the production of a
also observed in Ag ion-exchanged nanocrystalline zeolite mineralized matrix at earlier times in culture, indicating higher
ZSM-5 (Ag-Nano-ZSM-5) and in Ag ion-exchanged conventional osteoinductive properties of the SF than of Ti6Al4V alone.34,35
zeolite (Ag-ZSM-5). Biocompatibility assays suggested that Ag- Similarly, a SF on Ti-6Al-4V alloy stimulated osteogenic differen-
Nano-ZSM-5 and HAp grown in Ag-Nano-ZSM-5 did not tiation of mouse MC3T3-E1 preosteoblasts, as demonstrated by
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impose any toxicity on mouse RAW 264.7 macrophage-like the increased expression and activity of alkaline phosphatase,
cells and human colon adenocarcinoma Caco-2 cells. This i.e. an enzyme participating in bone matrix mineralization.
suggested that these materials have considerable potential for Moreover, this coating significantly enhanced osteointegration
biomedical applications, e.g. for constructing bone implants.64 and bone regeneration after the implantation of Ti-6Al-4V
In another study, ZSM-5 zeolite monocrystals with a disk-like samples into rabbit femoral condylar defects.127
shape (∼350 nm in diameter and ∼165 nm in thickness), pro- In our own studies, the a- and b-oriented SFs prepared on
vided good support for the spread and proliferation of human Si(100) substrates or on stainless steel substrates supported
bone marrow stromal cells. In addition, in comparison with the adhesion, subsequent growth, viability and osteogenic
conventional HAp particles, ZSM-5 zeolites possessed greater differentiation of human osteoblast-like Saos-2 cells.125,126
drug-loading efficiency and a greater drug-sustained release These cells adhered in higher numbers and proliferated to
property because of the ordered micropores, larger Brunauer– higher population densities than the cells on uncoated sub-
Emmett–Teller (BET) surface areas, and a higher content of strates, on microscopic glass coverslips and on standard cell
chemical functional groups. For gentamicin-loaded ZSM-5 zeo- culture polystyrene dishes. This was more apparent for SF with
lites, the sustained release of gentamicin significantly reduced a more developed three-dimensional structure of the outer
the bacterial adhesion and prevented biofilm formation.63 surface, i.e. for SF deposited on AISI-316L stainless steel sub-
Zeolites also enhanced the growth and osteogenic differen- strates (Fig. 4). However, on all tested materials, the Saos-2
tiation of osteoblasts, when added directly to cell culture cells formed well-developed vinculin-containing focal
media. Specifically, synthetic Na-A zeolite added into a cell adhesion plaques and an F-actin cytoskeleton (Fig. 5). In
culture medium enhanced the autocrine synthesis of trans- addition, SFs increased the activity of alkaline phosphatase, a
forming growth factor-β (TGF-β), DNA synthesis, the activity of marker of osteogenic cell differentiation.
alkaline phosphatase and the production of osteocalcin in Despite the hardness of zeolite crystals, zeolites also have
normal human osteoblast-like hOB cells.124 Zeolite A also potential for soft tissue engineering and regeneration, namely
inhibited osteoclast-mediated bone resorption in vitro.67 vascular and skin tissue engineering and wound healing.
In addition, zeolites A and ZSM-5 were applied as coatings Fluorinated zeolite Y crystals were embedded in 3D scaffolds
on stainless steel and zeolite ZSM-5 was applied as a coating made of polyurethane, i.e. a polymer suitable for the construc-
on an aluminum alloy, where they decreased the colonization tion of vascular replacements. These scaffolds significantly
of the material surface with Halomonas pacifica g, a marine increased the proliferation activity of human coronary artery
bacterium, in comparison with bare uncoated surfaces. This smooth muscle cells and the depth of their penetration into
effect was explained by the hydrophobicity of the zeolite coat- the scaffolds, in comparison with the control zeolite-free
ings and their electrostatic interactions with the bacteria.66 scaffolds. The reason was that the zeolite particles acted as a
Silicalite-1, i.e. a siliceous analog of ZSM-5 zeolite, can form reservoir of oxygen, and enhanced the oxygen delivery to the
a compact film (SF) which is highly corrosion-resistant.33–35 cells.128 Zeolite-Y powder functionalized with ferric iron-di-
For example, the SF synthesized on Ti-6Al-4 V alloy prevented ethyldithiocarbamate complexes is able to trap NO radicals in
the release of cytotoxic Al and V ions, even after exposure to liquids and in biological systems.129 It can therefore be uti-
highly corrosive solutions (in 0.856 M NaCl at pHs of 7.0 and lized as a radical scavenger, as a component of biosensors,
1.0). Thus, the anti-corrosive properties of dense SF eliminate and also as a reservoir of NO, i.e. an important vasodilator, in
a substantial drawback of metal supports in their application artificial vascular prostheses. In addition, NO released from
as a prosthetic material, i.e. the evolution of toxic ions when Co-ion exchanged zeolite-A inhibited platelet aggregation and
they interact with tissue.34,35 Another beneficial property of SF adhesion of human platelets in vitro.130 Platelet aggregation
is in this extent its mechanical properties, i.e. the elastic and platelet adhesion are serious complications when vascular
modulus value (30–40 GPa), which is close to that of bone replacements are used, and can lead to stenosis and oblitera-
(∼30 GPa).35 This reduces the resorption of implant materials tion of the lumen of the prosthesis. However, long-term
covered by SF. At the same time, SF significantly increased the contact with blood undoubtedly led to leaching of highly toxic
adhesion and proliferation of pluripotent mouse embryonic Co ions from zeolite A. A further investigation is required.
cells in vitro, in comparison with a glass surface. This was In skin tissue engineering and wound healing, hybrid
attributed to the three-dimensional structure of the zeolite scaffolds containing pectin, gelatin or gelatin/hyaluronan
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Fig. 5 Immunofluorescence staining of vinculin, a protein of focal adhesion plaques (green) in human osteoblast-like Saos-2 cells on day 3 after
seeding on SFs deposited on Si(100) (A), on SFs deposited on stainless steel (B), on bare Si(100) (C), on bare stainless steel (D) and on control micro-
scopic glass coverslips (E). The actin cytoskeleton is stained in red with phalloidin conjugated with tetramethylrhodamine (TRITC), and the cell nuclei
are stained in blue with 4’,6-diamidine-2’-phenylindole dihydrochloride (DAPI). Leica TCS SPE DH 2500 confocal microscope. Scale bar = 50 μm.
982 | Biomater. Sci., 2018, 6, 974–989 This journal is © The Royal Society of Chemistry 2018
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forms brittle, wool-like fibrous masses in the hollows of rock can affect Ca levels and Ca-dependent signalling pathways.137 In
formations, and thus has similar properties to asbestos (Fig. 6), addition, finely-ground clinoptilolite inhibited protein kinase B
causing lung cancer and malignant mesothelioma.46–48 The (c-Akt), induced the expression of p21WAF1/CIP1 and p27KIP1
mechanism of the cytotoxicity of erionite was further investi- tumor suppressor proteins, and blocked the growth in several
gated in experiments in vitro, where human monocyte U937 cancer cell lines. It can therefore be utilized as an adjuvant in
cells internalized erionite fibers, suspended in the cell culture anticancer therapy.138 In addition, excessive supplementation of
medium, through their cytoplasmic membrane. These fibers food for poultry with clinoptilolite can lead to an inflammatory
were then found in the cytosol and at the nucleus. In a period response in the intestine and damage to the intestinal barrier.
of 24 hours, first erionite fibers rich in sodium and potassium, This inflammatory reaction is mediated by the increase in CD4-
and then calcium-rich erionite fibers, induced cell necrosis.133 positive and CD25-positive T and B lymphocytes and by higher
Published on 26 March 2018. Downloaded by University of Rijeka on 6/26/2018 1:15:59 PM.
Other fibrous zeolites, such as offretite and scolecite, also acted serum concentrations of IL-2 and IL-10.139
as cytotoxic. They perturbed the cell structure and induced for- As was mentioned above, the as-synthesized SFs, deposited
mation of swollen mitochondria and squared cells.133 on stainless steel, supported the adhesion, proliferation and
Other adverse effects of zeolites were described after dietary osteogenic differentiation of human osteoblast-like Saos-2
supplementation of calves with sodium zeolite A (Na-A). This cells. However, DNA damage in human osteoblast-like U-2 OS
zeolite disturbed the mineral metabolism and the tissue cells cultured on their surface calcined to 300 °C and 500 °C
mineral composition of the animals. Retention of Al was was observed.140,141 U-2 OS cells are considered as a suitable
observed in all tissues, and there were increased concen- model for studies of markers of DNA damage response (DDR),
trations of Si in the aorta, spleen, lung, muscle, and kidney of because, unlike Saos-2 and MG-63 human osteoblast-like cell
the calves exposed to the Na-A, and Al was increased in all Na- lines, U-2 OS cells retain p53 (for a review, see ref. 140 and
A-exposed tissues. The concentrations of elements physiologi- 141). An important marker of the DDR is phosphorylated
cally present in the organism were also altered by Na-A. There histone H2AX (gamma H2AX), an indicator of breaks in DNA
were increased calcium concentrations in aorta, liver, muscle, molecules, which was present in cells on heat-treated SFs
and tendon; there were increased phosphorus concentrations (Fig. 7). Moreover, as revealed by fluorescence staining, the
in aorta, but decreased concentrations in plasma; there were cells on SFs treated at 500 °C were vacuolized, with a disturbed
increased magnesium concentrations in aorta, heart, kidney, F-actin cytoskeleton and with less-developed focal adhesion
liver, and pancreas, but decreased concentrations in plasma; plaques than on the control microscopic glass coverslips, non-
and there were decreased iron concentrations in kidney and heat-treated SFs and SFs treated at 300 °C (Fig. 7). At the same
liver.136 time, the initial adhesion and proliferation of Saos-2 cells was
Even clinoptilolite, a natural zeolite considered as non-toxic significantly lower on SFs treated at 500 °C than on non-
and with great potential for various biomedical applications, treated SFs and on SFs treated at 300 °C, as manifested by
reduced cell viability and DNA synthesis and increased cell lower cell numbers on days 1 and 3 after cell seeding.125
apoptosis when added in the form of nanoparticles into a cell
culture medium. These effects were more apparent in tumor
cell lines than in diploid fibroblasts. In tumor cell lines, clin-
optilolite reduced the activity of epidermal growth factor (EGF)
receptors, and also the activity of PKB/Akt and NFκB, i.e. key
proteins involved in cell survival and apoptosis. These effects
were attributed to the adsorptive and ion-exchange properties
of clinoptilolite, which can clear some components of the
serum supplement of the cell culture medium, e.g. EGF, and
This journal is © The Royal Society of Chemistry 2018 Biomater. Sci., 2018, 6, 974–989 | 983
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The SFs in our studies were synthesized using tetrapropyl project No. LM2015062 (Czech-BioImaging). Mr Robin Healey
ammonium hydroxide (TPAOH) as a template. According to (Czech Technical University in Prague) is gratefully acknowl-
our recent results, the heat-treated SF at 500 °C is covered by edged for his language revision of the manuscript.
products of TPAOH degradation, which are partially volatile
polyaromatic condensed hydrocarbons (PAHs), including
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