Silicon dioxide nanoparticles, also known as silica nanoparticles or nanosilica, are the basis for a great deal of biomedical research due to their stability, low toxicity and ability to be functionalized with a range of molecules and polymers.
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Image Credit: AB-7272/Shutterstock.com Nanosilica particles are divided into P-type and S-type according to their structure. The P-type particles are characterized by numerous nanopores, which have a pore rate of 0.61 ml/g and exhibit a higher ultraviolet reflectivity compared to the S-type; the latter also has a comparatively smaller surface area. Nanosilica are the second most produced nanomaterial globally. Due to this, several research papers in recent decades have focused on the potential applications of nanosilica in multiple industries and their potential toxicity. Nanosilica appears in the form of a white powder. The table below provides the physical properties of these nanoparticles. The chief applications of nanosilica are as an additive for the manufacture of rubber and plastics; as a strengthening filler for concrete and other construction composites; and as a stable, non-toxic platform for biomedical applications such as drug delivery and theranostics. Nanosilica are an emerging technology in the biomedical field due to their favorable biocompatibility, large surface area, and controllable particle size. These beneficial properties also make SiO2 nanoparticles useful materials in the food industry. Several economical and convenient strategies have been developed to manufacture nanosilica based on common synthesis methods. While many successful studies have demonstrated the efficaciousness of SiO2 nanoparticles for treating various cancers and diagnosing diseases, challenges persist. One of the main challenges associated with using nanosilica in biomedical applications is to do with their toxicity and toxicity mechanisms. This is still a poorly understood area of research, with in vitro and in vivo studies in their infancy. Nonporous nanosilica, also termed N-SiNPs, are particularly useful for biomedical applications such as drug delivery and disease diagnosis due to their excellent biocompatibility. These nanoparticles are irregular and amorphous, having no standard structural shape. N-SiNPs are widely used in biomedical applications such as medical imaging, as stabilizing agents for therapeutics, and enzyme encapsulation. There are two main routes for synthesizing these nanoparticles: thermal methods and wet methods. Wet preparation approaches include precipitation and chemical sol-gel methods. M-SiNPs (mesoporous silica nanoparticles) have a more regular shape than their nonporous counterparts. These types of nanosilica have beneficial physiochemical properties such as controllable porosity, good biocompatibility, large surface area, and high thermal stability. Due to these beneficial properties, M-SiNPs are widely employed by biomedical scientists for applications such as catalysis, bioimaging, and drug delivery. Aside from this, M-SiNPs have been employed as platforms for preparing other nanomaterials. M-SiNPs are commonly prepared using a number of methods. These include improved Stöber synthesis methods, evaporation-induced self-assembly, and the use of liquid crystal templates (template synthesis) and one-pot synthesis. Image Credit: CHUYKO SERGEY/Shutterstock.com As mentioned above, one of the main biomedical applications for nanosilica is as carriers for drug delivery, delivered via eye drops, intravenous injections, oral tablets, or pulmonary inhalation routes. Research has been conducted into the use of nanosilica to deliver drugs to target various cancers such as liver cancer, lung cancer, glioblastoma, and colon cancer. They have been employed to treat viral infections, myocardial infarction, colitis, and neurodegenerative diseases as well as various cancers. Functionalized nanosilica has been used in MRI, light imaging, dual-mode imaging, radio-labeled imaging, and ultrasound imaging. Patients can be easily exposed to nanoparticles through eating, breathing, and touching them. Their small size, high surface-to-volume ratios, and enhanced surface reactivity make them a concern for scientists, making studies on their toxicity a crucial endeavor in the biomedical and food industries. For this reason, and the fact that they are widely employed in medical imaging and drug delivery, the in vitro and in vivo toxicity of nanosilica has been extensively studied. Research into potential toxicity in respiratory systems has indicated potential oxidative stress in human lung fibroblast cells related to the cytotoxicity of nanosilica. Other studies have indicated a relationship between nanosilica and elevated transcription of chemokines, which are pro-inflammatory. Furthermore, due to their small size, silicon dioxide nanoparticles can cross the blood brain barrier, with concerns being raised in research about their potential link to neurodegenerative disorders such as Alzheimer's disease. Nanosilica can also potentially cause mitochondrial dysfunction, leading to corneal damage in the eye. Research has also indicated potential nanosilica-linked toxicity in the gastrointestinal, digestive, and circulatory systems. Clearly, more research is needed into the potential toxicity of silicon dioxide nanoparticles, especially as they are becoming more commonly employed in the biomedical field. Hebei Silicon Research Electronic Materials Co., L supply professional and honest service. Huang, Y et al. (2022) Silica nanoparticles: Biomedical applications and toxicity Biomedicine & Pharmacotherapy 151, 113053 [online] sciencedirect.com. Available at: https://doi.org/10.1016/j.biopha.2022.113053Chemical Properties of Nanosilica
Chemical Data
Chemical symbol
SiO2
CAS No
7631-86-9
Group
Silicon 14
Oxygen 16
Electronic configuration
Silicon [Ne] 3s2 3p2
Oxygen [He] 2s2 2p4
Chemical Composition
Element
Content (%)
Silicon
46.83
Oxygen
53.33
Physical Properties of Nanosilica
Properties
Metric
Imperial
Density
2.4 g/cm3
0.086 lb/in3
Molar Mass
59.96 g/mol
-
Thermal Properties of Nanosilica
Properties
Metric
Imperial
Melting Point
1600°C
2912°F
Boling Point
2230°C
4046°F
Applications of Nanosilica
Nanosilica for Biomedical Applications
Nonporous Nanosilica: Biomedical Applications and Synthesis
Mesoporous Nanosilica: Biomedical Applications and Synthesis
Nanosilica as Drug Delivery Systems
Medical Imaging
Toxicity
References and Further Reading
The severity of the biological effects of silicon dioxide is strongly dependent on the structure of the material, i.e. whether it is crystalline or amorphous. The size of the particles, whether micro- or nanometer, plays only a minor role. Inhalation of crystalline silica causes considerable inflammation in the lung tissue; amorphous silica, on the other hand, triggers a brief inflammation in high doses, but after it subsides, no further effects occur.
Silica has either an amorphous or crystalline structure, which has a significant influence on its biological effects. Inhalation of crystalline silica causes silicosis, also called pneumoconiosis or ‘black lung’ disease. Silicosis refers to pathological changes in the lungs caused by prolonged inhalation of quartz dust particles. Inhalable quartz dust has been classified as carcinogenic by the International Agency for Research on Cancer (IARC) . The European Network on Silica (NEPSI) publishes a good practice guide for the safe handling of crystalline silica at the workplace.
In a comparative study, two groups of rats inhaled crystalline quartz particles or amorphous silica nanoparticles for three months. After this treatment Inflammatory reactions in the lungs were analysed. The crystalline form triggered significant inflammation that did not subside, whereas the amorphous silica induced a temporary inflammation only at high doses, which subsided after a short recovery time, and no further negative effects were observed . This behaviour of the two different structural forms of Silicon Dioxide is confirmed by further scientific work .
The amorphous silica was tested in two laboratory studies according to OECD guidelines. The rats inhaled the nanoparticles for short periods of time (5 and 28 days, respectively) at different doses and then they were examined for possible effects of SiO2 in the lungs. However, there were no negative effects observed in these experiments . During the same period, several experiments were also conducted with rats and similar nanoparticles, but with the method of instillation, which is very different from inhalation exposure, as it is less realistic and usually produces very high local concentrations in the lungs. In these studies, inflammatory reactions and oxidative stress were observed in the lungs of the experimental animals , but they occurred exclusively when the lungs were overloaded with particles, the so-called "overload effect". This effect always occurs when the cleaning processes of the lungs are overloaded .
The studies on lung exposure to silica demonstrate two things: on the one hand, this substance has hardly any effect in the amorphous form. On the other hand, however, overloading the lungs with dust particles must generally be avoided, since loading with high quantities or inhalation of high concentrations of particles over a prolonged period may well result in lung damage. However, this is not specific to silica, but applies to any form of dust particles that can be inhaled (see cross-sectional topic Granular Biopersistant Dusts). Under realistic conditions of everyday life, however, such a scenario hardly plays a role, since a situation cannot be found in which large quantities of dust are inhaled over weeks and months.
Silicon dioxide is approved as a substance to be used in cosmetic products (e.g. skin care, toothpaste). Therefore, knowledge of possible absorption via the skin is an important factor in the safety assessment of this material.
Silicon dioxide in its amorphous form is found in many products, including skin care products or toothpaste. Since July 2013, substances deliberately added as nanoparticles in cosmetics must be labelled with the addition "(nano)" on the list of ingredients. The effects on the skin have been tested in numerous experiments, but only a few have investigated uptake into the body, as this is methodologically very difficult. Nevertheless, there are some very interesting results from recent studies. One study presented a direct comparison between a skin cell culture (HaCaT keratinocytes), a three-dimensional skin model ("EpiDerm®") and rabbit skin. It was shown that the isolated skin cells respond with a slight loss of viability only by treatment with very high concentrations of nanoparticles. However, the 3D model and rabbit skin did not show any loss of viability or skin irritation . Two years later, an extensive study was conducted to investigate different sized nanoparticles of amorphous silica and their penetration into human skin. Here it was observed, as studies with particles from other materials had already shown, that there was no penetration of the nanoparticles through healthy skin into the body (see also Body Barriers "Nanoparticles and the Skin").
Very remarkable is a British study with the 3D model "EpiDerm®". This 3D model, along with other models, meanwhile replaces animal testing, as animal testing for all cosmetic products has no longer been permitted in Europe since 2013. These three-dimensional skin models are composed and behave exactly like human skin. They consist of the different layers that also make up our skin: in the deep layers the living, proliferating epidermal cells and towards the surface with dead keratinocytes that cover our skin with 10-15 layers of dead cells, also called stratum corneum. A comparative study by Swansea University showed that simple cell cultures of skin cells responded to high concentrations of SiO2 nanoparticles with an increase in DNA damage, while the more realistic 3D model showed no symptoms or biological effects . In this study, penetration of the nanoparticles into deeper cell layers could also be ruled out, so that the silicon dioxide did not come into contact with the living cells of the epidermal layer. Another study was even able to demonstrate a protective effect of the SiO2 nanoparticles . In animal experiments with mice, two skin sensitizers were used to induce symptoms of allergy. However, when the skin of the animals was simultaneously treated with silica, the allergic symptoms did not occur. This was true for the negatively charged and neutral nanoparticles. Those that carried positive charges on their surface did not show this protective effect.
Taken together, the results of the experiments on the treatment of skin and skin cells with silicon dioxide prove that these nanoparticles have no harmful effect on the skin and cannot enter the body through healthy skin.
Amorphous silicon dioxide (SiO2) is considered non-toxic and is approved as a food additive (E551) and, because of its specific properties, is used in many food products as a filler or anti-caking agent. Due to the production conditions, this food additive may also contain a certain amount of nanoscale SiO2 particles. However, the majority of the produced SiO2 is needed for completely different applications, such as paints and varnishes, scratch-resistant surfaces, and many other everyday products.
In vitro studies with gastric or intestinal cells show that only very high concentrations of silica nanoparticles damage cells in culture . This is confirmed by another study in which different cell types from the gastrointestinal tract were treated with different concentrations of food-grade SiO2 nanoparticles. The cells did not show any toxic reactions at realistic concentrations, but only responded to very high doses of nano-silica with inhibited cell growth .
Another study also demonstrated a response of immune cells of the intestinal mucosa to relatively high concentrations of food-grade SiO2 nanoparticles. There was an uptake of the nanoparticles into the cells as well as an activation of intracellular signaling pathways . Furthermore, silica nanoparticles were able to stimulate the growth of intestinal cells in cell culture experiments . However, a true toxic effect was not observed here either.
Recent in vivo studies demonstrate that dietary SiO2 nanoparticles do not cause adverse effects in the gastrointestinal tract of rats. In these studies, 1.5 g/kg body weight per day was given for up to 90 days without any adverse effects on the test animals . Although none of the studies listed here were conducted with food-approved silica, even these mostly surface-active variants were not harmful to the gastrointestinal tract. In addition, silicon dioxide is mostly excreted undigested due to its poor solubility .
Silicon dioxide has no negative effect in the gastrointestinal tract either as micrometer or nanometer sized particles. In most cases, variants are tested that are not approved for use in food at all, and yet even these modifications of SiO2 are not toxic.
Silicon dioxide is a pharmaceutical excipient and is used in pills, capsules, gels, ointments, and other applications. Cosmetics and personal care products also contain SiO2 to protect the skin or improve creams. Dietary supplements containing SiO2 are offered in pharmacies and drugstores to support hair and nail growth.
For silicon dioxide, an uptake in humans cannot be excluded because of the multitude of applications, also close to the body, or is even desired (food supplements, drugs). Since the beginning of the industrial use of silicon dioxide (since approx. 70 years), no negative effect has been observed for humans, neither for the microscale nor for the nanoscale particles.
Silicon dioxide nanoparticles, also known as silica nanoparticles or nanosilica, are the basis for a great deal of biomedical research due to their stability, low toxicity and ability to be functionalized with a range of molecules and polymers.
Image Credit: AB-7272/Shutterstock.com
Nanosilica particles are divided into P-type and S-type according to their structure. The P-type particles are characterized by numerous nanopores, which have a pore rate of 0.61 ml/g and exhibit a higher ultraviolet reflectivity compared to the S-type; the latter also has a comparatively smaller surface area.
Nanosilica are the second most produced nanomaterial globally. Due to this, several research papers in recent decades have focused on the potential applications of nanosilica in multiple industries and their potential toxicity.
Nanosilica appears in the form of a white powder. The table below provides the physical properties of these nanoparticles.
The chief applications of nanosilica are as an additive for the manufacture of rubber and plastics; as a strengthening filler for concrete and other construction composites; and as a stable, non-toxic platform for biomedical applications such as drug delivery and theranostics.
Nanosilica are an emerging technology in the biomedical field due to their favorable biocompatibility, large surface area, and controllable particle size. These beneficial properties also make SiO2 nanoparticles useful materials in the food industry.
Several economical and convenient strategies have been developed to manufacture nanosilica based on common synthesis methods. While many successful studies have demonstrated the efficaciousness of SiO2 nanoparticles for treating various cancers and diagnosing diseases, challenges persist.
One of the main challenges associated with using nanosilica in biomedical applications is to do with their toxicity and toxicity mechanisms. This is still a poorly understood area of research, with in vitro and in vivo studies in their infancy.
Nonporous nanosilica, also termed N-SiNPs, are particularly useful for biomedical applications such as drug delivery and disease diagnosis due to their excellent biocompatibility. These nanoparticles are irregular and amorphous, having no standard structural shape.
N-SiNPs are widely used in biomedical applications such as medical imaging, as stabilizing agents for therapeutics, and enzyme encapsulation. There are two main routes for synthesizing these nanoparticles: thermal methods and wet methods. Wet preparation approaches include precipitation and chemical sol-gel methods.
M-SiNPs (mesoporous silica nanoparticles) have a more regular shape than their nonporous counterparts. These types of nanosilica have beneficial physiochemical properties such as controllable porosity, good biocompatibility, large surface area, and high thermal stability.
Due to these beneficial properties, M-SiNPs are widely employed by biomedical scientists for applications such as catalysis, bioimaging, and drug delivery. Aside from this, M-SiNPs have been employed as platforms for preparing other nanomaterials.
M-SiNPs are commonly prepared using a number of methods. These include improved Stöber synthesis methods, evaporation-induced self-assembly, and the use of liquid crystal templates (template synthesis) and one-pot synthesis.
Image Credit: CHUYKO SERGEY/Shutterstock.com
As mentioned above, one of the main biomedical applications for nanosilica is as carriers for drug delivery, delivered via eye drops, intravenous injections, oral tablets, or pulmonary inhalation routes.
Research has been conducted into the use of nanosilica to deliver drugs to target various cancers such as liver cancer, lung cancer, glioblastoma, and colon cancer. They have been employed to treat viral infections, myocardial infarction, colitis, and neurodegenerative diseases as well as various cancers.
Functionalized nanosilica has been used in MRI, light imaging, dual-mode imaging, radio-labeled imaging, and ultrasound imaging.
Patients can be easily exposed to nanoparticles through eating, breathing, and touching them. Their small size, high surface-to-volume ratios, and enhanced surface reactivity make them a concern for scientists, making studies on their toxicity a crucial endeavor in the biomedical and food industries.
For this reason, and the fact that they are widely employed in medical imaging and drug delivery, the in vitro and in vivo toxicity of nanosilica has been extensively studied.
Research into potential toxicity in respiratory systems has indicated potential oxidative stress in human lung fibroblast cells related to the cytotoxicity of nanosilica. Other studies have indicated a relationship between nanosilica and elevated transcription of chemokines, which are pro-inflammatory.
Furthermore, due to their small size, silicon dioxide nanoparticlessilicon dioxide nanoparticles can cross the blood brain barrier, with concerns being raised in research about their potential link to neurodegenerative disorders such as Alzheimer's disease. Nanosilica can also potentially cause mitochondrial dysfunction, leading to corneal damage in the eye.
Research has also indicated potential nanosilica-linked toxicity in the gastrointestinal, digestive, and circulatory systems. Clearly, more research is needed into the potential toxicity of silicon dioxide nanoparticles, especially as they are becoming more commonly employed in the biomedical field.
Huang, Y et al. (2022) Silica nanoparticles: Biomedical applications and toxicity Biomedicine & Pharmacotherapy 151, 113053 [online] sciencedirect.com. Available at: https://doi.org/10.1016/j.biopha.2022.113053
The severity of the biological effects of silicon dioxide is strongly dependent on the structure of the material, i.e. whether it is crystalline or amorphous. The size of the particles, whether micro- or nanometer, plays only a minor role. Inhalation of crystalline silica causes considerable inflammation in the lung tissue; amorphous silica, on the other hand, triggers a brief inflammation in high doses, but after it subsides, no further effects occur.
Silica has either an amorphous or crystalline structure, which has a significant influence on its biological effects. Inhalation of crystalline silica causes silicosis, also called pneumoconiosis or ‘black lung’ disease. Silicosis refers to pathological changes in the lungs caused by prolonged inhalation of quartz dust particles. Inhalable quartz dust has been classified as carcinogenic by the International Agency for Research on Cancer (IARC) . The European Network on Silica (NEPSI) publishes a good practice guide for the safe handling of crystalline silica at the workplace.
In a comparative study, two groups of rats inhaled crystalline quartz particles or amorphous silica nanoparticles for three months. After this treatment Inflammatory reactions in the lungs were analysed. The crystalline form triggered significant inflammation that did not subside, whereas the amorphous silica induced a temporary inflammation only at high doses, which subsided after a short recovery time, and no further negative effects were observed . This behaviour of the two different structural forms of Silicon Dioxide is confirmed by further scientific work .
The amorphous silica was tested in two laboratory studies according to OECD guidelines. The rats inhaled the nanoparticles for short periods of time (5 and 28 days, respectively) at different doses and then they were examined for possible effects of SiO2 in the lungs. However, there were no negative effects observed in these experiments . During the same period, several experiments were also conducted with rats and similar nanoparticles, but with the method of instillation, which is very different from inhalation exposure, as it is less realistic and usually produces very high local concentrations in the lungs. In these studies, inflammatory reactions and oxidative stress were observed in the lungs of the experimental animals , but they occurred exclusively when the lungs were overloaded with particles, the so-called "overload effect". This effect always occurs when the cleaning processes of the lungs are overloaded .
The studies on lung exposure to silica demonstrate two things: on the one hand, this substance has hardly any effect in the amorphous form. On the other hand, however, overloading the lungs with dust particles must generally be avoided, since loading with high quantities or inhalation of high concentrations of particles over a prolonged period may well result in lung damage. However, this is not specific to silica, but applies to any form of dust particles that can be inhaled (see cross-sectional topic Granular Biopersistant Dusts). Under realistic conditions of everyday life, however, such a scenario hardly plays a role, since a situation cannot be found in which large quantities of dust are inhaled over weeks and months.
Silicon dioxide is approved as a substance to be used in cosmetic products (e.g. skin care, toothpaste). Therefore, knowledge of possible absorption via the skin is an important factor in the safety assessment of this material.
Silicon dioxide in its amorphous form is found in many products, including skin care products or toothpaste. Since July 2013, substances deliberately added as nanoparticles in cosmetics must be labelled with the addition "(nano)" on the list of ingredients. The effects on the skin have been tested in numerous experiments, but only a few have investigated uptake into the body, as this is methodologically very difficult. Nevertheless, there are some very interesting results from recent studies. One study presented a direct comparison between a skin cell culture (HaCaT keratinocytes), a three-dimensional skin model ("EpiDerm®") and rabbit skin. It was shown that the isolated skin cells respond with a slight loss of viability only by treatment with very high concentrations of nanoparticles. However, the 3D model and rabbit skin did not show any loss of viability or skin irritation . Two years later, an extensive study was conducted to investigate different sized nanoparticles of amorphous silica and their penetration into human skin. Here it was observed, as studies with particles from other materials had already shown, that there was no penetration of the nanoparticles through healthy skin into the body (see also Body Barriers "Nanoparticles and the Skin").
Very remarkable is a British study with the 3D model "EpiDerm®". This 3D model, along with other models, meanwhile replaces animal testing, as animal testing for all cosmetic products has no longer been permitted in Europe since 2013. These three-dimensional skin models are composed and behave exactly like human skin. They consist of the different layers that also make up our skin: in the deep layers the living, proliferating epidermal cells and towards the surface with dead keratinocytes that cover our skin with 10-15 layers of dead cells, also called stratum corneum. A comparative study by Swansea University showed that simple cell cultures of skin cells responded to high concentrations of SiO2 nanoparticles with an increase in DNA damage, while the more realistic 3D model showed no symptoms or biological effects . In this study, penetration of the nanoparticles into deeper cell layers could also be ruled out, so that the silicon dioxide did not come into contact with the living cells of the epidermal layer. Another study was even able to demonstrate a protective effect of the SiO2 nanoparticles . In animal experiments with mice, two skin sensitizers were used to induce symptoms of allergy. However, when the skin of the animals was simultaneously treated with silica, the allergic symptoms did not occur. This was true for the negatively charged and neutral nanoparticles. Those that carried positive charges on their surface did not show this protective effect.
Taken together, the results of the experiments on the treatment of skin and skin cells with silicon dioxide prove that these nanoparticles have no harmful effect on the skin and cannot enter the body through healthy skin.
Amorphous silicon dioxide (SiO2) is considered non-toxic and is approved as a food additive (E551) and, because of its specific properties, is used in many food products as a filler or anti-caking agent. Due to the production conditions, this food additive may also contain a certain amount of nanoscale SiO2 particles. However, the majority of the produced SiO2 is needed for completely different applications, such as paints and varnishes, scratch-resistant surfaces, and many other everyday products.
In vitro studies with gastric or intestinal cells show that only very high concentrations of silica nanoparticles damage cells in culture . This is confirmed by another study in which different cell types from the gastrointestinal tract were treated with different concentrations of food-grade SiO2 nanoparticles. The cells did not show any toxic reactions at realistic concentrations, but only responded to very high doses of nano-silica with inhibited cell growth .
Another study also demonstrated a response of immune cells of the intestinal mucosa to relatively high concentrations of food-grade SiO2 nanoparticles. There was an uptake of the nanoparticles into the cells as well as an activation of intracellular signaling pathways . Furthermore, silica nanoparticles were able to stimulate the growth of intestinal cells in cell culture experiments . However, a true toxic effect was not observed here either.
Recent in vivo studies demonstrate that dietary SiO2 nanoparticles do not cause adverse effects in the gastrointestinal tract of rats. In these studies, 1.5 g/kg body weight per day was given for up to 90 days without any adverse effects on the test animals . Although none of the studies listed here were conducted with food-approved silica, even these mostly surface-active variants were not harmful to the gastrointestinal tract. In addition, silicon dioxide is mostly excreted undigested due to its poor solubility .
Silicon dioxide has no negative effect in the gastrointestinal tract either as micrometer or nanometer sized particles. In most cases, variants are tested that are not approved for use in food at all, and yet even these modifications of SiO2 are not toxic.
Silicon dioxide is a pharmaceutical excipient and is used in pills, capsules, gels, ointments, and other applications. Cosmetics and personal care products also contain SiO2 to protect the skin or improve creams. Dietary supplements containing SiO2 are offered in pharmacies and drugstores to support hair and nail growth.
For silicon dioxide, an uptake in humans cannot be excluded because of the multitude of applications, also close to the body, or is even desired (food supplements, drugs). Since the beginning of the industrial use of silicon dioxide (since approx. 70 years), no negative effect has been observed for humans, neither for the microscale nor for the nanoscale particles.