"Due to the sharp edges of GO and rGO, hemolytic effects might be expected in vivo, possibly caused by nanomaterial blades disrupting cell membranes, as reported for GO interactions with bacteria.
Feng and colleagues discovered RBC morphological alterations and aggregation above 100 mg mL1 and hemolytic effects above 10 mg mL1 reaching 96% at 500 mg mL1. Lower hemolytic concentrations have been reported by other groups. Small GO flakes (few hundreds of nm) seem to be more destructive."
"Hemostasis cascade prevents blood loss from injured tissue and maintains blood fluidity. The final hemostasis is driven by platelets, which form the clot, a mixture of red blood cells, aggregated platelets, fibrin and other cellular elements (Fig. 3-2b). If the clot forms abnormally, it can induce thrombosis.
Thrombogenicity is an important feature evaluated in nanomaterial design for in vivo delivery and represents the propensity to induce blood clotting and induce occlusion of a blood vessel by a thrombus."
"Furthermore, nanoparticles engineered to have longer systemic circulation times increase the likelihood of contact with blood components including the coagulation system, with thrombogenicity risks."
"When administered in vivo (250 mg kg1 body weight), 48% of lung vessels were partially occluded after 15 minutes"
"Biodistribution and biosafety of GO: future challenges
The focus of this review is the GO interaction with blood components and BC in light of the future design of GO pharmaceutical delivery systems. Intravenously injected drug delivery systems (DDS) developed so far include PEGylated nanographene sheets for tumor passive targeting, rGO functionalized with chitosan and iron oxide magnetic nanoparticles for the delivery of doxorubicin and epidermal growth factor receptor antibody-conjugated PEGylated nanographene oxide for epirubicin delivery in tumors.
Nanoparticles intended for drug delivery applications are being engineered to reduce their clearance and extend systemic
circulation times and thus increase the opportunity for targeted delivery. However, the disadvantage of prolonged circulation times is the greater chance of interaction with blood components and activation of adverse effects.
Before any nanomaterial translation into clinical therapy, there are biosafety concerns that need to be addressed. We have seen how GO interacts with blood system components and how BC can influence these interactions, but what is the biodistribution and the toxicity when GO is administered intravenously"
"The early study of Zhang and colleagues determined the distribution and biocompatibility of i.v. injected GO in mice.
The half-life of GO in blood is much longer than in other carbon nanomaterials (B5 hours). Within 48 hours after i.v. injection, GO is cleared from the bloodstream and distributed throughout various organs with preferred accumulation in the lungs, liver, and spleen. The lack of pathological changes was reported after 14 days of treatment at a low dose (1 mg kg1), Fig. 5 Illustration of the short-term effects of GONPs and rGONPs on THP-1 cells, and the long-term effects on THP-1a differentiation from THP-1 cells. GONPs and rGONPs could have induced ROS formation and activated the NF-kB pathway in THP-1 cells. rGONPs could not fully transcript proinflammatory genes due to lack of additional transcription factors but at a higher dose (10 mg kg1), granulomatous lesions, pulmonary edema, inflammatory cell infiltration, and fibrosis throughout the lung were observed. Many studies confirmed that the primary site of GO accumulation and toxicity in vivo is the lungs. It seems that the pathological effects on the lungs are proportional to the degree of dispersion and oxidation of GO."
"A systematic study on GO size, dose and dosing frequency was conducted by Liu and colleagues. Liu intravenously administered two types of GO: small GO flakes (s-GO, average hydrodynamic diameter of B250 nm) and large GO flakes (l-GO, average hydrodynamic diameter of B900 nm) at a single high dose (2.1 mg kg1) or seven repeated low doses (0.3 mg kg1); irrespective of size, the single high-dose administration of GO induced lung damage and infiltration of inflammatory cells. In the lungs, GO accumulated in the macrophages but not in the lymphocytes, which were recruited but were not able to trap GO. In this study, the authors claimed that although oxidative stress is a widely existent phenomenon in cells exposed in vitro to GO, the protective effect of proteins forming a BC around GO should be considered in vivo.
Interesting size-dependent results were reported for multipledose exposure. The s-GO did not induce renal damage or accumulate in the kidneys since it was quickly eliminated through the glomeruli. Conversely, l-GO failed to be cleared through kidneys and induced damage. The lungs were damaged only after multiple doses of l-GO. This effect depends on the aggregation of GO with proteins that induce the blockage of large GO-complexes in the lungs. The hypothesis relies on the formation of multiple complexes of l-GO and proteins that enter the capillaries and create multiple injury points and inflammatory cell recruitment. s-GO could instead pass through lungs capillaries after each low-dose administration. The kidneys and lungs were more damaged by l-GO, while the s-GO preferentially accumulated in the liver with toxic effects.
At a high single dose, s-GO can also damage the lungs since at high concentration it forms large complexes that reach a similar size to the l-GO protein complex"
"Finally, the degradation of injected GO is an important biosafety concern. Long-term interaction (14 days) of GO with plasma causes reduction and biodegradation with hole formation caused by the action of hydroxyl radicals. Once internalized by the immune cells, biodegradable particles are digested and cleared from the body, while non-biodegradable particles accumulate in cells for extended periods."
FF commentary: There's a lot of chemistry that informs us about the properties of graphene. It is a metal that develops some of the strongest bonds known to man. Graphene bonds in a honeycomb side-by-side coagulation of atoms, one-layer thick (one atom). Virtually indestructible. It's used on high performance brake pads, doesn't wear out. It has a very strong ionic charge that attracts and bonds with other graphene atoms in this configuration. Which makes for the sharpest nanorazor edges possible. An edge of a graphene knife one atom thick can cut through anything. Including blood cells and the inside of necessarily smooth blood vessels and internal organs it eventually embeds itself in. And when other graphene particles and flakes are present they are drawn to each other, growing in size. They become "scaffolding" that builds on itself. And fwiw, scaffolding is a lot like an antenna. For the more conspiratorial readers out there to infer the implications of.
Graphene Oxide and Graphene Hydroxide!! An important piece of research I've previously shared about that biotechnology developed for vaccines:
Graphene Oxide Touches Blood: In Vivo Interactions of Bio-Coronated 2D Materials
Nanoscale Horizons, October, 2018
https://www.researchgate.net/publication/328338305_Graphene_Oxide_Touches_Blood_In_Vivo_Interactions_of_Bio-Coronated_2D_Materials
"Due to the sharp edges of GO and rGO, hemolytic effects might be expected in vivo, possibly caused by nanomaterial blades disrupting cell membranes, as reported for GO interactions with bacteria.
Feng and colleagues discovered RBC morphological alterations and aggregation above 100 mg mL1 and hemolytic effects above 10 mg mL1 reaching 96% at 500 mg mL1. Lower hemolytic concentrations have been reported by other groups. Small GO flakes (few hundreds of nm) seem to be more destructive."
"Hemostasis cascade prevents blood loss from injured tissue and maintains blood fluidity. The final hemostasis is driven by platelets, which form the clot, a mixture of red blood cells, aggregated platelets, fibrin and other cellular elements (Fig. 3-2b). If the clot forms abnormally, it can induce thrombosis.
Thrombogenicity is an important feature evaluated in nanomaterial design for in vivo delivery and represents the propensity to induce blood clotting and induce occlusion of a blood vessel by a thrombus."
"Furthermore, nanoparticles engineered to have longer systemic circulation times increase the likelihood of contact with blood components including the coagulation system, with thrombogenicity risks."
"When administered in vivo (250 mg kg1 body weight), 48% of lung vessels were partially occluded after 15 minutes"
"Biodistribution and biosafety of GO: future challenges
The focus of this review is the GO interaction with blood components and BC in light of the future design of GO pharmaceutical delivery systems. Intravenously injected drug delivery systems (DDS) developed so far include PEGylated nanographene sheets for tumor passive targeting, rGO functionalized with chitosan and iron oxide magnetic nanoparticles for the delivery of doxorubicin and epidermal growth factor receptor antibody-conjugated PEGylated nanographene oxide for epirubicin delivery in tumors.
Nanoparticles intended for drug delivery applications are being engineered to reduce their clearance and extend systemic
circulation times and thus increase the opportunity for targeted delivery. However, the disadvantage of prolonged circulation times is the greater chance of interaction with blood components and activation of adverse effects.
Before any nanomaterial translation into clinical therapy, there are biosafety concerns that need to be addressed. We have seen how GO interacts with blood system components and how BC can influence these interactions, but what is the biodistribution and the toxicity when GO is administered intravenously"
"The early study of Zhang and colleagues determined the distribution and biocompatibility of i.v. injected GO in mice.
The half-life of GO in blood is much longer than in other carbon nanomaterials (B5 hours). Within 48 hours after i.v. injection, GO is cleared from the bloodstream and distributed throughout various organs with preferred accumulation in the lungs, liver, and spleen. The lack of pathological changes was reported after 14 days of treatment at a low dose (1 mg kg1), Fig. 5 Illustration of the short-term effects of GONPs and rGONPs on THP-1 cells, and the long-term effects on THP-1a differentiation from THP-1 cells. GONPs and rGONPs could have induced ROS formation and activated the NF-kB pathway in THP-1 cells. rGONPs could not fully transcript proinflammatory genes due to lack of additional transcription factors but at a higher dose (10 mg kg1), granulomatous lesions, pulmonary edema, inflammatory cell infiltration, and fibrosis throughout the lung were observed. Many studies confirmed that the primary site of GO accumulation and toxicity in vivo is the lungs. It seems that the pathological effects on the lungs are proportional to the degree of dispersion and oxidation of GO."
"A systematic study on GO size, dose and dosing frequency was conducted by Liu and colleagues. Liu intravenously administered two types of GO: small GO flakes (s-GO, average hydrodynamic diameter of B250 nm) and large GO flakes (l-GO, average hydrodynamic diameter of B900 nm) at a single high dose (2.1 mg kg1) or seven repeated low doses (0.3 mg kg1); irrespective of size, the single high-dose administration of GO induced lung damage and infiltration of inflammatory cells. In the lungs, GO accumulated in the macrophages but not in the lymphocytes, which were recruited but were not able to trap GO. In this study, the authors claimed that although oxidative stress is a widely existent phenomenon in cells exposed in vitro to GO, the protective effect of proteins forming a BC around GO should be considered in vivo.
Interesting size-dependent results were reported for multipledose exposure. The s-GO did not induce renal damage or accumulate in the kidneys since it was quickly eliminated through the glomeruli. Conversely, l-GO failed to be cleared through kidneys and induced damage. The lungs were damaged only after multiple doses of l-GO. This effect depends on the aggregation of GO with proteins that induce the blockage of large GO-complexes in the lungs. The hypothesis relies on the formation of multiple complexes of l-GO and proteins that enter the capillaries and create multiple injury points and inflammatory cell recruitment. s-GO could instead pass through lungs capillaries after each low-dose administration. The kidneys and lungs were more damaged by l-GO, while the s-GO preferentially accumulated in the liver with toxic effects.
At a high single dose, s-GO can also damage the lungs since at high concentration it forms large complexes that reach a similar size to the l-GO protein complex"
"Finally, the degradation of injected GO is an important biosafety concern. Long-term interaction (14 days) of GO with plasma causes reduction and biodegradation with hole formation caused by the action of hydroxyl radicals. Once internalized by the immune cells, biodegradable particles are digested and cleared from the body, while non-biodegradable particles accumulate in cells for extended periods."
FF commentary: There's a lot of chemistry that informs us about the properties of graphene. It is a metal that develops some of the strongest bonds known to man. Graphene bonds in a honeycomb side-by-side coagulation of atoms, one-layer thick (one atom). Virtually indestructible. It's used on high performance brake pads, doesn't wear out. It has a very strong ionic charge that attracts and bonds with other graphene atoms in this configuration. Which makes for the sharpest nanorazor edges possible. An edge of a graphene knife one atom thick can cut through anything. Including blood cells and the inside of necessarily smooth blood vessels and internal organs it eventually embeds itself in. And when other graphene particles and flakes are present they are drawn to each other, growing in size. They become "scaffolding" that builds on itself. And fwiw, scaffolding is a lot like an antenna. For the more conspiratorial readers out there to infer the implications of.