| 1. |
- Basu, Alex, et al.
(författare)
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Hemocompatibility of Ca2+-Crosslinked Nanocellulose Hydrogels : Toward Efficient Management of Hemostasis
- 2017
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Ingår i: Macromolecular Bioscience. - : Wiley. - 1616-5187 .- 1616-5195. ; 17:11
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Tidskriftsartikel (refereegranskat)abstract
- The present work investigates Ca2+-crosslinked nanofibrillated cellulose hydrogels as potential hemostatic wound dressings by studying core interactions between the materials and a central component of wounds and wound healing—the blood. Hydrogels of wood-derived anionic nanofibrillated cellulose (NFC) and NFC hydrogels that incorporate kaolin or collagen are studied in an in vitro whole blood model and with platelet-free plasma assays. The evaluation of thrombin and factor XIIa formation, platelet reduction, and the release of activated complement system proteins, shows that the NFC hydrogel efficiently triggered blood coagulation, with a rapid onset of clot formation, while displaying basal complement system activation. By using the NFC hydrogel as a carrier of kaolin, the onset of hemostasis is further boosted, while the NFC hydrogel containing collagen exhibits blood activating properties comparable to the anionic NFC hydrogel. The herein studied NFC hydrogels demonstrate great potential for being part of advanced wound healing dressings that can be tuned to target certain wounds (e.g., strongly hemorrhaging ones) or specific phases of the wound healing process for optimal wound management.
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| 2. |
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| 3. |
- Ekstrand-Hammarström, Barbro, et al.
(författare)
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TiO2 nanoparticles tested in a novel screening whole human blood model of toxicity trigger adverse activation of the kallikrein system at low concentrations
- 2015
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Ingår i: Biomaterials. - : Elsevier BV. - 0142-9612 .- 1878-5905. ; 51, s. 58-68
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Tidskriftsartikel (refereegranskat)abstract
- There is a compelling need to understand and assess the toxicity of industrially produced nanoparticles (NPs). In order to appreciate the long-term effects of NPs, sensitive human-based screening tests that comprehensively map the NP properties are needed to detect possible toxic mechanisms. Animal models can only be used in a limited number of test applications and are subject to ethical concerns, and the interpretation of experiments in animals is also distorted by the species differences. Here, we present a novel easy-to-perform highly sensitive whole-blood model using fresh non-anticoagulated human blood, which most justly reflects complex biological cross talks in a human system. As a demonstrator of the tests versatility, we evaluated the toxicity of TiO2 NPs that are widely used in various applications and otherwise considered to have relatively low toxic properties. We show that TiO2 NPs at very low concentrations (50 ng/mL) induce strong activation of the contact system, which in this model elicits thromboinflammation. These data are in line with the finding of components of the contact system in the protein corona of the TiO2 NPs after exposure to blood. The contact system activation may lead to both thrombotic reactions and generation of bradykinin, thereby representing fuel for chronic inflammation in vivo and potentially long-term risk of autoimmunity, arteriosclerosis and cancer. These results support the notion that this novel whole-blood model represents an important contribution to testing of NP toxicity. (C) 2015 Elsevier Ltd. All rights reserved.
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| 4. |
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| 5. |
- Frykstrand, Sara, et al.
(författare)
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Study of mesoporous magnesium carbonate in contact with whole human blood
- 2016
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Ingår i: RSC Advances. - : Royal Society of Chemistry (RSC). - 2046-2069. ; 6:58, s. 52810-52816
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Tidskriftsartikel (refereegranskat)abstract
- The interaction of mesoporours magnesium carbonate (Upsalite) particles (50-100 mm) with human whole blood was investigated using an in vitro loop model and the effect on the complement system, blood coagulation and red blood cell lysis was assessed. The removal of Ca2+ by Upsalite and the possible exchange with and/or release of Mg2+ were explored as well. Upsalite was found to present anticoagulant properties, most probably due to the uptake of Ca2+ by the particles. No hemolytic activity was detected at Upsalite concentrations up to 1 mg ml(-1). Moderate to high levels of C3a and sC5b-9 were observed for Upsalite, however such levels were statistically different from the negative control only when the particle concentrations were 0.25 mg ml(-1) and 1.0 mg ml(-1), respectively. The presented findings are promising for the future development of mesoporous magnesium carbonate-based materials for biomedical applications.
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| 6. |
- Hulsart Billström, Gry, 1982-, et al.
(författare)
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Thromboinflammation as bioactivity assessment of H2O2-alkali modified titanium surfaces
- 2019
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Ingår i: Journal of materials science. Materials in medicine. - : Springer Science and Business Media LLC. - 0957-4530 .- 1573-4838. ; 30:6
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Tidskriftsartikel (refereegranskat)abstract
- The release of growth factors from platelets, mediated by the coagulation and the complement system, plays an important role in the bone formation around implants. This study aimed at exploring the thromboinflammatory response of H2O2-alkali soaked commercially pure titanium grade 2 discs exposed to whole human blood, as a way to assess the bioactivity of the discs. Commercially pure titanium grade 2 discs were modified by soaking in H2O2, NaOH and Ca(OH)2. The platelet aggregation, coagulation activation and complement activation was assessed by exposing the discs to fresh whole blood from human donors. The platelet aggregation was examined by a cell counter and the coagulation and complement activation were assessed by ELISA-measurements of the concentration of thrombin-antithrombin complex, C3a and terminal complement complex. The modified surface showed a statistically significant increased platelet aggregation, coagulation activation and complement activation compared to unexposed blood. The surface also showed a statistically significant increase of coagulation activation compared to PVC. The results of this study showed that the H2O2-alkali soaked surfaces induced a thromboinflammatory response that indicates that the surfaces are bioactive.
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| 7. |
- Hårdstedt, Maria, 1971-, et al.
(författare)
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A novel model for studies of blood-mediated long-term responses to cellular transplants
- 2015
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Ingår i: Upsala Journal of Medical Sciences. - : Upsala Medical Society. - 0300-9734 .- 2000-1967. ; 120:1, s. 28-39
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Tidskriftsartikel (refereegranskat)abstract
- AimsInteraction between blood and bio-surfaces is important in many medical fields. With the aim of studying blood-mediated reactions to cellular transplants, we developed a whole-blood model for incubation of small volumes for up to 48 h.MethodsHeparinized polyvinyl chloride tubing was cut in suitable lengths and sealed to create small bags. Multiple bags, with fresh venous blood, were incubated attached to a rotating wheel at 37°C. Physiological variables in blood were monitored: glucose, blood gases, mono- and divalent cations and chloride ions, osmolality, coagulation (platelet consumption, thrombin-antithrombin complexes (TAT)), and complement activation (C3a and SC5b-9), haemolysis, and leukocyte viability.ResultsBasic glucose consumption was high. Glucose depletion resulted in successive elevation of extracellular potassium, while sodium and calcium ions decreased due to inhibition of energy-requiring ion pumps. Addition of glucose improved ion balance but led to metabolic acidosis. To maintain a balanced physiological environment beyond 6 h, glucose and sodium hydrogen carbonate were added regularly based on analyses of glucose, pH, ions, and osmotic pressure. With these additives haemolysis was prevented for up to 72 h and leukocyte viability better preserved. Despite using non-heparinized blood, coagulation and complement activation were lower during long-term incubations compared with addition of thromboplastin and collagen.ConclusionA novel whole-blood model for studies of blood-mediated responses to a cellular transplant is presented allowing extended observations for up to 48 h and highlights the importance of stringent evaluations and adjustment of physiological conditions.
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| 8. |
- Klingvall Ek, Rebecca, 1985-
(författare)
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Electron beam melting: Impact of part surface properties on metal fatigue and bone ingrowth
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- AbstractThe aim of this thesis is to investigate aspects on how additive manufacturing (AM) contributes to functional bone implants with the use of the electron beam melting (EBM) technology. AM manufactures parts according to computer-aided design, and the EBM technology melts powder using an electron beam, which acts similar to a laser beam. The topics discussed in this thesis are related to surface roughness that originate from the melted metal powder, and the thesis tries to define some aspects that affect implant functionality. Process parameters steering the electron beam and biocompatibility arising from the surface texture were the initial parts of the PhD studies, and the other half focused on post-processing and fatigue, which are important for medical and industrial applications. There are six studies in this compilation thesis. They are abbreviated as P - process parameters, M - medical applications, and F - fatigue. Studies P, M2, F2, and F3 are journal articles, and M1 and F1 are conference proceedings.Study P used design of experiments to investigate how process parameters affect the surface roughness of as-built EBM-manufactured parts and concluded that beam speed and energy (current) were the most important parameters that influence the surface roughness.In studies M1 and M2, EBM-manufactured specimens of cobalt-chromium and titanium alloys were used to evaluate biocompatibility. The blood chamber method quantified the reactions of the human whole blood in contact with the metal surfaces, and the results showed how the as-built EBM surface roughness contributed to coagulation and bone healing.Rotating beam fatigue equipment was used in studies F1–F3 and study F1 discussed the size effect on fatigue loaded as-built specimens and included specimens with different sizes and with or without hot isostatic pressing (HIP). Study F2 compared as-built and machined specimens and study F3 investigated how Hirtisation, which is a patented electrochemical surface treatment, and HIP affect the fatigue properties that originate from the electrochemical polishing surface topography. The studies showed that a decreased surface roughness increased the fatigue resistance while the stress concentrations (Kt) in the surface of EBM-manufactured specimens decreased.The thesis concludes that EBM-manufactured as-built surfaces are suitable for direct contact with the bone, and that HIP does not improve the fatigue resistance of parts with as-built surfaces, where crack initiation starts at notches.
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| 9. |
- Klingvall Ek, Rebecca, 1985-, et al.
(författare)
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Micro- to Macroroughness of Additively Manufactured Titanium Implants in Terms of Coagulation and Contact Activation
- 2017
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Ingår i: International Journal of Oral & Maxillofacial Implants. - : Quintessence Publishing. - 0882-2786 .- 1942-4434. ; 32:3, s. 565-574
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: This study aimed to evaluate how as-built electron beam melting (EBM) surface properties affect the onset of blood coagulation. The properties of EBM-manufactured implant surfaces for placement have, until now, remained largely unexplored in literature. Implants with conventional designs and custom-made implants have been manufactured using EBM technology and later placed into the human body. Many of the conventional implants used today, such as dental implants, display modified surfaces to optimize bone ingrowth, whereas custom-made implants, by and large, have machined surfaces. However, titanium in itself demonstrates good material properties for the purpose of bone ingrowth. Materials and Methods: Specimens manufactured using EBM were selected according to their surface roughness and process parameters. EBM-produced specimens, conventional machined titanium surfaces, as well as PVC surfaces for control were evaluated using the slide chamber model. Results: A significant increase in activation was found, in all factors evaluated, between the machined samples and EBM-manufactured samples. The results show that EBM-manufactured implants with as-built surfaces augment the thrombogenic properties. Conclusion: EBM that uses Ti6Al4V powder appears to be a good manufacturing solution for load-bearing implants with bone anchorage. The as-built surfaces can be used "as is" for direct bone contact, although any surface treatment available for conventional implants can be performed on EBM-manufactured implants with a conventional design.
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| 10. |
- Klingvall Ek, Rebecca, 1985-
(författare)
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SURFACE PROPERTIES OF IMPLANTS MANUFACTURED USING ELECTRON BEAM MELTING
- 2016
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis summarizes the results concerning the manufacture of medical implants for bone replacement using electron beam melting (EBM) which is an additive manufacturing (AM) technology, and aims to satisfy the engineering needs for the medical functionality of manufacturing technology. This thesis has focused on some microscopic properties for surfaces and bone integration. The process parameters of EBM manufacturing were studied to ascertain whether they have impacts on surface appearance, as surface properties have impacts on bone integration and implant performance.EBM manufacturing uses an electron beam to melt metal powder onto each layer in a manner akin to welding. The electron beam is controlled by process parameters that may be altered to a certain extent by the operator. There are individual process parameters for every material, and new parameters are set when developing new materials. In this thesis, process parameters in default settings were altered to ascertain whether it was possible to specify process parameters for implant manufacturing. The blood chamber model was used for thromboinflammation validation, using human whole blood. The model is used to identify early reactions of coagulation and immunoreactions. The material used in this study was Ti6Al4V-ELI, which is corrosion resistant and has the same surface oxide layers as titanium, and CoCr-F75, which has high stiffness, is wear-resistant and is commonly used in articulating joints.The study shows that among the process parameters researched, a combination of speed and current have the most impact on surface roughness and an interaction of parameters were found using design of experiment (DOE). As-built EBM surfaces show thrombogenicity, which in previous studies has been associated with bone ingrowth.Surface structure of as-build EBM manufactured surfaces are similar to implants surfaces described by Pilliar (2005), but with superior material properties than those of implants with sintered metals beads. By altering the process parameters controlling the electron beam, surface roughness of as-build parts may be affected, and the rougher EBM manufactured surfaces tend to be more thrombogen than the finer EBM manufactured surfaces. As-build EBM manufactured surfaces in general show more thrombogenicity than conventional machined implants surfaces.
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| 11. |
- Nilsson Ekdahl, Kristina, et al.
(författare)
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Contact (kallikrein/kinin) system activation in whole human blood induced by low concentrations of α-Fe2O3 nanoparticles
- 2018
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Ingår i: Nanomedicine. - : Elsevier. - 1549-9634 .- 1549-9642. ; 14:3, s. 735-744
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Tidskriftsartikel (refereegranskat)abstract
- Iron-oxide nanoparticles (NPs) generated by environmental events are likely to represent health problems. α-Fe2O3 NPs were synthesized, characterized and tested in a model for toxicity utilizing human whole blood without added anticoagulant. MALDI-TOF of the corona was performed and activation markers for plasma cascade systems (complement, contact and coagulation systems), platelet consumption and release of growth factors, MPO, and chemokine/cytokines from blood cells were analyzed. The coronas formed on the pristine α-Fe2O3 NPs contained contact system proteins and they induced massive activation of the contact (kinin/kallikrein) system, as well as thrombin generation, platelet activation, and release of two pro-angiogeneic growth factors: platelet-derived growth factor and vascular endothelial growth factor, whereas complement activation was unaffected. The α-Fe2O3 NPs exhibited a noticeable toxicity, with kinin/kallikreinactivation, which may be associated with hypotension and long-term angiogenesis in vivo, with implications for cancer, arteriosclerosis and pulmonary disease.
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| 12. |
- Nilsson Ekdahl, Kristina, et al.
(författare)
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Dangerous liaisons : complement, coagulation, and kallikrein/kinin cross-talk act as a linchpin in the events leading to thromboinflammation
- 2016
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Ingår i: Immunological Reviews. - : Wiley. - 0105-2896 .- 1600-065X. ; 274:1, s. 245-269
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Forskningsöversikt (refereegranskat)abstract
- Innate immunity is fundamental to our defense against microorganisms. Physiologically, the intravascular innate immune system acts as a purging system that identifies and removes foreign substances leading to thromboinflammatory responses, tissue remodeling, and repair. It is also a key contributor to the adverse effects observed in many diseases and therapies involving biomaterials and therapeutic cells/organs. The intravascular innate immune system consists of the cascade systems of the blood (the complement, contact, coagulation, and fibrinolytic systems), the blood cells (polymorphonuclear cells, monocytes, platelets), and the endothelial cell lining of the vessels. Activation of the intravascular innate immune system in vivo leads to thromboinflammation that can be activated by several of the system's pathways and that initiates repair after tissue damage and leads to adverse reactions in several disorders and treatment modalities. In this review, we summarize the current knowledge in the field and discuss the obstacles that exist in order to study the cross-talk between the components of the intravascular innate immune system. These include the use of purified in vitro systems, animal models and various types of anticoagulants. In order to avoid some of these obstacles we have developed specialized human whole blood models that allow investigation of the cross-talk between the various cascade systems and the blood cells. We in particular stress that platelets are involved in these interactions and that the lectin pathway of the complement system is an emerging part of innate immunity that interacts with the contact/coagulation system. Understanding the resulting thromboinflammation will allow development of new therapeutic modalities.
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| 13. |
- Nordling, Sofia, et al.
(författare)
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Vascular repair utilising immobilised heparin conjugate for protection against early activation of inflammation and coagulation
- 2015
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Ingår i: Thrombosis and Haemostasis. - 0340-6245 .- 2567-689X. ; 113:6, s. 1312-1322
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Tidskriftsartikel (refereegranskat)abstract
- Ischaemia-reperfusion injury (IRI) poses a major challenge in many thrombotic conditions and in whole organ transplantation. Activation of the endothelial cells and shedding of the protective vascular glycocalyx during IRI increase the risk of innate immune activation, cell infiltration and severe thrombus formation, promoting damage to the tissue. Here, we present a novel one-step strategy to protect the vas, culature by immobilisation of a unique multi-arm heparin conjugate to the endothelium. Applying a new in vitro blood endothelial cell chamber model, the heparin conjugate was found to bind not only to primary human endothelial cells but also directly to the collagen to which the cells adhered. Incubation of hypoxic endothelial cells with freshly drawn human blood in the blood chambers elicited coagulation activation reflected by thrombin anti-thrombin formation and binding of platelets and neutrophils. Immobilisation of the heparin conjugate to the hypoxic endothelial cells created a protective coating, leading to a Significant reduction of the recruitment of blood cells and coagulation activation compared to untreated hypoxic endothelial cells. This novel approach of immobilising multi-arm heparin conjugates on the endothelial cells and collagen of the basement membrane ensures to protect the endothelium against IRI in thrombotic disorders and in transplantation.
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| 14. |
- Rocha, Igor, et al.
(författare)
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Blood Compatibility of Sulfonated Cladophora Nanocellulose Beads
- 2018
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Ingår i: Molecules. - : MDPI AG. - 1431-5157 .- 1420-3049. ; 23:3
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Tidskriftsartikel (refereegranskat)abstract
- Sulfonated cellulose beads were prepared by oxidation of Cladophora nanocellulose to 2,3-dialdehyde cellulose followed by sulfonation using bisulfite. The physicochemical properties of the sulfonated beads, i.e., high surface area, high degree of oxidation, spherical shape, and the possibility of tailoring the porosity, make them interesting candidates for the development of immunosorbent platforms, including their application in extracorporeal blood treatments. A desired property for materials used in such applications is blood compatibility; therefore in the present work, we investigate the hemocompatibility of the sulfonated cellulose beads using an in vitro whole blood model. Complement system activation (C3a and sC5b-9 levels), coagulation activation (thrombin-antithrombin (TAT) levels) and hemolysis were evaluated after whole blood contact with the sulfonated beads and the results were compared with the values obtained with the unmodified Cladophora nanocellulose. Results showed that neither of the cellulosic materials presented hemolytic activity. A marked decrease in TAT levels was observed after blood contact with the sulfonated beads, compared with Cladophora nanocellulose. However, the chemical modification did not promote an improvement in Cladophora nanocellulose hemocompatibility in terms of complement system activation. Even though the sulfonated beads presented a significant reduction in pro-coagulant activity compared with the unmodified material, further modification strategies need to be investigated to control the complement activation by the cellulosic materials.
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| 15. |
- Sellberg, Felix, et al.
(författare)
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Polyvinylalcohol-carbazate (PVAC) reduces red blood cell hemolysis
- 2019
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Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 14:12
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Tidskriftsartikel (refereegranskat)abstract
- Background and objectives: The objective of this study was to investigate whether a soluble polymer and aldehyde-scavenger, polyvinylalcohol-carbazate (PVAC), can inhibit hemolysis in the storage of red blood cells (RBC).Study design and methods: The effect of PVAC was assessed over a wide range of concentrations, using absorption spectroscopy to evaluate the level of hemolysis. Moreover, osmotic stability and aldehyde-scavenging potential of RBC were assessed after storage in PVAC.Results: After test tube storage for two weeks, red blood cell hemolysis was lower with PVAC compared to controls (mean difference 23%, 95% CI 16-29%, p < 0.001). A higher level of hemolysis led to a pronounced effect with PVAC. RBC stored in PVAC improved both the binding of free aldehydes (p <0.001) and the osmotic stability (p = 0.0036).Conclusion: Erythrocytes stored with PVAC showed less hemolysis, which might be explained by the ability of PVACs to stabilize the cell membrane and decrease oxidative injury.
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