{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T19:28:29Z","timestamp":1784921309324,"version":"3.55.0"},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2022,3,22]],"date-time":"2022-03-22T00:00:00Z","timestamp":1647907200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,3,22]],"date-time":"2022-03-22T00:00:00Z","timestamp":1647907200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Drug Deliv. and Transl. Res."],"published-print":{"date-parts":[[2022,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The development of drug nanocarriers based on polymeric, lipid and ceramic biomaterials has been paving the way to precision medicine, where the delivery of poorly soluble active compounds and personalized doses are made possible. However, the nano-size character of these carriers has been demonstrated to have the potential to elicit pathways of the host response different from those of the same biomaterials when engineered as larger size implants and of the drugs when administered without a carrier. Therefore, a specific regulatory framework needs to be made available that can offer robust scientific insights and provide safety data by reliable tests of these novel nano-devices. In this context, the present work presents a multistep protocol for the in vitro assessment of the hemocompatibility of nanocarriers of different physicochemical properties. Poly (ethyl butyl cyanoacrylate) nanoparticles and lipid-based (LipImage\u2122 815) nanoparticles of comparable hydrodynamic diameter were tested through a battery of assays using human peripheral blood samples and recapitulating the main pathways of the host response upon systemic administration; i.e., protein interactions, fibrinogen-platelet binding, cytotoxicity, and inflammatory response. The data showed the sensitivity and reproducibility of the methods adopted that were also demonstrated to determine individual variability as well as to discriminate between activation of pathways of inflammation and unintended release of inflammatory signaling caused by loss of cell integrity. Therefore, this multistep testing is proposed as a reliable protocol for nanoparticle development and emerging regulatory frameworks.<\/jats:p>\n                <jats:p><jats:bold>Graphical abstract<\/jats:bold><\/jats:p>","DOI":"10.1007\/s13346-022-01141-6","type":"journal-article","created":{"date-parts":[[2022,3,22]],"date-time":"2022-03-22T19:03:41Z","timestamp":1647975821000},"page":"2089-2100","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["A multistep in vitro hemocompatibility testing protocol recapitulating the foreign body reaction to nanocarriers"],"prefix":"10.1007","volume":"12","author":[{"given":"Valeria","family":"Perugini","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth","family":"Schmid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00ddrr","family":"M\u00f8rch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Texier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Brodde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5260-7088","authenticated-orcid":false,"given":"Matteo","family":"Santin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,3,22]]},"reference":[{"issue":"sup2","key":"1141_CR1","doi-asserted-by":"publisher","first-page":"1053","DOI":"10.1080\/21691401.2018.1478843","volume":"46","author":"GK Rout","year":"2018","unstructured":"Rout GK, Shin HS, Gouda S, Sahoo S, Das G, Fraceto LF. Patra JK Current advances in nanocarriers for biomedical research and their applications. Artif Cells Nanomed Biotechnol. 2018;46(sup2):1053\u201362. https:\/\/doi.org\/10.1080\/21691401.2018.1478843.","journal-title":"Artif Cells Nanomed Biotechnol"},{"key":"1141_CR2","doi-asserted-by":"publisher","first-page":"2991","DOI":"10.3390\/nano11112991","volume":"11","author":"LM Ernst","year":"2021","unstructured":"Ernst LM, Casals E, Italiani P, Boraschi D, Puntes V. The interactions between nanoparticles and the innate immune system from a nanotechnologist perspective. Nanomaterials. 2021;11:2991. https:\/\/doi.org\/10.3390\/nano11112991.","journal-title":"Nanomaterials"},{"key":"1141_CR3","doi-asserted-by":"crossref","unstructured":"Mishra RK, Ahmad A , Vyawahare A , j Alam P , Khan TH , Rehan Khan R. Biological effects of formation of protein corona onto nanoparticles. Int J Macromol. 2021;175:1\u201318.","DOI":"10.1016\/j.ijbiomac.2021.01.152"},{"key":"1141_CR4","doi-asserted-by":"publisher","unstructured":"Liu L, Bai X, Martikainen MV, K\u00e5rlund A, Roponen M, Xu W, Hu G, Tasciotti E, Lehto VP. Cell membrane coating integrity affects the internalization mechanism of biomimetic nanoparticles. Nat Commun. 2021;30:12(1):5726. https:\/\/doi.org\/10.1038\/s41467-021-26052-x.","DOI":"10.1038\/s41467-021-26052-x"},{"issue":"12","key":"1141_CR5","doi-asserted-by":"publisher","first-page":"1519","DOI":"10.2217\/nnm-2016-0085","volume":"11","author":"N Di Maggio","year":"2016","unstructured":"Di Maggio N, Martella M, Meikle S, Columbaro M, Lucarelli E, Santin M, Banfi A. Rapid and efficient magnetization of mesenchymal stem cells by dendrimer-functionalized magnetic nanoparticles. Nanomedicine. 2016;11(12):1519\u201334. https:\/\/doi.org\/10.2217\/nnm-2016-0085.","journal-title":"Nanomedicine"},{"key":"1141_CR6","doi-asserted-by":"publisher","unstructured":"Varol C, Mildner A, Jung S. Macrophages: development and tissue specialization Annu Rev Immunol. 2015;33:643\u201375.\u00a0https:\/\/doi.org\/10.1146\/annurev-immunol-032414-112220.","DOI":"10.1146\/annurev-immunol-032414-112220"},{"key":"1141_CR7","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.smim.2017.08.013","volume":"34","author":"D Boraschia","year":"2017","unstructured":"Boraschia D, Italiania P, Palombab R, Decuzzib P, Duschlc A, Fadeeld B, Moghimie SM. Nanoparticles and innate immunity: new perspectives on host defence. Semin Immunol. 2017;34:33\u201351. https:\/\/doi.org\/10.1016\/j.smim.2017.08.013.","journal-title":"Semin Immunol"},{"key":"1141_CR8","doi-asserted-by":"publisher","unstructured":"Saha AK, Zhen MYS, Erogbogbo F, Anand K. Ramasubramanian AK. Design considerations and assays for hemocompatibility of FDA-approved nanoparticles. Semin Thromb Hemost. 2020;46(05):637\u201352.\u00a0https:\/\/doi.org\/10.1055\/s-0039-1688491.","DOI":"10.1055\/s-0039-1688491"},{"key":"1141_CR9","doi-asserted-by":"publisher","first-page":"1209","DOI":"10.3390\/cells8101209","volume":"8","author":"KM de la Harpe","year":"2019","unstructured":"de la Harpe KM, Kondiah PPD, Choonara YE, Marimuthu T, du Toit LC, Pillay V. The hemocompatibility of nanoparticles: a review of cell\u2013nanoparticle interactions and hemostasis. Cells. 2019;8:1209. https:\/\/doi.org\/10.3390\/cells8101209.","journal-title":"Cells"},{"issue":"41","key":"1141_CR10","first-page":"1213","volume":"6","author":"A Guildford","year":"2009","unstructured":"Guildford A, Poletti T, Osbourne LH, Di Cerbo A, Gatti AM, Santin M. Nanoparticles of a different source induce different patterns of activation in key biochemical and cellular components of the host response. Interface. 2009;6(41):1213\u201321.","journal-title":"Interface"},{"issue":"1","key":"1141_CR11","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1002\/smll.200700595","volume":"4","author":"N Lewinski","year":"2008","unstructured":"Lewinski N, Colvin V, Drezek R. Cytotoxicity of nanoparticles. Small. 2008;4(1):26\u201349. https:\/\/doi.org\/10.1002\/smll.200700595.","journal-title":"Small"},{"key":"1141_CR12","doi-asserted-by":"publisher","unstructured":"Sulheim E, Iversen TG, Nakstad VT, Klinkenberg G, Sletta H, Schmid R, Hatletveit AR, W\u00e5gb\u00f8 AM1, Sundan A, Skotland T, Sandvig K, M\u00f8rch Y. Cytotoxicity of poly(alkyl cyanoacrylate) nanoparticles. Int J Mol Sci. 2017;18:2454.\u00a0https:\/\/doi.org\/10.3390\/ijms18112454.","DOI":"10.3390\/ijms18112454"},{"key":"1141_CR13","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12645-014-0008-4","volume":"5","author":"S Snipstad","year":"2014","unstructured":"Snipstad S, Westr\u00f8m S, M\u00f8rch Y, Afadzi M, \u00c5slund AKO, de Lange Davies SC. Contact-mediated intracellular delivery of hydrophobic drugs from polymeric nanoparticles.\u00a0Cancer Nanotechnol. 2014;5:1\u20138.","journal-title":"Cancer Nanotechnology"},{"key":"1141_CR14","doi-asserted-by":"publisher","unstructured":"Snipstad S, Hak S, Baghirov H, Sulheim E. M\u00f8rch \u00dd, L\u00e9lu S, von Haartman E, B\u00e4ck M, Nilsson KPR, Klymchenko AS, Andreas KO, de Lange D.\u00a0Labeling nanoparticles: dye leakage and altered cellular uptake. Cytometry Part A 2017;91A:760\u201366.\u00a0https:\/\/doi.org\/10.1002\/cyto.a.22853.","DOI":"10.1002\/cyto.a.22853"},{"key":"1141_CR15","doi-asserted-by":"publisher","unstructured":"Jacquart A, K\u00e9ramidas M, Vollaire J, Boisgard R, Pottier G, Rustique E, rique Mittler F, Navarro FP, Boutet J, Coll JL, Isabelle Texier I. LipImage\u2122 815: novel dye-loaded lipid nanoparticles for long-term and sensitive in vivo near-infrared fluorescence imaging. J Biomed Optics.\u00a02013;18(10):101311.\u00a0https:\/\/doi.org\/10.1117\/1.JBO.18.10.101311.","DOI":"10.1117\/1.JBO.18.10.101311"},{"key":"1141_CR16","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/j.ejpb.2016.01.001","volume":"100","author":"D Sayag","year":"2016","unstructured":"Sayag D, Cabon Q, Texier I, Navarro FP, Boisgard R, Virieux-Watrelot D, Carozzo C, Ponce F. Phase-0\/phase-I study of dye-loaded lipid nanoparticles for near-infrared fluorescence imaging in healthy dogs. Eur J Pharm Biopharm. 2016;100:85\u201393.","journal-title":"Eur J Pharm Biopharm"},{"key":"1141_CR17","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/j.trsl.2015.12.001","volume":"170","author":"Q Cabon","year":"2016","unstructured":"Cabon Q, Sayag D, Texier I, Navarro FP, Boisgard R, Virieux-Watrelot D, Ponce F, Carozzo C. Evaluation of intra-operative fluorescence imaging guided surgery in cancer-bearing dogs\u202f: a prospective proof-of-concept phase ii study in 9 cases. Trans Res. 2016;170:73\u201388. https:\/\/doi.org\/10.1016\/j.trsl.2015.12.001.","journal-title":"Trans Res"},{"key":"1141_CR18","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1016\/j.colsurfb.2012.10.039","volume":"103","author":"SL Hirsha","year":"2013","unstructured":"Hirsha SL, McKenziea DR, Nosworthya NJ, Denmanb JA, Sezermanc OU, Bilek MMM. The Vroman effect: competitive protein exchange with dynamic multilayer protein aggregates. Coll Surf B: Biointerf. 2013;103:395\u2013404. https:\/\/doi.org\/10.1016\/j.colsurfb.2012.10.039.","journal-title":"Coll Surf B: Biointerf"},{"key":"1141_CR19","doi-asserted-by":"publisher","unstructured":"Zhang B, Xie M, Bruschweiler-Li L, Br\u00fcschweiler R. Nanoparticle-assisted removal of protein in human serum for metabolomics studies. Anal Chem. 2016;88(1):1003\u201307.\u00a0https:\/\/doi.org\/10.1021\/acs.analchem.5b03889.","DOI":"10.1021\/acs.analchem.5b03889"},{"issue":"8","key":"1141_CR20","doi-asserted-by":"publisher","first-page":"1894","DOI":"10.1111\/j.1538-7836.2005.01365.x","volume":"3","author":"MW Mosesson","year":"2005","unstructured":"Mosesson MW. Fibrinogen and fibrin structure and functions. Thromb Haemost. 2005;3(8):1894\u2013904. https:\/\/doi.org\/10.1111\/j.1538-7836.2005.01365.x.","journal-title":"Thromb Haemost"},{"issue":"10","key":"1141_CR21","doi-asserted-by":"publisher","first-page":"2777","DOI":"10.1002\/jbm.a.36460","volume":"106","author":"TA Horbett","year":"2018","unstructured":"Horbett TA, Fibrinogen adsorption to biomaterials,. J Biomed Mater Res A. 2018;106(10):2777\u201388. https:\/\/doi.org\/10.1002\/jbm.a.36460.","journal-title":"J Biomed Mater Res A"},{"issue":"3","key":"1141_CR22","doi-asserted-by":"publisher","first-page":"413","DOI":"10.3390\/biom10030413","volume":"10","author":"K Hyltegren","year":"2020","unstructured":"Hyltegren K, Hulander M, Andersson M, Skep\u00f6 M. Adsorption of fibrinogen on silica surfaces-the effect of attached nanoparticles biomolecules. 2020;10(3):413. https:\/\/doi.org\/10.3390\/biom10030413.","journal-title":"Adsorption of fibrinogen on silica surfaces-the effect of attached nanoparticles biomolecules"},{"issue":"2","key":"1141_CR23","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/j.colsurfb.2010.01.014","volume":"77","author":"CJ Nonckreman","year":"2010","unstructured":"Nonckreman CJ, Fleith S, Rouxhet PG, Dupont-Gillain CC. Competitive adsorption of fibrinogen and albumin and blood platelet adhesion on surfaces modified with nanoparticles and\/or PEO. Colloids Surf B Biointerf. 2010;77(2):139\u201349. https:\/\/doi.org\/10.1016\/j.colsurfb.2010.01.014.","journal-title":"Colloids Surf B Biointerf"},{"issue":"14","key":"1141_CR24","doi-asserted-by":"publisher","first-page":"1269","DOI":"10.1016\/s0142-9612(99)00021-6","volume":"20","author":"MT Peracchia","year":"1999","unstructured":"Peracchia MT, Harnisch S, Pinto-Alphandary H, Gulik A, Dedieu JC, Desma\u00eble D, d\u2019Angelo J, M\u00fcller RH, Couvreur P. Visualization of in vitro protein-rejecting properties of PEGylated stealth polycyanoacrylate nanoparticles. Biomaterials. 1999;20(14):1269\u201375. https:\/\/doi.org\/10.1016\/s0142-9612(99)00021-6.","journal-title":"Biomaterials"},{"key":"1141_CR25","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.ejpb.2019.05.006","volume":"141","author":"K Partikel","year":"2019","unstructured":"Partikel K, Korte R, Stein NC, Mulac D, Herrmann FC, Humpf HU, Langer K. Effect of nanoparticle size and PEGylation on the protein corona of PLGA nanoparticles. Eur J Pharmaceutic Biopharmaceutic. 2019;141:70\u201380. https:\/\/doi.org\/10.1016\/j.ejpb.2019.05.006.","journal-title":"Eur J Pharmaceutic Biopharmaceutic"},{"issue":"Pt A","key":"1141_CR26","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/j.addr.2015.09.012","volume":"99","author":"JS Suka","year":"2016","unstructured":"Suka JS, Xua Q, Kima N, Hanesa J, Ensign LM. PEGylation as a strategy for improving nanoparticle-based drug and gene delivery. Adv Drug Deliv Rev. 2016;99(Pt A):28\u201351. https:\/\/doi.org\/10.1016\/j.addr.2015.09.012.","journal-title":"Adv Drug Deliv Rev"},{"key":"1141_CR27","doi-asserted-by":"publisher","first-page":"552","DOI":"10.1016\/j.thromres.2011.07.031","volume":"128","author":"H Suzuki","year":"2011","unstructured":"Suzuki H, Okamura Y, Ikeda Y, Takeoka S, Handa M. Ultrastructural analysis of thrombin-induced interaction between human platelets and liposomes carrying fibrinogen \u03b3-chain dodecapeptide as a synthetic platelet substitute. Thromb Res. 2011;128:552\u20139. https:\/\/doi.org\/10.1016\/j.thromres.2011.07.031.","journal-title":"Thromb Res"},{"key":"1141_CR28","first-page":"2339","volume":"7","author":"MR Hern\u00e1ndez","year":"2012","unstructured":"Hern\u00e1ndez MR, Urb\u00e1n P, Casals E, Estelrich J, Escolar G, Gal\u00e1n AM. Liposomes bearing fibrinogen could potentially interfere with platelet interaction and procoagulant activity. Int J Nanomed. 2012;7:2339\u201347.","journal-title":"Int J Nanomed"},{"key":"1141_CR29","doi-asserted-by":"publisher","unstructured":"Ran Q, XiangY, Liu Y, Xiang L, Li F, Deng X, Xiao Y, Chen L, Chen L, Li Z. Eryptosis indices as a novel predictive parameter for biocompatibility of Fe3O4 magnetic nanoparticles on erythrocytes. Sci Rep. 2015;5:16209.\u00a0https:\/\/doi.org\/10.1038\/srep16209.","DOI":"10.1038\/srep16209"},{"issue":"2","key":"1141_CR30","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1097\/00002480-198804000-00005","volume":"34","author":"JM Anderson","year":"1988","unstructured":"Anderson JM. Trans inflammatory response to implants ASAIO. 1988;34(2):101\u20137. https:\/\/doi.org\/10.1097\/00002480-198804000-00005.","journal-title":"Trans inflammatory response to implants ASAIO"},{"key":"1141_CR31","doi-asserted-by":"publisher","unstructured":"Roya R, Kumara S, Tripathia A, Dasa M, Dwivedia PD. Interactive threats of nanoparticles to the biological system. Immunol Lett.\u00a02014;158 79\u201387.\u00a0https:\/\/doi.org\/10.1016\/j.imlet.2013.11.019.","DOI":"10.1016\/j.imlet.2013.11.019"},{"key":"1141_CR32","doi-asserted-by":"publisher","first-page":"32","DOI":"10.3389\/fcimb.2013.00032","volume":"3","author":"I Zanoni","year":"2013","unstructured":"Zanoni I, Granucci F. Role of CD14 in host protection against infections and in metabolism regulation. F Front Cell Infect Microbiol. 2013;3:32. https:\/\/doi.org\/10.3389\/fcimb.2013.00032.","journal-title":"F Front Cell Infect Microbiol"},{"issue":"2","key":"1141_CR33","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1038\/mi.2015.84","volume":"9","author":"M Duan","year":"2016","unstructured":"Duan M, Steinfort DP, Smallwood D, Hew M, Chen W, Ernst M, Irving LB, Anderson GP, Hibbs ML. CD11b immunophenotyping identifies inflammatory profiles in the mouse and human lungs. Nature. 2016;9(2):550\u201363. https:\/\/doi.org\/10.1038\/mi.2015.84.","journal-title":"Nature"},{"key":"1141_CR34","doi-asserted-by":"publisher","first-page":"33","DOI":"10.3390\/medsci6020033","volume":"6","author":"AA Khan","year":"2018","unstructured":"Khan AA, Alsahli MA, Rahmani AH. Myeloperoxidase as an active disease biomarker: recent biochemical and pathological perspectives. Med Sci. 2018;6:33. https:\/\/doi.org\/10.3390\/medsci6020033.","journal-title":"Med Sci"},{"key":"1141_CR35","doi-asserted-by":"publisher","unstructured":"Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill AM. M-1\/M-2 Macrophages and the Th1\/Th2. J Immunol.\u00a02000;164:6166\u201373.\u00a0https:\/\/doi.org\/10.4049\/jimmunol.164.12.6166.","DOI":"10.4049\/jimmunol.164.12.6166"}],"container-title":["Drug Delivery and Translational Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s13346-022-01141-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s13346-022-01141-6\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s13346-022-01141-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,8]],"date-time":"2022-08-08T13:56:33Z","timestamp":1659966993000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s13346-022-01141-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,22]]},"references-count":35,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2022,9]]}},"alternative-id":["1141"],"URL":"https:\/\/doi.org\/10.1007\/s13346-022-01141-6","relation":{},"ISSN":["2190-393X","2190-3948"],"issn-type":[{"value":"2190-393X","type":"print"},{"value":"2190-3948","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,22]]},"assertion":[{"value":"18 February 2022","order":1,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 March 2022","order":2,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was approved by the University of Brighton Ethics committee.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Consents to participate were obtained in the form of signed documents from all blood donors.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"Blood donors have consented to the use of the data for publication. All authors have reviewed the data and the manuscript and consented to their publication.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}