Mustafa Gorkem OZYURT, Ece BAYİR, Sule DOGAN, Sukru OZTURK, Aylin SENDEMİR

Coculture model of blood-brain barrier on electrospun nanofibers

The blood–brain barrier (BBB) is a control mechanism that limits the diffusion of many substances to the central nervous system (CNS). In this study, we designed an in-vitro 3-dimensional BBB system to obtain a fast and reliable model to mimic drug delivery characteristics of the CNS. A support membrane of polycaprolactone nanofiber surfaces was prepared using electrospinning. After confirming the fiber morphology and size, endothelial cells (HUVEC) and glial cells were cultured on either side of this membrane. The model’s similarity to in vivo physiology was tested with a home-designed transmembrane resistance (TR) device, with positive and negative control molecules. Finally, 2 doses of methotrexate (MTX), a chemotherapy agent, were applied to the model, and its permeability through the model was determined indirectly by a vitality test on the MCF-7 cell line. Nicotine, the positive control, completed its penetration through the model almost instantly, while albumin, the negative control, was blocked significantly even after 2 days. MTX reached a deadly threshold 24 h after application. The TR value of the model was promising, being around 260 ohm.cm2. The provided model proposes a disposable and reliable tool for investigating drug permeability through the BBB and has the potential to reduce the number of animal experiments.

Keywords:

Blood–brain barrier, electrospinning, methotrexate, 3-dimensional cell culture, transmembrane resistance,

PDF

___

Abbott NJ, 2012, METHODS MOL BIOL, V814, P415, DOI 10.1007/978-1-61779-452-0_28
Abbruscato TJ, 2002, J PHARM SCI-US, V91, P2525, DOI 10.1002/jps.10256
Akiyama H, 2000, BRAIN RES, V858, P172, DOI 10.1016/S0006-8993(99)02471-3
Appelt-Menzel A, 2017, STEM CELL REP, V8, P894, DOI 10.1016/j.stemcr.2017.02.021
Banks WA, 2000, J GERONTOL A-BIOL, V55, pB601, DOI 10.1093/gerona/55.12.B601
Bischel LL, 2016, J BIOMED MATER RES A, V104, P901, DOI 10.1002/jbm.a.35624
Borzova VA, 2016, PLOS ONE, V11, DOI 10.1371/journal.pone.0153495
BROOKS SC, 1973, J BIOL CHEM, V248, P6251
Burkhart A, 2015, FLUIDS BARRIERS CNS, V12, DOI 10.1186/s12987-015-0015-9
Chen ZG, 2010, ACTA BIOMATER, V6, P372, DOI 10.1016/j.actbio.2009.07.024
Correale J, 2009, NEUROCHEM RES, V34, P2067, DOI 10.1007/s11064-009-0081-y
CRONE C, 1982, BRAIN RES, V241, P49, DOI 10.1016/0006-8993(82)91227-6
Cucullo L, 2008, J CEREBR BLOOD F MET, V28, P312, DOI 10.1038/sj.jcbfm.9600525
Cucullo L, 2011, J CEREBR BLOOD F MET, V31, P767, DOI 10.1038/jcbfm.2010.162
Deli MA, 2005, CELL MOL NEUROBIOL, V25, P59, DOI 10.1007/s10571-004-1377-8
Eigenmann DE, 2013, FLUIDS BARRIERS CNS, V10, DOI 10.1186/2045-8118-10-33
Gaillard PJ, 2001, EUR J PHARM SCI, V12, P215, DOI 10.1016/S0928-0987(00)00123-8
Gaumer J, 2009, ACTA BIOMATER, V5, P1552, DOI 10.1016/j.actbio.2009.01.021
Gladson CL, 1999, J NEUROPATH EXP NEUR, V58, P1029, DOI 10.1097/00005072-199910000-00001
Huber JD, 2001, TRENDS NEUROSCI, V24, P719, DOI 10.1016/S0166-2236(00)02004-X
Jia YT, 2016, POLYM COMPOSITE, V37, P2847, DOI 10.1002/pc.23481
Joo F, 1996, PROG NEUROBIOL, V48, P255, DOI 10.1016/0301-0082(95)00046-1
Kalashnik L, 2000, MECH AGEING DEV, V120, P23, DOI 10.1016/S0047-6374(00)00179-2
Kohler N, 2005, LANGMUIR, V21, P8858, DOI 10.1021/la0503451
Kuppan P, 2013, J BIOMED NANOTECHNOL, V9, P1540, DOI 10.1166/jbn.2013.1653
Lobo AO, 2018, INT J NANOMED, V13, P7891, DOI 10.2147/IJN.S175619
Lockman PR, 2005, J PHARMACOL EXP THER, V314, P636, DOI 10.1124/jpet.105.085381
Lockman PR, 2005, J NEUROCHEM, V94, P37, DOI 10.1111/j.1471-4159.2005.03162.x
MALEKHEDAYAT S, 1992, J NEUROSCI RES, V31, P470, DOI 10.1002/jnr.490310309
Mangas-Sanjuan V, 2010, THER DELIV, V1, P535, DOI 10.4155/TDE.10.37
Neuhaus W, 2006, J BIOTECHNOL, V125, P127, DOI 10.1016/j.jbiotec.2006.02.019
Neuwelt E, 2008, LANCET NEUROL, V7, P84, DOI 10.1016/S1474-4422(07)70326-5
Pardridge WM, 2007, DRUG DISCOV TODAY, V12, P54, DOI 10.1016/j.drudis.2006.10.013
Patabendige A, 2013, BRAIN RES, V1521, P1, DOI 10.1016/j.brainres.2012.06.057
PAWLOWSKI NA, 1988, J EXP MED, V168, P1865, DOI 10.1084/jem.168.5.1865
Pazhanimala SK, 2019, APPL SCI-BASEL, V9, DOI 10.3390/app9081583
Qi DJ, 2018, ACS APPL MATER INTER, V10, P21825, DOI 10.1021/acsami.8b03962
Raub TJ, 1996, AM J PHYSIOL-CELL PH, V271, pC495
SHAPIRO WR, 1975, NEW ENGL J MED, V293, P161, DOI 10.1056/NEJM197507242930402
SHIMONHOPHY M, 1991, AM J PHYSIOL, V261, pR478
SMITH KR, 1989, PHARM RES-DORDR, V6, P466, DOI 10.1023/A:1015960205409
Srinivasan B, 2015, JALA-J LAB AUTOM, V20, P107, DOI 10.1177/2211068214561025
Weil RJ, 2005, AM J PATHOL, V167, P913, DOI 10.1016/S0002-9440(10)61180-7
Wilhelm I, 2014, MOL PHARMACEUT, V11, P1949, DOI 10.1021/mp500046f
Wuest DM, 2013, J NEUROSCI METH, V212, P211, DOI 10.1016/j.jneumeth.2012.10.016
Xu H, 2016, SCI REP-UK, V6, DOI 10.1038/srep36670
Xue Q, 2013, INT J BIOL SCI, V9, P174, DOI 10.7150/ijbs.5115
Yeon JH, 2012, BIOMED MICRODEVICES, V14, P1141, DOI 10.1007/s10544-012-9680-5
Zeybek B., 2014, USAK U J MAT SCI, V3, P121
Zhang ZQ, 2011, APPL BIOCHEM BIOTECH, V163, P278, DOI 10.1007/s12010-010-9037-6