Highly uniform silicon nanopore membranes were developed for applications in implantable bioartificial organs. A robust, readily scalable, non-fouling surface coating is required to enhance silicon nanopore membrane hemocompatibility. However, the coating must be ultrathin to keep the nanopores from occluding. Recently, zwitterionic brush polymers have demonstrated significantly lower fouling under biological conditions. In this study, we explore ultrathin zwitterionic poly(sulfobetaine methacrylate) (pSBMA) surface coating at sub-5 nm thickness. Membrane hydraulic permeability was measured before and after surface modification of silicon nanopore membranes, and pores were found to be patent and in agreement with coating thickness measurements. Coating stability was analyzed under biological shear as well as under blood flow in vitro and in vivo. Following exposure to shear over 24 h, coatings were characterized via X-ray photoelectron spectroscopy, goniometry, and ellipsometry, and found to survive biological shear. In vitro blood experiments with fresh human blood as well as in vivo 7-day and 26-day implants in a porcine model demonstrate minimal platelet adhesion and activation with pSBMA surface modification compared to unmodified silicon exposed to fresh human blood in vitro. These results demonstrate that ultrathin pSBMA surface modification is a viable choice for application in blood contacting implants with critical nanoscale features.
CheungKCRenaudP.BioMEMS for medicine: on-chip cell characterization and implantable microelectrodes. Solid State Electron2006;
50: 551–557.
2.
ScholvinJKinneyJPBernsteinJG, et al.
Close-packed silicon microelectrodes for scalable spatially oversampled neural recording. IEEE Trans Biomed Eng2016;
63: 120–130.
3.
DesaiTSharmaSWalczakR, et al.
Nanoporous implants for controlled drug delivery. In: Ferrari M. Desai T. Bhatia S. (eds) BioMEMS and Biomedical Nanotechnology, Boston, MA: Springer, 2006; pp.263–286.
4.
LesinskiGBSharmaSVarkerK. A, et al.
Release of biologically functional interferon-alpha from a nanochannel delivery system. Biomed Microdevices2005;
7: 71–79.
5.
ShawgoRSGraysonACRLiY, et al.
BioMEMS for drug delivery. Curr Opin Solid State Mater Sci2002;
6: 329–334.
6.
KangSMurphyRKJHwangS, et al.
Bioresorbable silicon electronic sensors for the brain. Nature2016;
530: 71–76.
7.
LuekeJMoussaWA.MEMS-based power generation techniques for implantable biosensing applications. Sensors2011;
11: 1433–1460.
RoySDubnishevaAEldridgeA, et al. Silicon nanopore membrane technology for an implantable artificial kidney. In: Transducers 2009 – 15th international conference on solid-state sensors, actuators microsystems, 2009, pp.755–760. Denver, CO: IEEE.
11.
FissellWHFleischmanAJHumesHD, et al.
Development of continuous implantable renal replacement: past and future. Transl Res2007;
150: 327–336.
12.
SongSBlahaCMosesW, et al.An intravascular bioartificial pancreas device (iBAP) with silicon nanopore membranes (SNM) for islet encapsulation under convective mass transport. Lab Chip2017;
17: 1778–1792.
13.
SongSFaleoGYeungR, et al.Silicon nanopore membrane (SNM) for islet encapsulation and immunoisolation under convective transport. Sci Rep2016;
6: 23679.
14.
Fernández-RosasEGómezRIbañezE, et al.
Internalization and cytotoxicity analysis of silicon-based microparticles in macrophages and embryos. Biomed Microdevices2010;
12: 371–379.
15.
AgrawalAANehillaBJReisigKV, et al.
Porous nanocrystalline silicon membranes as highly permeable and molecularly thin substrates for cell culture. Biomaterials2010; 20: 5408–5417.
16.
KotzarGFreasMAbelP, et al.
Evaluation of MEMS materials of construction for implantable medical devices. Biomaterials2002;
23: 2737–2750. Jul
17.
IqbalZMosesWKimS, et al.
Sterilization effects on ultrathin film polymer coatings for silicon-based implantable medical devices. J Biomed Mater Res Part B Appl Biomater2017; 106(6): 2327–2336.
18.
WernerCMaitzMFSperlingC.Current strategies towards hemocompatible coatings. J Mater Chem2007;
17: 3376.
19.
ZhangMFerrariM.Hemocompatible polyethylene glycol films on silicon. Biomed Microdevices1998; 1(1): 81–89.
20.
PopatKCDesaiT. A.Poly(ethylene glycol) interfaces: an approach for enhanced performance of microfluidic systems. Biosens Bioelectron2004;
19: 1037–1044.
21.
HanSKimCKwonD.Thermal/oxidative degradation and stabilization of polyethylene glycol. Polymer (Guildf)1997;
38: 317–323.
22.
SharmaSJohnsonRWDesaiTA.Evaluation of the stability of nonfouling ultrathin poly (ethylene glycol) films for silicon-based microdevices. Langmuir2004;
20: 348–356.
23.
ChenSLiuLJiangS.Strong resistance of oligo(phosphorylcholine) self-assembled monolayers to protein adsorption. Langmuir2006;
22: 2418–2421.
24.
JiangSCaoZZ.Ultralow-fouling, functionalizable, and hydrolyzable zwitterionic materials and their derivatives for biological applications. Adv Mater2010;
22: 920–932.
25.
ZhangZChaoTChenS, et al.
Superlow fouling sulfobetaine and carboxybetaine polymers on glass slides. Langmuir2006;
22: 10072–10077.
26.
MuthusubramaniamLLoweRFissellWH, et al.
Hemocompatibility of silicon-based substrates for biomedical implant applications. Ann Biomed Eng2011;
39: 1296–1305.
27.
CarrLRZhouYKrauseJE, et al.
Uniform zwitterionic polymer hydrogels with a nonfouling and functionalizable crosslinker using photopolymerization. Biomaterials2011;
32: 6893–6899.
28.
ZhangZZhangMChenS, et al.
Blood compatibility of surfaces with superlow protein adsorption. Biomaterials2008;
29: 4285–4291.
29.
SmithRSZhangZBouchardM, et al.
Vascular catheters with a nonleaching poly-sulfobetaine surface modification reduce thrombus formation and microbial attachment. Sci Transl Med2012;
4: 153ra132.
30.
NakabayashiNWilliamsDF.Preparation of non-thrombogenic materials using 2-methacryloyloxyethyl phosphorylcholine. Biomaterials2003;
24: 2431–2435.
31.
LaddJZhangZChenS, et al.
Zwitterionic polymers exhibiting high resistance to nonspecific protein adsorption from human serum and plasma. Biomacromolecules2008;
9: 1357–1361.
32.
ZhangLCaoZBaiT, et al.
Zwitterionic hydrogels implanted in mice resist the foreign-body reaction. Nat Biotechnol2013;
31: 553–556.
33.
WuHLeeCJWangH, et al.
Highly sensitive and stable zwitterionic poly(sulfobetaine-3,4-ethylenedioxythiophene) (PSBEDOT) glucose biosensor. Chem Sci2018;
9: 2540–2546.
34.
PlegueTJKovachKMThompsonAJ, et al.
Stability of polyethylene glycol and zwitterionic surface modifications in PDMS microfluidic flow chambers. Langmuir2018;
34: 492–502.
35.
ZhuJTianMHouJ, et al.
Surface zwitterionic functionalized graphene oxide for a novel loose nanofiltration membrane. J Mater Chem A2016;
4: 1980–1990.
36.
WangJXiaoTBaoR, et al.
Zwitterionic surface modification of forward osmosis membranes using N-aminoethyl piperazine propane sulfonate for grey water treatment. Process Saf Environ Prot2018;
116: 632–639.
37.
ZhangZChaoTLiuL, et al.
Zwitterionic hydrogels: an in vivo implantation study. J Biomater Sci Polym Ed2009;
20: 1845–1859.
38.
LiuP-SChenQLiuX, et al.
Grafting of zwitterion from cellulose membranes via ATRP for improving blood compatibility. Biomacromolecules2009;
10: 2809–2816.
39.
LeeSYLeeYLe ThiP, et al.
Sulfobetaine methacrylate hydrogel-coated anti-fouling surfaces for implantable biomedical devices. Biomater Res2018;
22: 3.
40.
ZhangZChenSChangY, et al.
Surface grafted sulfobetaine polymers via atom transfer radical polymerization as superlow fouling coatings. J Phys Chem B2006;
110: 10799–10804.
41.
DizonGVChouYNYehLC, et al.
Bio-inert interfaces via biomimetic anchoring of a zwitterionic copolymer on versatile substrates. J Colloid Interface Sci2018;
529: 77–89.
42.
LiuP-SChenQWuS-S, et al.
Surface modification of cellulose membranes with zwitterionic polymers for resistance to protein adsorption and platelet adhesion. J Memb Sci2010;
350: 387–394.
43.
ZhangLChenXLiuP, et al.Facile surface modification of glass with zwitterionic polymers for improving the blood compatibility. Mater Res Express2018;
5: 065401.
44.
LiLMarchantREDubnishevaA, et al.
Anti-biofouling sulfobetaine polymer thin films on silicon and silicon nanopore membranes. J Biomater Sci2011;
22: 91–106.
45.
ChengGZhangZChenS, et al.
Inhibition of bacterial adhesion and biofilm formation on zwitterionic surfaces. Biomaterials2007;
28: 4192–4199.
46.
LalaniRLiuL.Electrospun zwitterionic poly(sulfobetaine methacrylate) for nonadherent, superabsorbent, and antimicrobial wound dressing applications. Biomacromolecules2012;
13: 1853–1863.
47.
YangRXuJOzaydin-InceG, et al.
Surface-tethered zwitterionic ultrathin antifouling coatings on reverse osmosis membranes by initiated chemical vapor deposition. Chem Mater2011;
23: 1263–1272.
48.
YangWChenSChengG, et al.
Film thickness dependence of protein adsorption from blood serum and plasma onto poly(sulfobetaine)-grafted surfaces. Langmuir2008;
24: 9211–9214.
49.
ChangYChangWShihY, et al.
Zwitterionic sulfobetaine-grafted poly (vinylidene fluoride) membrane with highly effective blood compatibility via atmospheric plasma-induced surface copolymerization. Appl Mater Interfaces2011;
3: 1228–1237.
50.
YuH-YKangYLiuY, et al.Grafting polyzwitterions onto polyamide by click chemistry and nucleophilic substitution on nitrogen: a novel approach to enhance membrane fouling resistance. J Memb Sci2014;
449: 50–57.
51.
DongZMaoJYangM, et al.
Phase behavior of poly(sulfobetaine methacrylate)-grafted silica nanoparticles and their stability in protein solutions. Langmuir2011;
27: 15282–15291.
52.
ZhangHChiaoM.Anti-fouling coatings of poly(dimethylsiloxane) devices for biological and biomedical applications. J Med Biol Eng2015;
35: 143–155.
53.
ZhangZBorensteinJGuineyL, et al.
Polybetaine modification of PDMS microfluidic devices to resist thrombus formation in whole blood. Lab Chip2013;
13: 1963–1968.
54.
LopezCAFleischmanAJRoyS, et al.
Evaluation of silicon nanoporous membranes and ECM-based microenvironments on neurosecretory cells. Biomaterials2006;
27: 3075–3083.
55.
SharmaSJohnsonRWDesaiTA.XPS and AFM analysis of antifouling PEG interfaces for microfabricated silicon biosensors. Biosens Bioelectron2004;
20: 227–239.
56.
FeinbergBJHsiaoJCParkJ, et al.
Silicon nanoporous membranes as a rigorous platform for validation of biomolecular transport models. J Memb Sci2017;
536: 44–51.
KimSHellerJIqbalZ, et al.
Preliminary diffusive clearance of silicon nanopore membranes in a parallel plate configuration for renal replacement therapy. ASAIO J2016;
62: 169–175.
59.
RechendorffKHovgaardMBFossM, et al.
Enhancement of protein adsorption induced by surface roughness. Langmuir2006;
22: 10885–10888.
60.
ZhangMDesaiTFerrariM.Proteins and cells on PEG immobilized silicon surfaces. Biomaterials1998;
19: 953–960.
61.
DeeKCPuleoDABiziosR. Protein-surface interactions. In: An introduction to tissue-biomaterial interactions. Hoboken, New Jersey: John Wiley & Sons, Inc., 2002, pp.37–52.
62.
KurratRPrenosilJERamsdenJJ.Kinetics of human and bovine serum albumin adsorption at silica-titania surfaces. J Colloid Interface Sci1997;
185: 1–8.
63.
SharmaSJohnsonRWDesaiTA.Evaluation of the stability of nonfouling ultrathin poly (ethylene glycol) films for silicon-based microdevices. Langmuir2004;
20: 348–356.
64.
Goodman SL. Sheep, pig, and human platelet–material interactions with model cardiovascular biomaterials. Journal of Biomedical Materials Research: An Official Journal of The Society for Biomaterials, The Japanese Society for Biomaterials, and The Australian Society for Biomaterials 1999; 45(3): 240–250.
65.
MelvinMEFissellWHRoyS, et al.
Silicon induces minimal thromboinflammatory response during 28-day intravascular implant testing. ASAIO J2010;
56: 344–348.
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