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WO1996002838A1 - Surfaces modifiees au glutathione - Google Patents

Surfaces modifiees au glutathione Download PDF

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Publication number
WO1996002838A1
WO1996002838A1 PCT/SE1995/000825 SE9500825W WO9602838A1 WO 1996002838 A1 WO1996002838 A1 WO 1996002838A1 SE 9500825 W SE9500825 W SE 9500825W WO 9602838 A1 WO9602838 A1 WO 9602838A1
Authority
WO
WIPO (PCT)
Prior art keywords
substrate
glutathione
layer
immobilized
noble metal
Prior art date
Application number
PCT/SE1995/000825
Other languages
English (en)
Inventor
Ingemar LUNDSTRÖM
Pentti Tengvall
Magnus Lestelius
Håkan NYGREN
Original Assignee
Forskarpatent I Linköping Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Forskarpatent I Linköping Ab filed Critical Forskarpatent I Linköping Ab
Priority to EP95926070A priority Critical patent/EP0719413A1/fr
Priority to AU29950/95A priority patent/AU2995095A/en
Publication of WO1996002838A1 publication Critical patent/WO1996002838A1/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/551—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being inorganic
    • G01N33/553—Metal or metal coated
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
    • A61L33/0076—Chemical modification of the substrate
    • A61L33/0082—Chemical modification of the substrate by reacting with an organic compound other than heparin

Definitions

  • the present invention is within the field of substrates having at least a surface layer modified by an immobilized thiol compound. More specifically it relates to the immobilization of surface layers by a specific novel thiol compound which has unexpectedly been shown to possess outstanding biological activities as compared to previously known immobilized thiol compounds. The inventlon also relates to some specific favourable uses of said substrate, said uses being made possible by the new activities found.
  • Gold surfaces modified by immobilized thiol compounds are previously known per se. Generally such modified surfaces have appeared to be of interest as model systems for the study of protein-surface interactions. It has also been found by the inventors that the thiol-gold immobilization technique is a reliable technique for studies of coagulation and complement activation under well controlled conditions. Thus, the surface modification technique offers possibilites to separate the influence of different functionalities from those of physical factors, such as surface mobility (tail group) and morphology (surface roughness).
  • the new immobilized system according to the present invention shows a unique combination of non-adverse activities which makes it possible for a large number of medical applications, especially where blood contact is involved, particularly for short time blood contacts, such as up to about 2 hours.
  • the new system should be a competitor to the well known technique of heparinizing surfaces to be used for different medical purposes.
  • the fact that it may well be a strong competitor to heparin, especially at short time contacts, is not only because of its outstanding biological activities but also a result of the fact that the method of immobilizing glutathione onto a noble metal surface is extremely simple and reliable, as will be discussed more below.
  • a first object of the invention is to provide a new modified substrate possessing a unique combination of biological activities which makes it possible for a large number of valuable medical applications.
  • Another object of the invention is to provide a modified substrate that can be manufactured or prepared in an extremely simple and reliable way.
  • Still another object of the invention is to provide a modified substrate carrying an immobilized thiol compound that is non-synthetical, i.e. completely native to the human or animal body, as said substance per se is a substance found in blood and human and animal tissues.
  • One additional object of the invention is to provide a modified substrate, the other part of which, i.e. in addition to the thiol ingredient, is completely inactive or inert to its environment as it is of a noble metal.
  • Still another object of the invention is to provide a very simple and reliable process for the preparation of the above-mentioned substrate.
  • modified substrate referred to in various medical articles and assays for different medical or diagnostic purposes.
  • the immobilized new thiol compound should work similarly also on a polymer surface, which means that one additional object of the invention is to provide a modified substrate having at least a surface layer of a polymer, to which said thiol has been immobilized.
  • a polymer article should be especially well suited as a disposable article.
  • a substrate of the type having at least a surface layer modified by an immobilized thiol compound, the characteristic feature of said substrate being that said surface layer is a noble metal or polymer layer modified by immoblized glutathione.
  • noble metal in its common sense, i.e. generally a metal or alloy that is relatively superior in resistance to corrosion or oxidation. Generally it can also be said that the term is an equivalent to precious metal.
  • the noble metal is selected from the group consisting of gold, silver and platinum, most preferably gold.
  • polymer generally relates to rather inert polymers, especially such which have been modified according to previously known techniques.
  • polymer is selected from the group consisting of polyethylene, polypropylene, polystyrene, polyurethane or terephtalates.
  • substrate is used in a broad sense in connection with the invention.
  • it means any part, substance, element, etc., which lies beneath and supports another, i.e. in this case it supports the glutathione.
  • the substrate may well be a part of a larger article, e.g. a medical article, or represent such an article per se.
  • a person skilled in the art should have no problem in making a proper choice of said substrate, neither as to configuration or shape, nor as to the nature thereof.
  • the nature of the substrate is selected according to known principles, as this part of the invention also represents prior knowledge.
  • the substrate base material is selected from the group consisting of silicon, glass, polymer and metal. Theoretically the substrate might be of said noble metal in its entirety, but for obvious cost reasons this is not the case for larger articles.
  • the invention works extremely well with a rather thin surface layer of said noble metal or polymer, preferably within the range of 50-500 nm.
  • the thickness of said surface layer is 100-300 nm, such as approximately 200 nm.
  • a preferable embodiment of the invention means that said noble metal layer has been sputterdeposited or physically vaporized onto the substrate referred to.
  • Such sputtering technique is well known and has been utilized per se in connection with immobilizing thiol compounds onto gold surfaces, and reference is therefore made to prior literature as to the preparation of said noble metal layers.
  • a preferable range thereof is 5-25 A, preferably 5-13 A, e.g. about 10 A. Extremely good results have been obtained when using a mono-layer of glutathione immobilized on said surface layer.
  • the substrate is a substrate for which the glutathione has been immobilized on to the surface layer by chemisorption from an aqueous solution thereof, which technique is especially preferable for said noble metal layer.
  • concentration of said aqueous solution of glutathione is within the range of 0.1-10 mM.
  • a process for the preparation of the substrate defined above is characterized by starting from a substrate having a noble metal or polymer surface or alternatively sputter-depositing on a substrate a noble metal surface and modifying said surface with glutathione by chemisorption from an aqueous solution of said glutathione so as to immobilize the same thereupon.
  • the technique of sputter-depositing the noble metal onto a substrate is well known and such principles may be used here. Although further details can be found in the literature it may perhaps be added that to improve the adherence of the noble metal layer to the substrate a very thin layer of an adherence-promoting metal, such as chromium, could be used.
  • the surface is preferably cleaned, for instance in distilled water, ammonium hydroxide and/or hydrogen peroxide, before immobilizing the glutathione. In addition thereto the surface is also rinsed, for instance in distilled water and stored therein until the chemisorption takes place.
  • the chemisorption of the glutathione can also be performed according to known principles. For instance this means that it may well be performed at room temperature or at slightly elevated temperatures, which Is of course extremely advantageous.
  • the glutathione layer is preferably treated by sonication, which sonication is suitably performed after having rinsed the glutathione layer in water, such as distilled water.
  • an article which comprises a substrate as defined above or as manufactured in the above described way, for use in medical or diagnostic treatment of the human or animal body.
  • medical is to be understood in a very broad sense, i.e. the article referred to need not primarily be used for a the- rapeutic purpose but may well be utilized for applications like implants, surgical instruments and sensors.
  • the article is useful for almost any application where coagulation and compelement activities are to be avoided, such as in all contacts with blood. For instance this means that the article is well suited for cell culture uses.
  • other medical uses should be obvious to a person skilled in the art and need not be enumerated here.
  • the substrate as defined above or as manufactured above, for the manufacture of any article to be used in blood contacting medical or diagnostic treatments or surgical treatment of the human or animal body.
  • this may for instance be a use of the substrate for the manufacture of an implant or a surgical instrument article.
  • Fig. 1 Suggested molecular structures of 3-mercaptopropionic acid, L-cysteine and glutathione respectively, at physiological pH (7.4)
  • Fig. 2 FT-IRAS spectra of a) 3-mercaptopropionic acid, b) L-cysteine and c) glutathione monolayers on gold, formed at spontaneous pH (3.3, 5.3 and 3.4, respectively).
  • F XII and F XII a on surfaces and in solutions.
  • the sodium glass surface was used as a highly activating reference.
  • Fig. 4 Anti-C3c depositions (15 min incubations) after incubation in human serum for 10 min, under room conditions.
  • Fig. 5 Total plasma protein and antlsera adsorptions onto gold, gold-MPA, gold-L-cys and gold-GSH surfaces at room conditions. The surfaces were incubated in 10% citrated human plasma for 10 min and then in antisera for X5 min (for details, see Materials & Methods).
  • the horizontal dashed line indicates the over-all pasma level and all samples to the right of the vertical dashed line have been treated with amplification antlsera.
  • Gold films about 200 nm thick each, were sputterdeposited on glass substrates precoated with a thin layer of chromium ⁇ 1 nm. Scanning force microscopy (contact mode, 400 nm scanside) indicated that the surfaces were flat with a surface roughness ⁇ 6 nm (see Table 1). The gold surfaces were cleaned in five parts (v/v) distilled water, one part ammonium hydroxide (25%) and one part of hydrogen peroxide (30%) for 10 min at 80°C. After the cleaning procedure, the hydrophilic surfaces were rinsed and stored in distilled water for no more than 15 min before chemisorption of the thiol.
  • the molecular structure of the formed monolayers were analysed using Fourier Transform Infrared Reflection- Absorption Spectroscopy (FT-IRAS) in a dry state under mild vacuum.
  • FT-IRAS Fourier Transform Infrared Reflection- Absorption Spectroscopy
  • the analyses were performed using a BRUKER IFS 113 v Fourier transform spectrometer, equipped with a DTGS detector and a GIR (Grazing angle Infrared Reflection) accessory aligned at 83°. All spectra were obtained at a spectral resolution of 4 cm by averaging 500 interferograms.
  • sample-surfaces were incubated for 10 min in 10% citrated human plasma in 0.01 M Phosphate Buffered Saline (PBS, 82 volume % 0.01 M Na 2 HPO 4 , 18 volume % 0.01 M
  • the maximum error of the calculated organic layer thicknesses was low, ⁇ 0.3 nm.
  • the error of the calculated thickness was determined using the formula for pooled standard deviations, the standard deviation was then multiplied with values from the Student's t-table (95%-level of confidence).
  • the error bars in figures 4-5 thus represent the calculated error (from standard deviation) plus the estimated error for the ellipsometer ( ⁇ 0.3 nm).
  • the thicknesses of the L-cys, MPA and GSH layers were calculated from the changes in the optical properties of the gold surface after the chemical modification.
  • the ellipsometer used was a Rudolph Research AutoE1 III, equipped with a He-Ne laser working at 632.8 nm.
  • Citrated plasma and serum were prepared from blood from apparently healthy donors and stored at -80°C until use.
  • the IgG fraction-antisera used were Swine anti-Albumin (SwaAlb), Swine anti-Immunoglobulin G (SwalgG) and Swine anti-Complement 3c (SwaC3c) from Orion Diagnostica, Finland; Rabbit anti-Fibrinogen (RbaFG), Rabbit antiFibronectin (RbaFN), Rabbit anti- ⁇ 2 Macroglobulin (Rba ⁇ 2 M) and Rabbit anti-Complement 3c (RbaC3c) from Dakopatts a/s, Denmark; Goat andi-High Molecular Weight Kininogen
  • GtaAThXII Goat anti-Lipoprotein
  • GtaPK Goat anti- Prekallikrein
  • Complement factor deposition on solid surfaces can be detected using elllpsometry and antisera techniques.
  • detection of complement-activation as Indicated by anti- C3c binding, was performed in the following manner. Surfaces were incubated in 10% serum diluted in HANK's buffer (solution A:30 g NaCl, 4 g KCl, 2 g MgSO 4 . 7 H 2 O, 0.94 g CaCl 2 .
  • solution B 0.6 g Na 2 HPO 4 , 0.6 g KH 2 PO 4 , 10 g dextrose and 500 ml distilled water
  • a and B were mixed and the pH set with NaOH/HCl) at pH 7.4 for 10 min, rinsed in buffer followed by distilled water and blown drv.
  • the adsorbed layer thickness was measured in five points.
  • the surfaces were again rinsed in buffer and incubated in an anti-C3c solution diluted 1/50 in HANK's, for ten minutes. Finally, the surfaces were removed and rinsed with buffer and distilled water, blown dry and the organic layer thickness was once more determined in five points.
  • kallikrein and kallikrein in solution were determined using soda watch-glass surfaces covered with (200 nm thick) gold films.
  • the gold films were made by thermal evaporation on top of a thin layer (4 nm) of chromium. Pure glass, known to be a rapid contact active- tor, served as the reference material.
  • the glass, gold and thiolated gold watch-glasses were cleaned like the other gold substrates and incubated in 10% citrated human plasma in PBS, pH 7.4, for 10 min.
  • Trls buffer 25 ml Tris-(hydroxymethyl)- amino-methane, 42 ml 0.1 M C1 and 100 ml distilled water
  • 0.15 M NaCl 0.15 M NaCl, at pH 7.5.
  • the kallikrein assays (described below) were made using normal citrated plasma, citrated factor XII deficient (F XII de f ) plasma from Sigma as the extra prekallikrein source, and Cephotest (cephalin, phosphatidylethanol-amine) from Nycomed AB, Lidingö, Sweden, was used to activate F XII.
  • the kallikrein-specific H-D-Pro-Phe-Arg-pNA was used to activate F XII.
  • 2HCl peptide S-2302 was from Chromogenlx AB, M ⁇ lndal, Sweden. The principle of the test is kallikrein cleavage of the S-2302 substrate.
  • the end product (pNA) has a high absorbance at 405 nm and is quantified by sepctrophotometry.
  • Peptide-pNA (S-2302) kallikrein - Peptide-OH+pNA (yellow, 405 nm).
  • the kallikrein assays were performed as follows:
  • the surfaces were rinsed thoroughly with Trls buffer and incubated in 400 ⁇ l, 10% (PBS, pH 7.4) plasma for ten min. The rinsed surfaces were then tested for (the boxes indicate additions into the watch glasses after plasma treatment) total amount of surface bound Factor XII.
  • All three modified surfaces were hydrophilic with water contact angles smaller than 15o.
  • the MPA and L-cys are likely to give weakly negatively charged and zwitterionic surfaces, respectively, at physiological pH.
  • Glutathione presents one negatively charged and one zwitterionic end, separated by a polypeptide-like backbone as shown in Figure 1.
  • R-A reflection absorption
  • L-cys and GSH showed low or undetectable kallikrein formation in all the assays (Fig. 3), indicating a low surface F XII activity. This was expected for L-cys since contact activation of coagulation is known to preferentially take place on negatively charged surfaces and L-cys is suggested to be non-charged (zwitterionic) at pH 7 (Fig. 1). The low kallikrein formation on GSH is, however, not yet understood, since significant amounts of COO- groups are expected to be present at pH 7.
  • Gold exhibited large and significant amounts of surface bound F XII and kallikrein, respectively, although the plasma levels appeared to be low.
  • the low release of kallikrein from the gold surface indicates a low F XII. formation in plasma. This in turn suggests that gold binds and activates F XII, but the F XIIa. and kallikrein turnover is low.
  • the results may be due to plasma proteins being tightly bound to the surface. Control experiments for unspecific kallikrein formation with pure gold substrates showed that
  • kallikrein was formed by using cephalin in the plasma after Incubation on Au, implying that the plasma was not depleted of F XII or kallikrein.
  • the kalllkrein assays (Fig. 3) also showed elevated F XII. and kalllkrein formation on and outside the MPA surfaces.
  • the L-cys surfaces bound significant amounts of a- IgG, a-ATh III, a-LP and a-PK and relatively low amounts of a-FG and a-HMWK after the plasma incubations.
  • the significant a-IgG deposition could be related to the increased a-C3c binding after exposure to human serum (Fig. 4).
  • the glutathione surfaces did not deposit detectable amounts of any of the antisera tested for.
  • the thickness of the total adsorbed protein layer after plasma incubations and rinsings was less than 1 nm. This suggests that GSH, when chemisorbed onto gold, presents a surface with advantageous properties for blood contact applications.

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  • Health & Medical Sciences (AREA)
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  • Immunology (AREA)
  • Hematology (AREA)
  • Engineering & Computer Science (AREA)
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Abstract

La présente invention concerne un nouveau substrat ou article modifié par un thiol. Ce substrat ou cet article comporte un métal noble (ou une surface polymère) sur lequel a été immobilisé un glutathione. Ce nouveau produit associe de façon remarquable des activités biologiques qui le rendent utilisable pour le contact sanguin, comme dans le cas des implants. Ce produit est préparé de préférence par chimisorption de glutathione à partir d'une solution aqueuse de glutathione.
PCT/SE1995/000825 1994-07-13 1995-07-04 Surfaces modifiees au glutathione WO1996002838A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP95926070A EP0719413A1 (fr) 1994-07-13 1995-07-04 Surfaces modifiees au glutathione
AU29950/95A AU2995095A (en) 1994-07-13 1995-07-04 Glutathione modified surfaces

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9402472A SE9402472L (sv) 1994-07-13 1994-07-13 Modifierade ytor
SE9402472-6 1994-07-13

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WO1996002838A1 true WO1996002838A1 (fr) 1996-02-01

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AU (1) AU2995095A (fr)
SE (1) SE9402472L (fr)
WO (1) WO1996002838A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6270952B1 (en) * 1998-01-06 2001-08-07 Cerus Corporation Methods for quenching pathogen inactivators in biological materials
US6919326B1 (en) 1998-08-24 2005-07-19 Toshio Miyata Carbonyl-stress improving agent and peritoneal dialysate
US7655392B2 (en) 2004-10-29 2010-02-02 Cerus Corporation Quenching methods for red blood cell inactivation process
US8900805B2 (en) 2008-04-09 2014-12-02 Cerus Corporation Quenching methods for red blood cell pathogen inactivation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0485874A2 (fr) * 1990-11-14 1992-05-20 F. Hoffmann-La Roche Ag Transducteur pour immunosenseur et méthode de sa production
WO1993022320A1 (fr) * 1992-04-24 1993-11-11 Biocompatibles Limited Revetements destines a des metaux

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0485874A2 (fr) * 1990-11-14 1992-05-20 F. Hoffmann-La Roche Ag Transducteur pour immunosenseur et méthode de sa production
WO1993022320A1 (fr) * 1992-04-24 1993-11-11 Biocompatibles Limited Revetements destines a des metaux

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DIALOG INFORMATION SERVICES, file 55, Biosis, Dialog accession no. 9051642, Biosis accession no. 93036642, BATISTA-VIERA F.: "A new method for Reversible Immobilization of Thiol Biomolecules Based on Solid-Phase Bound Thiol Sulfonate Groups"; & APPL. BIOCHEM. BIOTECHNOL. 31 (2), 1991, 175-195. *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6270952B1 (en) * 1998-01-06 2001-08-07 Cerus Corporation Methods for quenching pathogen inactivators in biological materials
US7293985B2 (en) 1998-01-06 2007-11-13 Cerus Corporation Methods for quenching pathogen inactivators in biological materials
US6919326B1 (en) 1998-08-24 2005-07-19 Toshio Miyata Carbonyl-stress improving agent and peritoneal dialysate
US7297689B2 (en) 1998-08-24 2007-11-20 Kiyoshi Kurokawa Method for preparing peritoneal dialysate
US7655392B2 (en) 2004-10-29 2010-02-02 Cerus Corporation Quenching methods for red blood cell inactivation process
US8900805B2 (en) 2008-04-09 2014-12-02 Cerus Corporation Quenching methods for red blood cell pathogen inactivation
US9713627B2 (en) 2008-04-09 2017-07-25 Cerus Corporation Pathogen-inactivated red blood cell compositions
US10357516B2 (en) 2008-04-09 2019-07-23 Cerus Corporation Pathogen-inactivated red blood cell compositions

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SE9402472D0 (sv) 1994-07-13
EP0719413A1 (fr) 1996-07-03
AU2995095A (en) 1996-02-16
SE9402472L (sv) 1996-01-14

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