CN108472412A

CN108472412A - Cover cated medical instrument

Info

Publication number: CN108472412A
Application number: CN201680079676.1A
Authority: CN
Inventors: 维克拉姆·沙林达·辛格; 吉安弗兰可·阿拉斯塔; 安德鲁·西蒙·布鲁克斯; 加雷思·亨尼根; 达伦·贝齐纳
Original assignee: Semblant Global Ltd
Current assignee: Semblant Global Ltd; Semblant Ltd
Priority date: 2015-11-20
Filing date: 2016-11-16
Publication date: 2018-08-31
Also published as: GB201520483D0; EP3377125A1; WO2017085482A1

Abstract

The present invention relates to a kind of medical instrument for being adapted for insertion into or being implanted into the patient, the medical instrument has laminated coating at least one surface thereof, wherein：Each layer of the laminated coating includes by the plasma-deposited acquisition of precursor mixture, the precursor mixture：(a) one or more organo-silicon compound, (b) optional O₂、N₂O、NO₂、H₂、NH₃、N₂、SiF₄And/or hexafluoropropene (HFP), (c) optional He, Ar and/or Kr, and (d) optional silver, gold, titanium, platinum and/or palladium；And first layer/lowest level of the laminated coating contacted at least one surface of the medical instrument is organic.

Description

Cover cated medical instrument

Technical field

The present invention relates to the methods covered cated medical instrument and coat these instruments.The coating is bio-compatible, no Biodegradable, and inhibit the formation of biomembrane on it.

Background technology

Biofilm formation is well-known phenomenon, and the cell of wherein microorganism is adhering to each other and forms film on the surface.

When biomembrane is on the surface for the medical instrument for being inserted or implanted into patient's body, for example, it is conduit, respirator, artificial The instrument and contact lenses used in cardiovascular implant, prosthetic joint, gynaecology's device, orthopedic implants, operation, biomembrane shape At especially throwing into question.This is because the bacterium being present in biomembrane such as staphylococcus epidermis (Staphylococcus Epidermidis) may cause to infect when biomembrane is with patient contact.

For being implanted into patient and indwelling is in the medical instrument of patient's body, this problem is especially serious.Even if medical Before implantation without biomembrane, the still oriented medical apparatus surface of staphylococcus epidermis present on patient skin colonizes instrument Tendency, to form biomembrane.It is now recognized that about 2/3rds biofilm formation is by staphylococcus epidermis on indwelling equipment It is caused.

The main reason for biomembrane is nosocomial infection, therefore to global in terms of the extra cost for the treatment of infected patient Medical system causes white elephant.Bacterial antibiotic treatment in biomembrane has highly resistant, with human pathogen The increase of middle antibiotic resistance is combined so that the treatment of biomembrane infections relating becomes difficult.

It therefore, if can be with biofilm formation can be inhibited and coating with biocompatibility is come coating medical instrument Surface so that medical instrument can be safely inserted or be implanted into the patient and reduce the relevant infection of biomembrane, this will be Beneficial.

Invention content

The present inventor is surprisingly it has been found that organo-silicon compound can be deposited by plasma-deposited, to provide Go out the laminated coating that high biofilm formation resistance is provided.The coating is bio-compatible, is consequently adapted to be implanted into or be inserted into patient's body It is interior.These properties mean that the coating can be used for coating medical instrument, medical instrument are being implanted into or are being inserted into patient to reduce The risk of biomembrane infections relating occurs when in vivo.This discovery means that the prevalence of nosocomial infection may be reduced, this is to suffering from Person is beneficial, and can greatly save medical expense.The present invention another discovery is that, if at least one surface with medical instrument The first layer of the laminated coating of contact is organic, then laminated coating will adhere well to the surface of medical instrument.This meaning Taste, which to be typically without, carries out individually pretreatment or post-processing step to improve the adhesiveness of coating and medical apparatus surface.

Therefore, the present invention provides a kind of medical instrument for being adapted for insertion into or being implanted into the patient, and the medical instrument is at it There is laminated coating at least one surface, wherein：

Each layer of the laminated coating passes through the plasma-deposited acquisition of precursor mixture, the precursor mixture packet It includes：(a) one or more organo-silicon compound, (b) optional O₂、N₂O、NO₂、H₂、NH₃、N₂、SiF₄And/or hexafluoropropene (HFP), (c) optional He, Ar and/or Kr, and (d) optional silver, gold, titanium, platinum and/or palladium；And

First layer/lowest level of the laminated coating contacted at least one surface of the medical instrument is that have Machine.

Invention further provides it is a kind of for reduce be adapted for insertion into or be implanted into patient medical instrument it is at least one The method of biofilm formation on surface, this method include by plasma-deposited, by the present invention's as herein defined Laminated coating deposits at least one surface.

The present invention also provides the purposes of the laminated coating of the present invention as herein defined, are adapted for insertion into or are implanted into reduce Biofilm formation on the medical apparatus surface of patient's body.

Description of the drawings

Fig. 1 to Fig. 3 shows the cross section of the preferable example of the laminated coating of the present invention.

Fig. 4 shows fourier-transform infrared (the Fourier transform of prepared coating in example 1 Infrared, FTIR) spectrum.

Fig. 5 shows the FTIR spectrum of prepared coating in example 3.

Fig. 6 shows the result from example 5, wherein rake is coated with various laminated coatings, then uses drop (deionized water) test carrys out test resistance.These results demonstrate tested laminated coating and resist the energy degraded caused by water Power.These tests are accelerated tests, and wherein element biases are 5V, to assess the adherency of the barrier property and coating and surface of coating Property.

Specific implementation mode

The present invention relates to a kind of medical instruments for being adapted for insertion into or being implanted into the patient.Medical instrument is in its at least one table There is laminated coating on face.Laminated coating by plasma-deposited generation, and be bio-compatible and can inhibit, from And it prevents from being formed on biomembrane.

Medical instrument

The medical instrument coated according to the present invention is adapted for insertion into or is implanted into the patient.It is adapted for insertion into or is implanted into patient Internal any medical instrument can easily be coated according to method described herein.Some of suitable medical instrument are non exhaustive Example include Hearing aid assembly, conduit, respirator, artificial cardiovascular's implantation material, prosthetic joint, bone implant, gynaecology's device, The instrument (such as scalpel) and contact lenses used in orthopedic implants, surgical operation.

At least one surface of medical instrument is coated with laminated coating as herein defined.In general, medical instrument is extremely A few surface is when medical instrument is inserted or implanted into patient's body and the surface of patient contact.For implantation and therefore indwelling Device, at least one surface of medical instrument is typically as device (in situ) in place and the surface of patient contact.These Surface is the surface for most having biofilm formation risk, therefore the laminated coating of the present invention can play and prevent or reduce on those surfaces The effect of the upper risk for forming biomembrane.

Preferably, when medical instrument is inserted or implanted into patient's body, all surface with the medical instrument of patient contact It is each coated with the laminated coating of the present invention.For being implanted into simultaneously the therefore medical instrument of indwelling, it is preferred that when medical instrument is in place When, the laminated coating of the present invention is each coated with all surface of patient contact.Therefore, for the medical instrument being suitable for implantation into, It is particularly preferred that medical instrument is when being implanted and all surface of patient contact and medical instrument are when in place and patient The all surface of contact is each coated with the laminated coating of the present invention.It is typically to contact or be exposed to patient with the surface of patient contact Tissue or body fluid surface.

Laminated coating

The laminated coating of the present invention includes multilayer, wherein every layer can pass through the plasma-deposited of organo-silicon compound It obtains.Organo-silicon compound can be deposited presence or absence of reaction gas and/or nonreactive gas.Deposition institute Obtaining layer has general formula SiO_xH_yC_zF_aN_bM_c, wherein x, y, z, the value of a, b and c depend on：(a) particular silicone used in Close object；(b) the specific common precursor containing metal used in；(c) it whether there is reaction gas and the determination of the reaction gas； (d) it whether there is nonreactive gas and the determination of the nonreactive gas.For example, if fluorine is not present in organo-silicon compound Or nitrogen, and not using the reaction gas containing fluorine or nitrogen, then the value of a and b will be 0.As will be discussed in further detail, The value of x, y, z, a and b can be adjusted by selecting suitable organo-silicon compound and/or reaction gas, and correspondingly be controlled Make the attribute of every layer and entire coating.In chemical formula SiO_xH_yC_zF_aN_bM_cIn, M indicates silver, gold, titanium, platinum and/or palladium, they can Selection of land mixes in coating.When omitting metal, the value of c will be 0, and can be for example, by changing for plasma-deposited The amount of metal precursor/common precursor present in precursor mixture is adjusted.

In order to avoid doubt, it should be understood that although the precursor mixture for being used to form laminated coating has organic nature, Be the laminated coating of the present invention every layer can be according to specific precursor mixture with organic or inorganic characteristic.In general formula SiO_xH_yC_zF_aN_bM_cOrganic layer in, the value of y and z will be greater than zero, and in general formula SiO_xH_yC_zF_aN_bM_cInorganic layer in, y and z's Value would tend to zero.Those skilled in the art use conventional analytical techniques, such as by using well known to those skilled in the art Spectral technique detects that there are carbon-hydrogen link and/or carbon-carbon bonds, you can is readily determined the organic nature of layer.For example, can make Carbon-hydrogen link is detected with Fourier Transform Infrared Spectroscopy.Similarly, those skilled in the art use conventional analytical techniques, such as It detects that carbon-hydrogen link and/or carbon-carbon bond is not present by using spectral technique well known to those skilled in the art, you can be easy Ground determines the inorganic in nature of layer.It is, for example, possible to use Fourier Transform Infrared Spectroscopy is to assess, there is no carbon-hydrogen links.

Plasma deposition process

Layer present in the laminated coating of the present invention by the plasma-deposited acquisition of precursor mixture, usually it is equal from Daughter enhances chemical vapor deposition (PECVD) or plasma enhancing physical vapour deposition (PVD) (PEPVD), preferably PECVD.Deng from Daughter deposition process usually carries out under reduced pressure, and typically 0.001 to 10mbar, preferably 0.01 to 1mbar, for example, about 0.7mbar.Deposition reaction is happened on the surface of medical instrument in situ, or on the surface of deposited layer.

Plasma-deposited usually to be carried out in the reactor for generating plasma, which includes the sum of ionization Other neutral substances that neutral unstripped gas/precursor, ion, electronics, atom, free radical and/or plasma generates.Reaction Device generally includes chamber, vacuum system and one or more energy sources, but configures to generate any suitable of plasma The reactor of type can use.Energy source may include configuring one or more gases are converted to plasma Any suitable device.Preferably, energy source includes heater, radio frequency (radio frequency, RF) generator and/or micro- Wave producer.

It is plasma-deposited to produce a kind of unique material, it can not be prepared with other technologies.Plasma-deposited material With highly disordered structure, and it is usually highly cross-linked, containing random branch and retain some reactive sites.These chemistry Difference physically is well-known and is described in, for example, the graceful empire of plasma polymer film editor's H. Bhides is learned Publishing house of institute (Plasma Polymer Films, Hynek Biederman, Imperial College Press in 2004 2004) it is published with material process principle second edition editor M.A. profits Berman and the Willies A.J. Li Xitengbeige with plasma discharge Society 2005 (Principles of Plasma Discharges and Materials Processing, 2^ndEdition, Michael A.Lieberman, Alan J.Lichtenberg, Wiley 2005).

In general, the medical treatment device that will apply laminated coating is placed in the chamber of reactor, and use vacuum system will Chamber is evacuated to 10^-3To the pressure of 10mbar.Then usually by one or more gases (with controlled flow) injecting chamber, and And energy source generates stable gaseous plasma.Then, usually using one or more precursor compounds as gas and/or steaming Gas is introduced into the plasma phase in chamber.Alternatively, precursor compound can be firstly introduced into, secondly generate stable gas etc. from Daughter.When being introduced into plasma phase, precursor compound is usually decomposed (and/or ionization), to generate one in the plasma The active material (i.e. free radical) of series, the active material deposit on the exposed surface of medical instrument and form one layer.

The definite property and ingredient of institute's deposition materials generally depend on following one or more condition (i) it is selected etc. from Daughter gas；(ii) specific precursor compound used in；(iii) (it can pass through precursor compound to the amount of precursor compound The combination of pressure, flow and gas injection system determine)；(iv) ratio of precursor compound；(v) precursor compound is suitable Sequence；(vi) plasma pressure；(vii) plasma driving frequency；(viii) power pulse and pulse width timing；(ix) it applies Cover the time；(x) plasma power (including peak value and/or average plasma power)；(xi) chamber electrode is arranged；(xii) Bias voltage control in temperature and electrode；And/or (xiii) is sent into the preparation of component.

In general, plasma driving frequency is 50Hz to 4GHz.In general, plasma power density is 0.001 to 50W/ cm², preferably 0.01W/cm²To 0.02W/cm², e.g., about 0.0175W/cm².In general, mass flow is 5 to 1000sccm, It is preferred that 5 to 20sccm, for example, about 10sccm.In general, operation pressure is 0.001 to 10mbar, preferably 0.01 to 1mbar, such as About 0.7mbar.In general, coating time is 10 seconds to ＞ 60 minutes, such as 10 seconds to 60 minutes.

By using the plasma chamber of bigger, corona treatment can easily amplify.However, as this field Technical staff it is to be understood that preferred condition by the size and geometry depending on plasma chamber.Therefore, it depends on just In the particular plasma fluid chamber used, it may be beneficial to those skilled in the art to change operating condition.

The favorable characteristics of the plasma deposition method used in the present invention are can be mixed by the suitable precursor of selection Object changes the property of each layer and the property of laminated coating (for example, to optimize adhesiveness, hydrophobicity/hydrophily, oleophobic property or hard Degree), as discussed in further detail below.This means that without carrying out (the doctor before coating to obtain required property Treat instrument) pre-treatment step or (every layer after deposition and/or entire coating) post-processing step.It is previously used for improving and apply Layer performance pretreatment and post-processing step include there is no actually by the precursor compound deposited in substrate (i.e. It is one or more organo-silicon compound in the case of invention) in the case of, with such as O₂、O₃、NH₃、NO、NO₂、N₂O or N₂O₄ Etc the corona treatment that carries out of gas, or with such as H₂O₂Or H₂The corona treatment that the liquid of O etc carries out.

Precursor compound

The laminated coating of the present invention includes the layer by the plasma-deposited acquisition of precursor mixture.The precursor mixture Including one or more organo-silicon compound, and further include optionally reaction gas (such as O₂) and/or nonreactive gas (example Such as Ar).Deposition gained layer has general formula SiO_xH_yC_zF_aN_bM_c, the value of wherein x, y, z, a and b depends on：(i) specific used in Organo-silicon compound；The determination of (ii) with the presence or absence of reaction gas and the reaction gas.

In general, precursor mixture is by or mainly by one or more organo-silicon compound, optional reaction gas and optional Nonreactive gas composition.As used herein, it includes that it is main that term " mainly by ... form ", which refers to precursor mixture, The component of composition and other components, condition are that other components the fundamental characteristics for the gained layer not formed by precursor mixture There is materially affect.In general, the precursor mixture being mainly grouped as by certain groups will contain these groups more than or equal to 95wt% Divide, preferably greater than or equal to those of 99wt% components.

When there is no the reactant gas of excessive oxygen-containing and nitrogen (such as NH₃、O₂、N₂O or NO₂) in the case of to one When kind or a variety of organo-silicon compound carry out plasma-deposited, the layer of gained will be Organic, and have general formula SiO_xH_yC_zF_aN_bM_c.The value of y and z will be greater than 0.If there are O, F or N in precursor mixture, either as organosilicon compound A part for object is still used as reaction gas, then the value of x, a and b all will be greater than 0.

When there are oxygen-containing reaction gas (such as O₂Or N₂O or NO₂) in the case of to one or more organo-silicon compound When carrying out plasma-deposited, the hydrocarbyl group in organosilicon precursor is reacted with oxygen-containing reaction gas, forms CO₂And H₂O.This will increase Add the inorganic in nature of gained layer.If there is enough oxygen-containing reaction gas, then all hydrocarbon parts (moiety) can be removed, So that the layer of gained is substantially inorganic nature/ceramics (wherein in general formula SiO_xH_yC_zF_aN_bIn, y, z, a and b, which will have, to be tended to Zero insignificant value).By raising RF power densities and plasma pressure is reduced, hydrogen content can be further decreased, from And enhance oxidation process, and fine and close inorganic layer is obtained (wherein in general formula SiO_xH_yC_zF_aN_bIn, x is up to 2, and y, z, a and b will With the insignificant value to go to zero).

In general, precursor mixture includes a kind of organo-silicon compound, but in certain cases, it may be desirable to using two kinds or More kinds of different organo-silicon compound, such as two kinds, three kinds or four kinds different organo-silicon compound.

In general, organo-silicon compound are organosiloxane, organosilan or nitrogen-containing organosilicon compound, such as silicon nitrogen Alkane or amino silane or halogen organo-silicon compound, such as halogen organosilan.Organo-silicon compound can be linear or ring Shape.

Organo-silicon compound can be the compound of formula (I)：

Wherein, R₁To R₆In each independently indicate C₁-C₆Alkyl, C₂-C₆Alkenyl or hydrogen, condition are R₁To R₆In It is at least one not indicate that hydrogen.Preferably, R₁To R₆In each independently indicate C₁-C₃Alkyl, C₂-C₄Alkenyl or hydrogen, such as Methyl, ethyl, vinyl, allyl or hydrogen, condition are R₁To R₆At least one of do not indicate that hydrogen.It is preferred that R₁To R₆In extremely Lack two or three, such as four, five or six, does not represent hydrogen.Preferred example includes hexamethyldisiloxane (HMDSO), tetramethyl disiloxane (TMDSO), 1,3- divinyl tetramethyl disiloxanes (DVTMDSO) and six vinyl two Siloxanes (HVDSO).Particularly preferred hexamethyldisiloxane (HMDSO) and tetramethyl disiloxane (TMDSO), most preferably pregnancy Base disiloxane (HMDSO).

Alternatively, organo-silicon compound can be the compound of formula (II)：

Wherein, R₇To R₁₀In each independently indicate C₁-C₆Alkyl, C₁-C₆Alkoxy, C₂-C₆Alkenyl, hydrogen or- (CH₂)_1-4NR ' R " groups, wherein R ' and R " independently indicate C₁-C₆Alkyl, condition are R₇To R₁₀At least one of do not represent Hydrogen.It is preferred that R₇To R₁₀In each independently indicate C₁-C₃Alkyl, C₁-C₃Alkoxy, C₂-C₄Alkenyl, hydrogen or-(CH₂)_2- ₃NR ' R " groups, wherein R ' and R " independently indicate methyl or ethyl, for example, methyl, ethyl, isopropyl, methoxyl group, ethyoxyl, Vinyl, allyl, hydrogen or-CH₂CH₂CH₂N(CH₂CH₃)₂, condition is R₇To R₁₀At least one of do not represent hydrogen.It is preferred that R₇ To R₁₀In at least two, such as three or four, do not represent hydrogen.Preferred example includes allyl trimethyl silane, allyl Base trimethoxy silane (ATMOS), ethyl orthosilicate (TEOS), 3- (lignocaine) propyl trimethoxy silicane, trimethyl silicane Alkane (TMS) and tri isopropyl silane (TiPS).

Alternatively, organo-silicon compound can be the cyclic compound of formula (III)：

Wherein, n indicates 3 or 4, R₁₁And R₁₂Each independently represent C₁-C₆Alkyl, C₂-C₆Alkenyl or hydrogen, condition are R₁₁With R₁₂At least one of do not indicate that hydrogen.Preferably, R₁₁And R₁₂In each independently indicate C₁-C₃Alkyl, C₂-C₄Alkenyl or Hydrogen, such as methyl, ethyl, vinyl, allyl or hydrogen, condition are R₁₁And R₁₂At least one of do not indicate that hydrogen.Preferred example Attached bag includes divinyltetraphenylcy,lotrisiloxane (V₃D₃), tetravinyl tetramethyl-ring tetrasiloxane (V₄D₄), tetramethyl cyclotetrasiloxane Siloxanes (TMCS) and octamethylcy-clotetrasiloxane (OMCTS).

Alternatively, organo-silicon compound can be the compound of formula (IV)：

Wherein, X₁To X₆In each independently indicate C₁-C₆Alkyl, C₂-C₆Alkenyl or hydrogen, condition are X₁To X₆In It is at least one not indicate that hydrogen.Preferably, X₁To X₆In each independently indicate C₁-C₃Alkyl, C₂-C₄Alkenyl or hydrogen, such as Methyl, ethyl, vinyl, allyl or hydrogen, condition are X₁To X₆At least one of do not indicate that hydrogen.It is preferred that X₁To X₆In extremely Lack two or three, such as four, five or six, does not indicate that hydrogen.One preferred example is hexamethyldisilazane (HMDSN)。

Alternatively, organo-silicon compound can be the cyclic compound of formula (V)：

Wherein, m indicates 3 or 4, X₇And X₈In each independently indicate C₁-C₆Alkyl, C₂-C₆Alkenyl or hydrogen, condition are X₇And X₈At least one of do not indicate that hydrogen.Preferably, X₇And X₈In each independently indicate C₁-C₃Alkyl, C₂-C₄Alkenyl Or hydrogen, such as methyl, ethyl, vinyl, allyl or hydrogen, condition are X₇And X₈At least one of do not indicate that hydrogen.One preferably Example be 2,4,6- trimethyls -2,4,6- trivinyl cyclotrisilazanes.

Alternatively, organo-silicon compound can be the compound of formula (VI)：

H_a(X⁹)_bSi(N(X¹⁰)₂)_4-a-b

(VI)

Wherein, X⁹And X¹⁰Independently indicate C₁-C₆Alkyl, a indicate that 0,1 or 2, b indicate 1,2 or 3, and the summation of a and b It is 1,2 or 3.In general, X⁹And X¹⁰Indicate C₁-C₃Alkyl, such as methyl or ethyl.Preferred example is dimethylamino trimethyl silicane Alkane (DMATMS), bis- (dimethylamino) dimethylsilanes (BDMADMS) and three (dimethylamino) methyl-monosilanes (TDMAMS).

Alternatively, organo-silicon compound can be the compound of formula (VII)：

Wherein, Y₁To Y₄In each independently indicate C₁-C₈Halogenated alkyl, C₁-C₆Alkyl, C₁-C₆Alkoxy or C₂- C₆Alkenyl or hydrogen, condition are Y₁To Y₄At least one of indicate C₁-C₈Halogenated alkyl.Preferably, Y₁To Y₄In each solely On the spot indicate C₁-C₃Alkyl, C₁-C₃Alkoxy, C₂-C₄Alkenyl or C₁-C₈Halogenated alkyl, such as methyl, ethyl, methoxyl group, ethoxy Base, vinyl, allyl, trifluoromethyl or 1H, 1H, 2H, 2H- perfluoro capryls, condition are Y₁To Y₄At least one of indicate halogen Substituted alkyl.Preferred example is trimethyl (trifluoromethyl) silane and 1H, 1H, 2H, 2H- perfluoro capryl triethoxysilane.

It is preferred that organo-silicon compound are hexamethyldisiloxane (HMDSO), tetramethyl disiloxane (TMDSO), 1,3- bis- Vinyl tetramethyl disiloxane (DVTMDSO), six vinyl disiloxane (HVDSO), allyl trimethyl silane, allyl Trimethoxy silane (ATMOS), ethyl orthosilicate (TEOS), 3- (lignocaine) propyl-trimethoxysilane, trimethyl silane (TMS), tri isopropyl silane (TiPS), divinyltetraphenylcy,lotrisiloxane (V₃D₃), tetravinyl tetramethyl cyclotetrasiloxane silica Alkane (V₄D₄), tetramethyl-ring tetrasiloxane (TMCS), octamethylcy-clotetrasiloxane (OMCTS), hexamethyldisilazane (HMDSN), 2,4,6- trimethyls -2,4,6- trivinyls cyclotrisilazane, dimethylamino trimethyl silane (DMATMS), bis- (dimethylaminos) Dimethylsilane (BDMADMS), three (dimethylamino) methyl-monosilanes (TDMAMS), trimethyl (trifluoromethyl) silane or 1H, 1H, 2H, 2H- perfluoro capryl triethoxysilane.Particularly preferred hexamethyldisiloxane (HMDSO) and tetramethyl disiloxane (TMDSO), most preferably hexamethyldisiloxane (HMDSO).

As used herein, term C₁-C₆Alkyl include have 1 to 6, preferably 1 to 3, the straight chain of carbon atom or Branched hydrocarbyl.Example includes methyl, ethyl, n-propyl and isopropyl, butyl, amyl and hexyl.

As used herein, term C₂-C₆Alkenyl includes having 2 or 6 carbon atoms, preferably 2 to 4 carbon atoms, Linear chain or branched chain alkyl and carbon-to-carbon double bond.Preferred example includes vinyl and allyl.

As used herein, halogen is usually chlorine, fluorine, bromine or iodine, and preferably chlorine, bromine or fluorine, most preferably Fluorine.

As used herein, term C₁-C₆Halogenated alkyl includes being replaced by one or more halogen atoms C₁-C₆Alkyl.In general, it is replaced by 1,2 or 3 halogen atom.Particularly preferred halogenated alkyl is-CF₃With-CCl₃。

As used herein, term C₁-C₆Alkoxy is the alkyl being connect with oxygen atom.Preferred example packet Include methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, tert-butoxy, amoxy and hexyloxy.

Precursor mixture further includes optionally reaction gas.Reaction gas is selected from O₂、N₂O、NO₂、H₂、NH₃、N₂、SiF₄With/ Or hexafluoropropene (HFP).These reaction gas usually chemically participate in plasma-deposited mechanism, therefore may be considered that It is common precursor.

O₂、N₂O and NO₂It is oxygen containing common precursor, and is added typically to the inorganic spy for increasing deposition gained layer Property.It has been discussed above this process.N₂O and NO₂It is also nitrogenous common precursor, and is added typically to additionally increasing Add nitrogen content (and the therefore general formula SiO of deposition gained layer_xH_yC_zF_aN_bThe value of middle b will increase).

H₂Reproducibility common precursor, and be added typically to reduce deposit gained layer oxygen content (and because This general formula SiO_xH_yC_zF_aN_bThe value of middle x can reduce).Under such reducing condition, carbon and hydrogen are also usually from deposition gained layer Be removed (therefore general formula SiO_xH_yC_zF_aN_bThe value of middle y and z can also reduce).H is added₂It can increase deposition gained as common precursor Cross-linking level in layer.

N₂Nitrogenous common precursor, and be added typically to increase deposit gained layer nitrogen content (and therefore General formula SiO_xH_yC_zF_aN_bThe value of middle b will increase).

NH₃It is also nitrogenous common precursor, and is therefore added and deposits the nitrogen content of gained layer (simultaneously typically to increase And therefore general formula SiO_xH_yC_zF_aN_bThe value of middle b will increase).However, NH₃Also there is reproducibility.As added H₂Equally, this is meaned It to work as and uses NH₃When as common precursor, deoxygenation, carbon and hydrogen (and therefore general formula are usually removed from gained sedimentary SiO_xH_yC_zF_aN_bIn the value of x, y and z can reduce).NH is added₃It can increase the crosslinking water in deposition gained layer as common precursor It is flat.Obtained layer tends to silicon nitride structure.

SiF₄It is fluorine-containing common precursor with hexafluoropropene (HFP), and is added and deposits gained layer typically to increase Fluorinated volume (and therefore general formula SiO_xH_yC_zF_aN_bThe value of middle a will increase).

Those skilled in the art can easily adjust reaction gas and organosilicon under any power density of application The ratio of compound, to realize to the deposition gained desired modification of layer.

Precursor mixture also optionally further comprises nonreactive gas.Nonreactive gas is He, Ar or Kr.Non- reaction gas Body does not participate in plasma-deposited mechanism in a manner of chemistry, but usually influences the physical attribute of resulting materials really.For example, Addition He, Ar or Kr would generally increase the density of gained layer, to increase its hardness.Addition He, Ar or Kr also increase gained The bridging property of deposition materials.

Precursor mixture also optionally further comprises silver, gold, titanium, platinum and/or palladium.It is mixed when these metals are present in precursor When closing in object, the gained layer of deposition will contain metal.This is desirable, because it is known that these metals have antimicrobial and anti- Bacterium characteristic, therefore the ability that coating of the present invention inhibits biofilm formation can be enhanced.Silver, gold, titanium, platinum and/or palladium usually as Complex compound or common precursor are present in precursor mixture, exist preferably as common precursor, such as trimethyl-phosphine-(hexafluoro second Acyl acetone) silver-colored (I), 2,2- dimethyl -6,6,7,7,8,8- seven fluoro-octane -3,5- diketos) silver-colored (I) triethyl phosphine, dimethyl (acetylacetone,2,4-pentanedione) gold (III), dimethyl (trifluoroacetylacetone (TFA)) golden (III), isopropyl titanate (IV), four (dimethylamino) titaniums (IV), trimethyl (methyl cyclopentadienyl) platinum (IV) or Pd (hfac) 2 (wherein hfac is hexafluoroacetylacetone).

It is silver and/or gold, most preferably silver to be included in the preferred metal in precursor mixture.As will be further begged in detail below Opinion, it is usually preferred to which silver, gold, titanium, platinum and/or palladium exist only in the precursor mixture for the top layer for being used to prepare laminated coating In, it may be not present in being used to form in the precursor mixture of other layers of laminated coating.

The structure and attribute of laminated coating

The laminated coating of the present invention includes at least two layers.The table of first layer or lowest level and medical instrument in laminated coating Face contacts.End layer or top layer in laminated coating are contacted with environment.When laminated coating includes more than two layers, then those are attached Add layer between first layer/lowest level and end layer/top layer.

In general, laminated coating includes two layers to ten layers.Therefore, laminated coating can have 2,3,4,5,6,7,8,9 or 10 Layer.Preferably, laminated coating has two layers to eight layers, for example, two layers to six layers either three layers to seven layers or four layers to eight layers.

Boundary between every layer can be discontinuous or gradual change.In with the laminated coating more than two layers, layer it Between each boundary can be discontinuous or gradual change.Therefore, all boundaries can be discontinuous or all side Boundary can be that the boundary of gradual change or coating can be discontinuous and gradual change.

During plasma deposition process, pass through the precursor needed for the first layer as time goes by from being formed two layers Mixture gradually switches to the precursor mixture to be formed needed for the second layer in two layers, can realize gradual change boundary between the two layers. The thickness of gradation zone between two layers can be by changing from the first precursor mixture to when the switching of the second precursor mixture Between adjust.In some cases, it may be advantageous on gradual change boundary, because the adherency between layer is generally increased by gradual change boundary Add.

During plasma deposition process, cut immediately by the precursor mixture needed for the first layer from being formed two layers The precursor mixture to be formed needed for the second layer in two layers is shifted to, can realize noncoherent boundary between the two layers.

Different layers is deposited by changing precursor mixture and/or plasma deposition conditions, to obtain with institute Need the layer of attribute.Select the attribute of each individual course so that obtained laminated coating has desired attribute.

In general, all layers of the laminated coating of the present invention can pass through the plasma of precursor mixture as defined herein Deposition obtains, and the precursor mixture includes one or more organo-silicon compound.Therefore, laminated coating of the invention is not preferably Containing plasma-deposited not obtainable other layers by precursor mixture defined herein, such as pass through non-plasma The organosilicon compound nitride layer that method is formed such as dipping.

First layer/undermost attribute

It is generally desirable to laminated coatings, and excellent adhesiveness is shown between the layer in the surface and coating of medical instrument.This is Preferably, so that laminated coating is firm during use.It can be tested using test well known by persons skilled in the art Adhesiveness, such as according to 3198 specifications of VDI (Verein Deutscher Ingenieure Normen, VDI 3198, VDI- Verlag, Dusseldorf, 1991) as defined in Scotch adhesive tape tests or scrape adherency test or Rockwell C indentations survey Examination.

It is therefore preferable that first layer/lowest level of the laminated coating contacted with the surface of medical instrument is by precursor mixture shape At the precursor mixture generates the layer adhered to well with the surface of medical instrument.Required specific precursor mixture will take Certainly in the certain material for constituting medical apparatus surface, and those skilled in the art will correspondingly adjust precursor mixing Object.One of the present invention is the discovery that the layer of organic trait can adhere well on the surface of medical instrument.With organic trait Layer (can be free of or be substantially free of O by using being free of or being substantially free of oxygen-containing reaction gas₂、N₂O or NO₂) before Body mixture is realized.It is therefore preferable that using free or substantially free of O₂、N₂O or NO₂Precursor mixture it is more to deposit First layer/lowest level of layer coating.

As used herein, all to mention the precursor mixture containing specified ingredients " substantially not ", refer to precursor mixing Object may include the specified ingredients of trace, and condition is the fundamental characteristics for the gained layer that the specified ingredients form the precursor mixture There is no materially affect.Therefore, in general, the precursor mixture for being substantially free of specified ingredients includes the specified ingredients less than 5wt%, The specified ingredients of preferably less than 1wt%, the specified ingredients of most preferably in less than 0.1wt%.

The layer for being free of or being substantially free of fluorine is generally also good with the surface adhesion of substrate.The layer for being free of or being substantially free of fluorine can It (is free of by using being free of or being substantially free of fluorine-containing organic silicon compound and be free of or be substantially free of reactive fluorochemical gas Or it is substantially free of SiF₄Or HFP) precursor mixture realize.It is therefore preferred that having using free or substantially free of fluorine-containing Organic silicon compound, SiF₄Or the precursor mixture of HFP carrys out first layer/lowest level of depositing multilayer coatings.

Therefore, particularly preferably use is free or substantially free of O₂、N₂O、NO₂, fluorine-containing organic silicon compound, SiF₄Or The precursor mixture of HFP carrys out first layer/lowest level of depositing multilayer coatings.Obtained coating will be organic nature, and It is not fluorine-containing, therefore will adhere well on the surface of medical instrument.

First layer/lowest level of laminated coating is typically free of any silver, gold, titanium, platinum or palladium.This is because laminated coating First layer/lowest level does not need the antimicrobial property of these metals.Therefore, first layer/lowest level of laminated coating usually makes It is deposited with the precursor mixture for being free of or being substantially free of silver, gold, titanium, platinum and/or palladium.

Usually it is also expected to first layer/lowest level of laminated coating can absorb before coating deposition on medical apparatus surface Existing residual moisture.Then first layer/lowest level will substantially be retained in residual moisture in the coating, to reduce Medical treatment device The nucleation of corrosion and corrosion location on tool surface.

Adherency of the coating in substrate is extremely important for medical instrument, and either implantable medical devices are still performed the operation and set It is standby.The integrality of coating is for avoiding failure/biodeterioration from being important in substrate, and further any layering may Jeopardize patient vitals.The adhesiveness of coating of the present invention is assessed usually using VDI 3198, the wherein at least adhesiveness of HF2 is preferred 's.

One favorable characteristics of the laminated coating of the present invention are first layer/lowest level (organic layer) and medical apparatus surface Excellent adhesion and laminated coating in excellent adhesion between each layer, it means that be not usually required to be pre-processed Step (before coating deposition) or post-processing step (after coating deposition) are to reach acceptable adhesion level.

The attribute of end layer/top layer

End layer/top layer of laminated coating is exposed to during implantation, insertion and/or indwelling and/or is connect with patient Tactile layer is bio-compatible, and inhibits the formation of biomembrane on it.

The ability that the end layer of laminated coating/top layer inhibits biomembrane to be formed on usually can be by this layer Increase including silver, gold, titanium, platinum and/or palladium.This can by including that silver, gold, titanium, platinum and/or palladium are realized, the silver, Gold, titanium, platinum and/or palladium are present in usually as or mixtures thereof complex compound or common precursor and are used to prepare laminated coating most In whole layer/top layer's precursor mixture.It is therefore preferable that being deposited using the precursor mixture containing silver, gold, titanium, platinum and/or palladium End layer/top layer of laminated coating.

Other than inhibiting the certain capabilities of biofilm formation, also it is desirable to which end layer/top layer of laminated coating usually has There is antifouling and corrosion resistance.For the Si sills in the present invention, the layer with Organic would generally show high-caliber anti- Dirty and corrosion resistance.Therefore, end layer/top layer of laminated coating is typically organic.Organic trait can be by using It is free of or is substantially free of oxygen-containing reaction gas and (be free of or be substantially free of O₂、N₂O or NO₂) precursor mixture realize.Cause This is, it is preferable to use free or substantially free of O₂、N₂O or NO₂Precursor mixture carry out the end layer of depositing multilayer coatings/most Upper layer.Precursor mixture can optionally contain halogen-containing organo-silicon compound, SiF₄And/or HFP, thus increase this layer Fluorinated volume, this would generally further increase antifouling and corrosion resistance.

Usually it is also desirable that end layer/top layer of laminated coating is hydrophobic.Hydrophobicity can be by using standard technique Water contact angle (water contact angle, WCA) is measured to determine.In general, the WCA of end layer/top layer of laminated coating For 90 ° of ＞, preferably 95 ° to 115 °, more preferable 100 ° to 110 °.

The hydrophobicity of layer can be changed by adjusting precursor mixture.For example, the layer with Organic would generally be thin Aqueous.As described above, the layer with organic trait can be by using being for example free of or be substantially free of oxygen-containing reaction gas (be free of or be substantially free of O₂、N₂O or NO₂) precursor mixture realize.As described above, if being deposited in precursor mixture In the oxygen-containing gas of significant quantity, then the Organic of gained layer and hydrophobicity will reduce.It is therefore preferable that using being free of or substantially not Containing O₂、N₂O or NO₂Precursor mixture come end layer/top layers of depositing multilayer coatings.

It can also be increased by using halogen-containing organo-silicon compound (such as compound of Formula VII defined above) The hydrophobicity of layer.With this precursor, obtained layer will contain halogen atom, and would generally be hydrophobic.Halogen atom It can also be by including SiF in precursor mixture₄Or HFP is introduced as reaction gas, this will be so that in gained coating Including fluorine.In general, other than the component discussed above for realizing Organic, it is preferable that using containing containing halogen Organo-silicon compound SiF₄And/or the precursor mixture of HFP comes end layer/top layer of depositing multilayer coatings.

Usually it is also desirable that end layer/top layer of laminated coating is oleophobic.In general, hydrophobic layer is also oleophobic. Fluorine-containing coat is especially true.Therefore, it if the water contact angle (WCA) of end layer/top layer of laminated coating is more than 100 °, applies Layer will be oleophobic property.It is preferred for increased oleophobic property that WCA, which is more than 105 °,.

Usually it is also expected to end layer/top layer of laminated coating has at least nano hardness of 1.0GPa, and at least The Young's modulus of the reduction of 3GPa.The hardness and Young's modulus can be tested by nano hardness well known by persons skilled in the art Instrument technology measures.The hardness of layer can be changed by adjusting precursor mixture, such as adjusted to including nonreactive gas, example Such as He, Ar and/or Kr.This can make layer finer and close, and therefore harder.It is therefore preferred that using including He, Ar and/or Kr Precursor mixture comes end layer/top layer of depositing multilayer coatings.

Hardness can also be adjusted by changing plasma deposition conditions.Therefore, the pressure that deposition occurs is reduced to obtain Layer it is usually finer and close and therefore harder.Increasing radio-frequency power would generally make layer finer and close, and therefore harder.It can hold It changes places and adjusts these conditions and/or precursor mixture, to reach desired hardness as described above.

Moisture-proof attribute

It is expected that laminated coating serves as damp-proof layer so that body fluid (such as will be with Medical treatment device when being inserted or implanted into patient's body Those of tool contact body fluid) coating cannot be destroyed and damage following medical instrument.Can be tested by using MOCON etc. Standard technique measures moisture-vapor transmission (WVTR) to assess the damp-proof layer property of laminated coating.In general, the WVTR of laminated coating For 10g/m²/ day~0.001g/m²/ day.

In general, by being 0.5g/m by WVTR²/ day~0.1g/m²At least one layer in/day, which is included, can enhance multilayer The damp-proof layer property of coating.Such damp-proof layer is not usually first layer/lowest level or the end layer/top layer of laminated coating. May exist several damp-proof layers in laminated coating, wherein each damp-proof layer there can be identical or different ingredient.

In general, substantially inorganic nature and be most effective damp-proof layer containing the layer of seldom carbon.Such layer can be with By, for example, to including organo-silicon compound and oxygen-containing reaction gas (i.e. O₂、N₂O or NO₂) precursor mixture carry out etc. from Daughter deposits to obtain.Add the nonreactive gas such as He, Ar or Kr, using high RF power densities and/or reduction plasma Body pressure may also contribute to form the layer with good moisture-proof attribute.

It is therefore preferred that at least one layer of laminated coating can be by including organo-silicon compound and O₂、N₂O and/or NO₂Precursor mixture carry out it is plasma-deposited obtain, further preferably include the precursor mixture of He, Ar and/or Kr.It is preferred that Ground, precursor mixture are grouped as by these components or substantially by these groups.

Layer containing nitrogen-atoms can generally also have desired moisture-proof attribute.Such layer can be by using nitrogenous organic Silicon compound obtains, typically silazane or amino silane precursor, the compound of formula (IV) to (VI) such as defined above. Nitrogen-atoms can also be by including N in precursor mixture₂、NO₂、N₂O or NH₃It is introduced as reaction gas.Preferably, preceding Body mixture is grouped as by these components or substantially by these groups.

Therefore, it is also preferred that at least one layer of laminated coating can be by including organic compounds containing nitrogen, N₂、NO₂、N₂O And/or NH₃Precursor mixture carry out plasma-deposited obtain.Preferably, precursor mixture is by these components or basic On be grouped as by these groups.

Other attributes

The thickness of laminated coating is usually 20nm to 2000nm, such as 100nm to 500nm or 200nm to 400nm.

Every layer of thickness depends on the overall thickness of the number of plies and laminated coating of deposition in the laminated coating of the present invention.With more Every layer of layer coating can have identical or approximately uniform thickness.Alternatively, in certain cases, it may be desirable to a certain layer or more Layer than it is other certain one or more layers it is thicker.

Those skilled in the art can easily control every layer of thickness.Plasma method is under prescribed conditions with uniform Rate deposition materials, therefore the thickness of layer is directly proportional to sedimentation time.Therefore, once it is determined that deposition rate, so that it may with logical The duration of control deposition is spent to deposit the layer with specific thicknesses.

Laminated coating and each thickness for constituting layer can be substantially uniform or can change from point to points, but excellent It is substantially homogeneous to select thickness.

Thickness can be measured using technology well known by persons skilled in the art, such as contour measurement, reflection measurement Method or elliptically polarized light spectrometry.

In case of need, laminated coating can be improved by introducing gradual change boundary between layers as described above Adhesiveness between layer.For fluorine-containing layer, gradual change boundary is especially preferred, because these layers tend to performance and go on business Adhesiveness.Therefore, if given layer is fluorine-containing, preferably there is gradual change boundary with adjacent layer.

Alternatively, in the case of necessary, the discontinuity layer in laminated coating can be selected so that they are adhered to well On adjacent layer in coating.

The attribute of the laminated coating of the present invention

The laminated coating of the present invention inhibits the formation of biomembrane, therefore can prevent or reduce biomembrane on medical instrument It is formed.The laminated coating that the present invention can be easily assessed using ex vivo technique well known to those skilled in the art inhibits biomembrane The ability of formation.Usually using staphylococcus epidermis in these technologies, it is related to forming biomembrane because it is typically considered The representative of bacterium.It is preferred that studying the life of coating of the present invention in vitro by static and perseveranceization (continuous flowing) biofilm formation system Object film inhibition activity.Static biofilm formation system is particularly useful including initial for checking the early stage of biofilm formation It is adhered to the formation of surface and microcolony.Permanentization system can be used for similar situation in analogue body.

The laminated coating of the present invention is bio-compatible.This means that they are nontoxic, and during being implanted into insertion Or then during indwelling with will not cause unfavorable or harmful influence when patient contact.The property of biocompatibility needed for coating Matter depends on device.For example, the blood compatibility, such as hemolytic, hemolytic toxicity of device etc. that test is in direct contact with blood. Other tests for assessing biocompatibility include gene toxicology, irritation and cytotoxicity.Generally according to relevant device standard Execute test.

Attached drawing is described in detail

Each aspect of the present invention is described now with reference to example shown in Fig. 1 to Fig. 3, it is in the drawings, identical The same or analogous component of digital representation.

Fig. 1 shows the cross section of the preferable example of the laminated coating 2 of the present invention.Laminated coating 2 has and medical instrument 1 Surface contact first layer/lowest level 3, also have end layer/top layer 4.The laminated coating 2 has two layers 3 and 4, and Boundary between layer 3 and layer 4 is discontinuous.

Fig. 2 shows the cross sections of another preferable example of laminated coating 2.Laminated coating 2 has the table with medical instrument 1 First layer/lowest level 3 of face contact, also has end layer/top layer 4.Also have other two layers 5 and 6 between layer 3 and layer 4.It should Laminated coating 2 have four layer 3,4,5 and 6, and the boundary between layer 3,4,5 and 6 is discontinuous.

Fig. 3 shows the cross section of another preferable example of laminated coating 2.Laminated coating 2 has the table with medical instrument 1 First layer/lowest level 3 of face contact, also has end layer/top layer 4.The laminated coating 2 has two layers 3 and 4, and 3 He of layer Boundary 7 between layer 4 is gradual change.

Example

Each aspect of the present invention is described hereinafter with reference to example.

Example 1- deposits single SiO_xC_yH_zLayer, using He as common precursor

Substrate is put into plasma enhanced chemical vapor deposition (PECVD) chamber, pressure is then made to reach ＜ 10^- ³mbar.To cause chamber pressure to inject He for the flow of 0.480mbar, then (passing through throttle valve) increases to chamber pressure 0.50mbar.In 0.573Wcm^-2RF power densities under light plasma 3-5 seconds.Next, by HMDSO with the stream of 6sccm Amount and 0.225,0.382,0.573 or 0.637Wcm^-2RF power densities injecting chamber 20 minutes.In deposition process, pressure (passing through throttle valve) is maintained at 0.5 millibar.

Polymer organic silicon SiO is obtained in substrate_xC_yH_zLayer.It is shown using 0.637Wcm in Fig. 4^-2RF power it is close Spend the FT-IR transmitted spectrums of the layer obtained.

SiO_xC_yH_zThe WCA (water contact angle) of layer is~100 °, shows hydrophobicity.

Test the described layer deposited with 0.637Wcm-2 to organic solvent (i.e. isopropanol (IPA) and acetone) and Acid and alkaline aqueous solution chemical resistance.Acid solution is the HC1 aqueous solutions for having following pH：6；5；4；3；2；With 1.Alkalinity Solution is the NaOH aqueous solutions for having following pH：8；9；10；11；12；With 13.

First, it is wiped on the surface of the layers with cotton swab (being soaked with solvent/solution), thus with above-mentioned solvent and solution to each Layer is wiped.Secondly, these layers are immersed in above-mentioned solvent and solution.In the two tests, these layers, which are not shown, appoints The sign of what layering, scratch or damage.

Example 2- deposits single SiO_xC_yH_zLayer, using Ar as common precursor

Substrate is put into plasma enhanced chemical vapor deposition (PECVD) chamber, then pressure is made to reach~10^- ²mbar.Ar and HMDSO are injected with the flow of 20sccm respectively, then wait for pressure stabilization quietly.Then by RF plasmas (with 0.057W·cm^-2RF power densities) light, obtain~the process pressure of 0.14mbar.Coating procedure after five minutes, pass through It keeps plasma and does not destroy vacuum, stop HMDSO flows and the coating of deposition is exposed in Ar plasmas (at this With the flow of 15sccm in step) 30 seconds.After this is 30 seconds, in the case where not destroying vacuum always, Ar flows is made to reach 20sccm, and HMDSO is injected with the flow of 20sccm.The process is repeated 5 times, in addition to last 5 minutes coating steps, the step End be not exposed to Ar plasmas.Total deposition processes time is 32.5 minutes.

SiO_xC_yH_zThe WCA of layer is~104 °, shows hydrophobicity.SiO is tested as described in example 1_xC_yH_zThe chemically-resistant of layer Property (IPA and acetone), and again by two test.SiOxCyHz layers of mechanical performance is also tested by pencil hardness test, It is measured according to D 3363-00 standards Mitsubishi UNI pressure resistance high density pencils, shows the scratch hardness and 2H of HB-F Dig into hardness.

Example 3- deposits single SiO_xH_zLayer

Substrate is put into PECVD deposition chambers, pressure is then made to reach ＜ 10^-3mbar.It bets in this base pressure Enter O₂, until chamber pressure is 0.250mbar.After this, He is injected, to reach the chamber pressure of 0.280mbar.Most Afterwards, HMDSO is injected with the flow of 2.5sccm, and pressure is increased to 0.300mbar by (passing through throttle valve).Then, with 0.892Wcm^-2Power density light plasma, and continue the process, the expectation thickness until reaching about 750nm.So Obtain SiO_xH_zLayer, FT-IR transmitted spectrums are as shown in Figure 5.The SiO_xH_zThe WCA of layer is~50 °, shows hydrophily.

The SiO_xH_zLayer carries out chemical resistance test as described in example 1, and is still tested by two.

Example 4- deposits SiO_xC_yH_z/SiO_xH_zMultilayer

SiO in substrate_xC_yH_z/SiO_xH_zMultilayer PECVD deposition experiment condition substantially with institute in example 1 and example 3 That states is identical.In short, the same steps deposition SiO by example explained in 1_xC_yH_z(this experiment RF power densities used are 0.637Wcm^-2), so that chamber is reached vacuum (＜ 10^-3Mbar), according to it is explained in example 3 the step of, in SiO_xC_yH_zLayer Upper deposition SiO_xH_z.Then, by the 2nd SiO_xC_yH_zLayer is deposited on SiO_xH_zOn layer.2nd SiO_xC_yH_zThe thickness of layer is first SiO_xC_yH_zThe half of layer thickness.This is realized by halving sedimentation time.These steps generate the multilayer having following structure Coating：SiO_xC_yH_z/SiO_xH_z/SiO_xC_yH_z。

Then, the process is repeated in some substrates to add second couple of SiO_xC_yH_z/SiO_xH_zLayer, thus obtains structure： SiO_xC_yH_z/SiO_xH_z/SiO_xC_yH_z/SiO_xH_z/SiO_xC_yH_z。

Two multilayers carry out chemical resistance test as described in example 1, and are still tested by two.

The attribute of example 5- assessment coatings

Coating is deposited on rake (a kind of electronic component) under the following conditions.

1. being used for SiO_xThe sedimentary condition of coating

10^-3O is injected under the base pressure of mbar₂, until chamber pressure is raised to 0.250mbar.After this, it injects He, to reach the chamber pressure of 0.280mbar.HMDSO is added with the flow of 2.5sccm.Pressure set is 0.280mbar. Plasma is with 0.892Wcm^-2Power density light.

2. being used for SiO_xC_yH_zThe sedimentary condition of coating

10^-3Under the base pressure of mbar, then make according to the flow injection He for making chamber pressure reach 0.480mbar Pressure (passing through throttle valve) increases to 0.50mbar.In 0.573Wcm^-2RF power densities under light plasma 3-5 seconds.It connects Get off, by HMDSO with the flow and 0.637Wcm of 6sccm^-2RF power densities injecting chamber in.

3. being used for SiO_xC_yH_z/SiO_xThe sedimentary condition of coating

Described in above-mentioned 2nd section, SiO is deposited_xC_yH_zLayer.Then, deposition chambers are vacuumized, and presses above-mentioned paragraph 1 institute It states, by SiO_xLayer is deposited on SiO_xC_yH_zOn layer.

4. being used for SiO_xC_yH_z/SiO_x/SiO_xC_yH_zThe sedimentary condition of coating

Described in above-mentioned 2nd section, SiO is deposited_xC_yH_zLayer.Then, settling chamber is vacuumized, and pressed and institute in above-mentioned paragraph 1 (in addition to HMDSO and He mixtures to be injected and RF plasmas are directly with 0.637Wcm for the same terms stated^-2Power density Light), by SiO_xCoating is deposited on SiO_xC_yH_zOn layer.Finally, deposition chambers are vacuumized, and by described in above-mentioned 2nd section Condition, by the 2nd SiO_xC_yH_zLayer is deposited on SiO_xOn layer.

5. depositing SiO_xC_yH_z/SiO_xH_yC_zN_b/SiO_xC_yH_z/SiO_xH_yC_zN_b/SiO_xC_yH_zCoating

In 0.057Wcm^-2RF power densities under, by mixing the HMDSO of 17.5sccm with the Ar of 20sccm, deposit SiO_xC_yH_zLayer, while in 0.057Wcm^-2RF power densities under, by by the N of the HMDSO of 17.5sccm and 15sccm₂O is mixed It closes, deposits SiO_xH_yC_zN_bLayer.

6. being used for SiO_xH_yC_zF_aThe sedimentary condition of layer

In 0.057Wcm-²RF power densities under, the HMDSO of 17.5sccm is mixed with the HPF of 20sccm, deposit SiO_xC_yH_zF_aLayer.

Then, test is performed as follows in coated rake.Water is placed on coated rake, is then being applied The two poles of the earth of the rake covered apply electric power.Passage at any time measures resistance, and high resistance shows that coating is intact, without electric current.One Denier coating starts leak, and between electric current begins flow through the two poles of the earth of component, and resistance reduces.When resistance drops to 10⁸Ω or less When, it is considered as coating failure.As a result the coating when being contacted with the tissue or body fluid of patient (its water for containing high-content) is provided The instruction of performance.

The results are shown in Figure 6 for this test.SiO_xC_yH_z/SiO_x/SiO_xC_yH_zCoating performance is good (see black circle), entirely High resistance is all embodied during test.SiO_xC_yH_z/SiO_xH_yC_zN_b/SiO_xC_yH_z/SiO_xH_yC_zN_b/SiO_xC_yH_zAlso performance is good (see black star) has all embodied higher resistance during entire test.And three signal layer coating (SiO_x[black box], SiO_xC_yH_z [open triangles] and SiO_xH_yC_zF_a[diamond shape]) then fail to pass through, otherwise it is less than 10 when resistance originates⁸Ω is (for SiO_x Layer) or it is brought down below 10 dduring test⁸Ω is (for SiO_xC_yH_zLayer and SiO_xH_yC_zF_aLayer).

SiO_xC_yH_z/SiO_xDuplex coating (hollow square) also fails to, by this test, show not as good as SiO_xC_yH_zSingle layer applies Layer.It is possible to note that as previously mentioned, in SiO_xC_yH_z/SiO_xIn addition a SiO is added on coating_xC_yH_zLayer can be greatly Improve performance.It is believed that although with SiO_xThe painting that layer may cause the number of plies less in some conditions as the top layer of coating Layer (such as SiO_xC_yH_z/SiO_x) reduced performance, but when the number of plies in coating is more, it is unlikely to observe this performance It reduces.

Claims

1. a kind of medical instrument for being adapted for insertion into or being implanted into the patient, the medical instrument have at least one surface thereof Laminated coating, wherein：

Each layer of the laminated coating includes by the plasma-deposited acquisition of precursor mixture, the precursor mixture： (a) one or more organo-silicon compound, (b) optional O₂、N₂O、NO₂、H₂、NH₃、N₂、SiF₄And/or hexafluoropropene HFP, (c) optional He, Ar and/or Kr, and (d) optional silver, gold, titanium, platinum and/or palladium；And

First layer/lowest level of the laminated coating contacted at least one surface of the medical instrument is organic 's.

2. medical instrument according to claim 1, wherein the laminated coating has 2 to 10 layers, preferably 4 to 8 layers.

3. medical instrument according to claim 1 or 2, wherein it is described it is plasma-deposited be plasma enhanced chemical gas Mutually deposition PECVD.

4. medical instrument according to any one of the preceding claims, wherein it is described it is plasma-deposited 0.001 to Occur under the pressure of 10mbar.

5. medical instrument according to any one of the preceding claims, wherein described at least one with the medical instrument First layer/the lowest level of the laminated coating of surface contact is by being free of or being substantially free of O₂、N₂O or NO₂Precursor it is mixed Close the plasma-deposited acquisition of object.

6. medical instrument according to claim 5 the, wherein first layer/lowest level of the laminated coating is by being free of Or it is substantially free of O₂、N₂O、NO₂, fluorine-containing organic silicon compound, SiF₄Or the plasma-deposited acquisition of the precursor mixture of HFP.

7. medical instrument according to any one of the preceding claims, wherein end layer/top layer of the laminated coating By being free of or being substantially free of O₂、N₂O or NO₂Precursor mixture plasma-deposited acquisition.

8. medical instrument according to any one of the preceding claims, wherein the end layer of the laminated coating/most Upper layer is by containing one or more halogen-containing organo-silicon compound, SiF₄And/or HFP precursor mixtures is plasma-deposited It obtains.

9. medical instrument according to any one of the preceding claims, wherein the end layer of the laminated coating/most The plasma-deposited acquisition that upper layer passes through the precursor mixture containing He, Ar and/or Kr.

10. medical instrument according to any one of the preceding claims, wherein the end layer of the laminated coating/most The plasma-deposited acquisition that upper layer passes through the precursor mixture of argentiferous, gold, titanium, platinum and/or palladium.

11. medical instrument according to claim 10, wherein in addition to the end layer/top layer of the laminated coating Layer not argentiferous, gold, titanium, platinum and/or palladium.

12. medical instrument according to any one of the preceding claims, wherein at least one layer of the laminated coating is logical It crosses and contains O₂、N₂O and/or NO₂Precursor mixture plasma-deposited and the damp-proof layer that obtains.

13. medical instrument according to any one of the preceding claims, wherein at least one layer of the multilayer conformal coating It is by containing nitrogenous organic compound, N₂、NO₂、N₂O and/or NH₃Precursor mixture plasma-deposited and obtain Damp-proof layer.

14. medical instrument according to claim 12 or 13, wherein described can acquire at least one damp-proof layer Precursor mixture also contain He, Ar and/or Kr.

15. the medical instrument according to any one of claim 12 to 14, wherein at least one damp-proof layer is located at institute It states between first layer/lowest level of laminated coating and end layer/top layer.

16. medical instrument according to any one of the preceding claims, wherein by by one or more organosilicons Compound is plasma-deposited and acquires every layer of the laminated coating, and one or more organo-silicon compound are independently It is selected from：Hexamethyldisiloxane HMDSO, tetramethyl disiloxane TMDSO, 1,3- divinyl tetramethyl disiloxanes DVTMDSO, Six vinyl disiloxane HVDSO, allyl trimethyl silane, allyltrimethoxysilanis ATMOS, ethyl orthosilicate TEOS, trimethyl silane TMS, tri isopropyl silane TiPS, divinyltetraphenylcy,lotrisiloxane V₃D₃, tetravinyl tetramethyl Basic ring tetrasiloxane V₄D₄, tetramethyl-ring tetrasiloxane TMCS, octamethylcy-clotetrasiloxane OMCTS, hexamethyldisilazane HMDSN, 2,4,6- trimethyls -2,4,6- trivinyls cyclotrisilazane, dimethylamino trimethyl silane DMATMS, bis- (diformazans Amino) dimethylsilane BDMADMS, three (dimethylamino) methyl-monosilane TDMAMS, trimethyl (trifluoromethyl) silane or 1H, 1H, 2H, 2H- perfluoro capryl triethoxysilane, 3- (lignocaine) propyl-trimethoxysilane.

17. medical instrument according to any one of the preceding claims, wherein silver, gold, titanium, platinum and/or palladium are as front three Base phosphine-(hexafluoroacetylacetone) silver (I), 2,2- dimethyl -6,6,7,7,8,8- seven fluoro-octane -3,5- diketos) silver (I) three second Base phosphine, dimethyl (acetylacetone,2,4-pentanedione) golden (III), dimethyl (trifluoroacetylacetone (TFA)) golden (III), isopropyl titanate (IV), four (diformazans Base amino) titanium (IV), trimethyl (methyl cyclopentadienyl) platinum (IV) or Pd (hfac) 2 be present in the precursor mixture, Wherein hfac is hexafluoroacetylacetone.

18. the biomembrane shape on a kind of at least one surface for reducing the medical instrument for being adapted for insertion into or being implanted into the patient At method, it is plasma-deposited the method includes passing through the laminated coating according to any one of claim 1-17 To deposit at least one surface.

19. a kind of purposes of laminated coating according to any one of claim 1-17 is adapted for insertion into or plants for reducing Enter the biofilm formation on the medical apparatus surface of patient's body.