EP2032181A2

EP2032181A2 - Method for applying a bioactive, tissue-compatible layer onto shaped articles and the use of such shaped articles

Info

Publication number: EP2032181A2
Application number: EP07725214A
Authority: EP
Inventors: Christoph Schultheiss
Original assignee: Forschungszentrum Karlsruhe GmbH
Current assignee: Karlsruher Institut fuer Technologie KIT
Priority date: 2006-06-23
Filing date: 2007-05-15
Publication date: 2009-03-11
Also published as: DE102006028856A1; US20090232864A1; WO2007147462A3; DE102006028856B4; WO2007147462A2

Abstract

A method for providing a target composed of a bioactive tissue-compatible glass mixture, and the surface of the shaped articles which is presented to the environment, with a layer of the target material. The method permits application to temperature-sensitive shaped articles which had not previously been suitable for such a procedure. The coated surface of implanted shaped articles/casings has the potential to connect and to grow together with living soft tissue. Shaped articles/casings coated in this way and implanted subcutaneously/ transcutaneously are therefore suitable for diagnosis and therapy when the intended substance has previously been introduced into them. However, it is also possible to incorporate an electronic device with which it is thus possible to locate and identify the carrier.

Description

Method for applying a bioactive, tissue-compatible layer on shaped articles and use of such shaped articles

The invention relates to a method for the at least partial application of a bioactive, tissue-compatible layer on moldings, such moldings and the use of such coated, molded body.

A novel class of substances that can be implanted into living tissue and also have the potential to associate with soft tissue is called bioactive glass-ceramic, BAG. BAG is an amorphous bioceramic that contains not only the typical glass components such as sodium, silicon and calcium but also low levels of phosphorus. Specifically, the ceramic is used in the composition range S53P4 with the composition 53% SiO ₂ , 4% P ₂ O ₅ , about 21% CaO, about 21% Na ₂ O and other physiological salts. At the University of Florida, evidence was provided that within close limits of the mixing ratio, not only does osteointegration of the implant with the surrounding bone occur, but also soft tissue coalescence with the BAG surface is observed.

Since BAG is very brittle and can not be processed into implants or parts thereof, it is mainly used in the form of granules for building up bones in the jaw area. A coating of implants by immersion in liquid BAG is possible, but this requires high temperature resistance on the part of the implant material. Further methods for coating implants with BAG are the sol-gel technique and the plasma spraying technique, both of which lead to a high thermal load on the implants, followed by ion sputtering (sputtering) and laser evaporation, which play only a ^subordinate role, since in both the glass property or the stoichiometry are changed.

In particular, the following should be noted with respect to these procedures: In the plasma spraying technique BAG powder is replaced by an electric

Blown sheet and applied to the implant with up to a layer thickness of about 100 microns. Such layer thicknesses are required because of "turret growth" to ensure that the implant surface is hermetically sealed to the BAG surface, yet penetration and creep of body fluid into the layer can not be ruled out Implant surface observed.

The thermal stress during production requires requirements for the material properties of the implant. Plastics, glasses and metals with a low melting point are excluded, as are implants that already contain electronic components. Another problem is the decomposition temperature of BAG, which is given according to the literature between 900 ⁰ C and 1400 ⁰ C and at high temperatures in the electric arc easily leads to the formation of undesirable mineralogical phases of calcium phosphate. For comparison, the temperatures in the production of layers with the sol-gel technique are much lower, but are also 400 ⁰ C, so that most plastics are not suitable as implant material.

Ion sputtering, sputtering in technical language, is characterized by low film growth rates, only a few angstroms per minute and deviations from the stoichiometry to 20%. The main reason for the low layer growth is the electrical charging of the non-conductive, dielectric BAG target by fast positive ions and the resulting reduced sputtering ion current to the target. Restrictions also apply to the laser, whereby the pulsed UV laser can be used to produce high-quality coatings via the ablation process, but investment and operating costs limit the cost-effectiveness. So far, flexible, subcutaneous and transcutaneous tubes, such as catheters, etc., or sensitive dielectric material encased electronic components that need to be implanted subcutaneously, such as pacemakers, a coating with BAG.

The exit site of a transcutaneous implant through the tissue of the skin is an open wound, which is a perpetual inflammation. In addition, the border between implant and tissue forms a passage for bacteria and germs into the interior of the body and is therefore problematic because of the inflammatory potential. An ingrowth of the implants with the soft tissue would be a great progress. The same applies to a subcutaneously implanted molding / housing.

By way of example, so-called transponders are mentioned as sensitive, subcutaneous implants. These are electronic receiver and transmitter units that can be used as an identification system in animals. For this purpose, such a transponder is installed in a outwardly coated with BAG, dielectric housing, which is then, hermetically sealed, injected or implanted. Coded excitation of the implanted transponder provides an individual identification system.

The BAG-coated transponder housing fuses with the tissue. Liability is important because a hike in the body can lead to spontaneous complications that are unacceptable to the user. Both in slaughter cattle, as well as in experimental animals, the accurate and reliable localization of an implanted transponder is a crucial criterion for use as an identification system.

So far, one tries to counteract the migration of such implanted housing / molded body with integrated transponder by a plastic tube pushed over. However, the plastic provokes a proliferative, inflammatory defense process, in the course of which fiber-forming cells and later an intermediate cell substance is formed, which in the best case to an encapsulation of the housing caused by scarring. Especially in experimental animal husbandry a health restriction of the population by an identification system is not tolerable. Reference is made to catheters as subcutaneous implants, such as the renal catheter or the catheter for abdominal dialysis, which are of increasing importance. The most common complications are inflammation of the kidney or the abdomen, which can take life-threatening course, apart from the fact that the catheter method is often the last resort to help a patient with an underlying disease.

The object of the invention is to provide a method for coating temperature-sensitive implants with bioactive, tissue-compatible substances / coatings which grow together with the soft tissue. The applied, exposed layer should be liquid-tight and can be applied in specified thickness and roughness. Furthermore, coated moldings / housings are to be provided which can be implanted in a living organism without being repelled by it.

The object is achieved by a method according to the characteristics of claim 1, by coated moldings / housing according to claim 4 and the use of such moldings. Such moldings / housings according to the invention can be planted in living tissue without causing rejection reactions. The method of at least partially applying a bioactive, tissue-compatible layer to molded articles to provide a contact surface with the property of colonization and spreading, proliferation, of surrounding soft tissue body cells on the layer is characterized in that bioactive glass, BAG, used in the composition range S53P4 as target material. The moldings 5 are cleaned and the surfaces to be coated are each activated with ions. The shaped bodies 5 are exposed on an exposure table to a BAG-beam pulse 7 ablated by pulsed electron beam radiation from a BAG target 3. The thermal load due to condensation is heat is controlled during the BAG deposition on the surface of the housing 5 via the pulse frequency of the electron 2 or BAG beam pulse 7, to the intended housing surfaces a BAG layer of 1 to lOum thickness is deposited and thus is so thick that In the subsequent contact with liquids, ions are eluted from the depth of the BAG layer which initiate a morphological transformation of the surface necessary for cell colonization.

Prior to implantation to avoid initial cytotoxicity, the BAG-coated molded article is subjected to at least three times 24 hour exposure to culture medium (SBL), demineralized water, or 0.9% NaCl electrolyte. Or subject to wet steam sterilization at a minimum of 134 ⁰ C for at least 13 minutes or at least 121 ° C for a period of at least 30 minutes.

According to claim 4, the moldings are dielectric and plastic, have ampoule or lens shape or form a tube or sheath a wire and have a size that is bearable for implantation into tissue without affecting the natural functions. According to claim 5, the moldings of glass, ceramic, both dielectric, or metal, and thus electrically conductive, and also have a shape and size that is bearable for implantation into tissue without affecting the natural functions.

In the subclaims 2 and 3 special process steps are described. According to claim 2, the surface to be coated of the shaped body / housing with Ar or O or N ions or otherwise suitable for the process ions or their ionized molecules is activated. According to claim 3, the implant is sterilized after at least three contact with liquids by a dry process, such as rinsing with methylene oxide gas.

The use of such coated moldings / housings is set forth in use claims 6-8. According to claim 6 is use a dielectric or metallic shaped body for injection or transcutaneous / subcutaneous implantation into a living body / organism, where such engages with the adjacent tissue at the deposition site or at the transcutaneous entry site into the body without rejection reaction. According to claim 7, it is used for diagnosis or therapy, in the previously a corresponding medium was included. Finally, according to claim 8, the shaped body / housing is used for the physical stimulation of the body / organism / organs or for the transmission of measurement data or as locating medium into which a corresponding electronic therapy device or transponder device has previously been enclosed.

For the process is an important part of how the surface to be coated of the molding / housing is designed. It is advantageous to activate the surfaces with ions such as Ar, O or N or their ionized molecules.

The provision of the rough surface for better adhesion of the tissue cells and for engraftment at the site of implantation accelerates the solubility of BAG. Therefore, the layer thickness at their thinnest points, the roughness valleys should be correspondingly strong, they should not be less than 1 micron there.

The method is carried out with a device for generating pulsed, magnetically self-insulating electron beams, as described in DE-PS 42 08 764 C2. These electron beams can be used to ablate material from the dielectric target via the ablation process and grow on an exposed surface. The ability of the electron beam to ablate dielectric material is closely related to the property of the magnetically self-focused electron beam to propagate in a dielectric gas. The dielectric background gas is ionized by the beam and a column of positive gas ions for space charge neutralization is formed in its propagation channel. This is the case when the beam hits a BAG target.

The beam electrons ionize the molecules in the area of the solid surface. Thermal electrons from the ionization process escape from depths of 200 nm from the initially very dense ablation plasma to the outside and thus prevent an accumulation of negative space charge brought about by the beam, which would repel the beam.

The energy of the electrons in the beam is between 10 and 15 keV, the time is about 100 ns, and the energy transported is about 1 J. The cross section of the beam is 10 mm ² when it hits the target surface. This corresponds to a power density of 10 ⁸ watts / cm ² . Depending on the range of 10 - 15 keV electrons they penetrate about 200 nm into the target (density = 3 g / cm ³ ) and deposit the energy in this thin layer. The result is an energy charge of the 200 nm layer corresponding to a specific energy of 60 kJ / g. In fact, the effective specific energy is lower, because even during deposition, heat drains into deeper areas of the target. Since BAG has a sublimation energy in the amount of slightly more than 10 kJ / g, there is an explosive ablation of the layer, the ablation. The eroded mass per shot is in the range of 10 μg.

The removed BAG material escapes only partially molecularly. The vast majority is in the form of hot, boiling droplets whose size distribution extends to 40 nm. Due to the pressure conditions during ablation, vapor and droplets move normally away from the target surface. The velocity distribution is large, for doubly positively charged ions speeds up to 10 km / s were measured, followed by simply positively charged (1 km / s). Molecules, molecular patterns and droplets follow, with the droplets still moving at speeds of 100 m / s.

The surface of the implant must be treated before coating. After cleaning and degreasing the implant, it is the Beam exposed to an ion beam extraction source to rid the surface of adsorbates and activate. The ion energy and current density move in the usual way and are 3 - 5 keV at 10 mA / cm2. The ion selection is optional, as long as it is nonmetallic, but it decreases the ready availability because of ions of the type Ar, O or N or their ionized molecules, if existing. Another common method for surface cleaning is a radio frequency (RF) treatment.

A substrate exhibits film growth when it is arranged to be struck by the ablated components. The molten droplets integrate homogeneously into the layer because they flow when impacted. Typical growth rate of the layer per shot is 1 nm, the distance: target - substrate typically 6 cm.

The ablation is considered to be a "cold" coating process because ideally only the surface layer of the target captured by the energy deposition ablates and the underlying area is not heated during the coating, the heat input per time on the molding / housing, the implant dielectric body, dielectric elastic body, determined only by the heat content of the precipitated ablative vapors per pulse, multiplied by the pulse repetition frequency By choosing the pulse repetition frequency, the heating of the substrate is controllable.

The stoichiometric deviation of the composition of BAG in the layer is low. In Rutherford's retrospective studies, deviations of typically 5% are measured and thus are at the resolution limit of the measurement method. The reason for the small deviation is due to the maintenance of the stoichiometry in the droplets.

Since the stoichiometry of the target and that is the fact hergestell ^¬ th coatings critical parameters, a commercially available BAG was overall with the designation S53P4 as a starting substrate which contains 53% silicon and 4% phosphorus. This glass composition is in the range of the desired stoichiometry following inevitable losses of slightly vaporized sodium levels when ablated in the layer.

The results of the mechanical tests for adhesion and scratch resistance on dielectric surfaces, a titanium alloy as well as on PDMS (polymethyl methacrylate or silicone rubber used in medicine) proved positive.

Elution experiments indicating the elicitation of calcium, sodium, silicon and phosphorus ions as a result of the morphological transformation of the coated surface after contact with artificial body fluid were positive. They indicate that crystallites of hydroxyapatite and various other calcium phosphates, which are required for the growth and proliferation of soft tissue cells, have formed on the surface of the coating.

An unexpected result with BAG was that the cell attachment and cell growth of L 929 mouse fibroblast cells on the layer surface in SFB (s _^ imulated body fluid) were disturbed and the coatings were found to be cytotoxic in standard in vitro experiments according to ISO 10993 -5 proved. The cytotoxicity could be attributed to an increased silicon concentration on contact with the artificial body fluid SFB. This increased solubility and ion concentration in the SFB does not show up in the commercially available S53P4 BAG, but only on the layer. The reason for this is the so-called frozen energy in the production of the layer by ablation, which strongly favors the elution behavior of ions.

The solution of the problem is achieved with the pretreatment of the layer. Three times 24-hour surface contact with culture medium (SFB), demineralized water or 0.9% NaCl electrolyte reduced eligibility to normal levels. Furthermore, it has been shown that the so-called. Wet steam sterilization at 134 ° C for the duration of 18 minutes or 121 ⁰ C for the duration of 30 minutes has the same effect, which has the advantage that the most cost-effective sterilization and the necessary pre-treatment in a job can be done.

Initial biosensitivity tests of BAG-coated implants / moldings produced by the pulsed electron beam method and implanted into rats were successful. Coated and uncoated substrates were implanted into rats and tissue reactions examined at two and four weeks. In each case implants made of a titanium alloy and PDMS (silicone rubber) were coated and used as a reference uncoated. No macroscopic signs of incompatibility were found for both implantation intervals (uncoated, coated). The histological findings indicate that two weeks after implantation, the titanium implants were slightly encapsulated in a limited and relatively non-inflammatory response. No signs of delamination of the layer were detected. Likewise, the coated and uncoated silicone implants also show an acceptable low level of inflammation. During the preparation of the implants, it was apparent for the first time that the layer had delaminated from the substrate and hung on the soft tissue or grown together with it. This is considered an indication of the desired adhesion between the layer and soft tissue. Also noteworthy is the macroscopic finding that after four weeks of small blood vessels around the implantation site have formed to ensure that the tissue is healthy around the implant and provides nutrients ver ^¬ is.

In the single figure of the description, the coating system is shown schematically. The electron beam source is only indicated with its output, the tube 1, in which the electron beam 2 is formed as a channel sparks. For this tube 1 occurs Electron beam 2 and flies onto the BAG target 3, on which he ablated the coating substance. From the plasma coil 4 formed in front of the target 3, the ablation components are then spun into the housing 5 to be coated, depending on the input of the energy in a more or less molecular, cluster-like or droplet-like form in the direction of the implant to be coated. The removal target - shaped body 5 is at least 40 mm. The implant 5, glass in this example, has an ampule-like shape and rotates to obtain a uniform layer thickness during the coating process about its longitudinal axis 6.

LIST OF REFERENCE NUMBERS

1 tube

2 electron beam

3 BAG target

4 plasma coil

5 shaped body, housing, implant

6 longitudinal axis

7 BAG beam pulse, ablation beam longitudinal axis

Claims

claims

Anspruch [en] A process for at least partially applying a bioactive, tissue-compatible layer to shaped articles, for obtaining a contact surface having the property of settling and spreading, proliferation, of being conducive to surrounding soft tissue body cells, characterized in that: bioactive glass BAG, in the composition area S53P4 is used as the target material, the moldings (5) are cleaned and the respective surfaces to be coated are activated with ions, the moldings (5) are exposed on an exposure table by pulsed electron beam ablation by a BAG target (3) ablated BAG jet pulse (7) are exposed, while the thermal stress due to heat of condensation during the BAG landfill on the surface of the shaped body (5) via the pulse frequency of the electron (2) and BAG beam pulse (7) is controlled except for the intended housing surfaces of the shaped body (5) a BAG layer of 1 to 10 microns thick and is so thick that in the subsequent contact with liquids ions are eluted from the depth of the BAG layer, which initiate a cell migration necessary morphological transformation of the surface, prior to implantation to avoid initial cytotoxicity of the BAG coated moldings: either at least three times a 24 hour contact with culture medium (SBL), demineralized water or 0.9% NaCl electrolyte is subjected, or a wet steam sterilization at least 134 ⁰ C for at least 13 minutes or at least 121 ⁰ C for the Duration of at least 30 minutes is suspended.

2. The method according to claim 1, characterized in that the surface to be coated of the shaped body (5) with Ar or O or N ions or otherwise suitable for the process ions or their ionic activated molecules is activated.

3. The method according to claim 1, characterized in that the implant is sterilized after at least three contact with liquids by a dry process, such as rinsing with methylene oxide gas.

4. Shaped body, which are produced according to one of claims 1 to 3, characterized in that the shaped bodies of dielectric material such as plastic, have ampoule or lens shape or form a tube or encase a wire.

5. Shaped bodies, which are produced according to one of claims 1 to 3, characterized in that the shaped bodies (5) made of glass, ceramic or metal.

6. Use of dielectric and metallic moldings according to claims 4 to 5, characterized in that the moldings are used for injection or transcutaneous / subcutaneous implantation in a living body / organism, where such with the adjoining tissue at the deposition site or at the transcutaneous entry site into the body without rejection reaction.

7. Use according to claim 6, characterized in that the shaped bodies (5) are used for diagnosis or therapy and for this purpose a diagnostic or therapeutic medium has been included.

8. Use according to claim 7, characterized in that the shaped bodies (5) are used for the physical stimulation of the body / organism / organs or for the transmission of measurement data or as a locating medium into which an electronic transponder device was previously included.