WO2021001506A1

WO2021001506A1 - Implant and method for the production thereof

Info

Publication number: WO2021001506A1
Application number: PCT/EP2020/068731
Authority: WO
Inventors: Ingo Grunwald; Dirk Salz; Sebastian Boris Hein; Kai BORCHERDING; Uwe Specht; Thomas LUKASCZYK
Original assignee: Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung eingetragener Verein
Priority date: 2019-07-04
Filing date: 2020-07-02
Publication date: 2021-01-07
Also published as: EP3993844A1

Abstract

The invention relates to an implant, comprising a plurality of openings on at least one surface, wherein the openings cause a receiving volume of > 0,1 pL/cm², preferably > 1 pL/cm², particularly preferably > 5 pL/cm², and wherein the receiving volume is filled with a matrix to 1 - 95 vol.%, preferably to 20 - 40 vol.% and the matrix is loaded with an active substance.

Description

Implant and process for its manufacture

The present invention relates to an implant comprising at least one surface with a multiplicity of openings, the openings causing a high receiving volume and this volume being partially filled with a matrix which in turn is loaded with an active substance. The invention also relates to a method for producing an implant according to the invention.

The uptake and subsequent delayed release of single or multiple liquid, viscous, powdery substances dissolved or suspended in solvents in the surface boundary layer of an implant requires a surface structure that can absorb the substances. Through the uptake, temporary storage and the targeted release of substances such as antibiotics or other antibacterial active ingredients or organisms (e.g. phages) as well as with other active ingredients (chemical or biological nature such as proteins, peptides or nucleic acids), z. B. implant-associated infections can be contained and treated more effectively at the point of origin. Surfaces in which several active substances or substances are stored have proven to be particularly efficient, as these provide a broader range of active substances. A successive release of different active ingredients, for example the release of bacteriophages in combination with a delayed release of antibiotics, has clear advantages in the treatment of infections. Bacteriophages are viruses that show rapid action against specific bacteria without harming the patient. Resistance to phages is not known. The delayed release of an antibiotic then has a prophylactic effect against non-specific postoperative infections. Such a release mechanism enables infections to be fought in a targeted manner and at the same time the amount of antibiotics used is optimally available locally. This avoids the development of resistance and side effects. If this release occurs with synergistic metals such as silver or tungsten, the effect of the antibiotic can be increased by several potencies.

An absorption of substances filtered according to size or viscosity so that these are present in spatially variable concentrations in the near-surface edge zone and are released to the environment together or with a time delay, is achieved through a special adaptation of absorbent surface structures. Alternatively, step-by-step impregnation could take place in simple surface cavities with different densities and / or solubilities of the substances. However, the latter leads to a high preparation effort.

The uptake of bone morphogenetic proteins (BMPs) represents a further possibility for using the storage properties, which in combination with stored bone substitute materials such as tricalcium phosphate or hydroxyapatite allow optimal use of the hardened microstructured surface for connection to the bone. Here, swelling substances such as alginates or hydrogels, the aforementioned substances, can fill the bone gap between the implant and the bone and represent an optimal basis for growing in / anchoring the implant. The production or deposition of special storable layers on, in particular, metallic material surfaces, can take place by means of different methods. The aim of these methods can be to create different sizes or density distributions of pores / cavities on a surface. For this purpose, pores can have a tapering opening diameter (e.g. a cone). Different substances can be separated due to their viscosity or primary particle size within the different pore sizes or by different pore diameters. The absorption capacity and delivery speed are in turn influenced by the viscosity, pore geometry and layer thickness.

Structured and storable surfaces on metallic materials can already be created during the manufacturing process of the substrate using special embossing, rolling or etching processes. Alternatively, pores can subsequently be created by depositing a coating or by removing material or by changing the structure of the boundary layer from the material itself. However, coating processes mean a phase jump in physical properties or uncontrolled inhomogeneous pore formation. Coating materials can produce pore structures by means of thermal spraying processes (e.g. flame or arc spraying). Depending on the coating material and parameters, layers with a porosity between 3% and 15% with different pore sizes can be produced in this way. Other structural shapes cannot be produced using thermal spraying processes. Since these techniques typically lead to significant thermal inputs into the substrate, they are not suitable for temperature-sensitive materials. There may be smaller pores within the large pores.

Another method is the sol-gel process. By suitably setting the reaction parameters, immersion brines can be produced which produce a porous layer with a porosity of 50% to 85% on the substrate (cf. S. Van Bael, G . Kerckhofs, M. Moesen, G. Pyka, J. Schrooten, and JP Kruth, “Micro-CT-based improvement of geometrical and mechanical controllability of selective laser melted Ti6AI4V porous structures”, Mater. Sei. Eng. A, Vol. 528, No. 24, pp. 7423-7431, Sep. 2011).

A general limitation with coatings is that there must be a good layer connection to the material, especially with mechanical loads. In contrast, structures that are created directly from the base material and additives prove to be advantageous.

In the MAO process ("Microarc Oxidation" or alternatively "Plasma Electrolytic Oxidation (PEO)"), oxide layers are built up on metallic surfaces, for example titanium or titanium alloys. With a suitable choice of the process parameters, pore structures with a pronounced aspect ratio can be created. The disadvantage of this process are the chemicals that are necessary, some of which are extremely hazardous to health, depending on the metal.

The anodizing process is also known for aluminum or aluminum alloys. Electrolytic oxidation converts the top metal layers into an open-pore oxide or hydroxide. The pores can be closed by subsequent compression, for example in hot steam or water. The use of the anodizing process is limited to aluminum. Structured surfaces, which may be suitable for the absorption of pasty substances, can also be produced by certain wet-chemical pickling processes. However, the structures typically do not have a regular shape. The process is also strictly limited to the respective substrate materials (eg aluminum alloys).

For the local structuring of metallic surfaces, laser processes, in particular using ultra-short pulse lasers in the femto- or picosecond range, have also become established. The technology enables material to be removed without significant temperature being introduced into the base material. This also allows different pore sizes to be created on one surface. In contrast to the present invention, however, the substrate material is not reshaped, but removed.

US2008216926 describes the production of nanostructures by means of a femtosecond laser. For the storage and release of substances or active ingredients, however, a nanostructured surface has proven to be insufficient. WO10130528 describes the production of microstructures by repeated treatment with a pulsed laser in the picosecond range. The method enables the creation of pores with reduced pore opening diameters (“keyholes”) or with partial overhangs at the pore opening. Structures of this kind can be used for medical implants (improved growth behavior and strength) or mechanical clasping in adhesive connections. With regard to the storage volume that can be generated, however, there are still wishes open.

US2016059353 describes a method for the production of micropores by a laser treatment below the material-specific ablation threshold (necessary energy density for material removal). The laser treatment continues (more than 1000 or 2000 times) until the pore structure is created. This type of process management leads to a low area performance of the treatment. There is no specific definition of a laser type. Treatment below the ablation threshold, however, means that only weakly pronounced structures with shallow structure depths can form (lack of material removal). Accordingly, they only have a low storage capacity for liquid or pasty media.

CN105798454 describes a structure for treating surfaces with nanosecond lasers to generate cracks in the area near the surface. Van Bael (see above) describes the creation of pores of different sizes in bone cements. These should be able to absorb and release antibiotics close to the surface.

The documents described above in the laser sector mainly relate to lasers with ultra-short pulses in the picosecond or femtosecond range. These systems can be used to create defined structures without any significant thermal input on the surrounding material. Disadvantages are the comparatively high investment costs and the low realizable area rate. In addition, layers close to the surface and heavily structured, which were produced from a metallic base material, typically have only low mechanical resistance.

Against the background of the prior art, it was the object of the present invention to provide an implant which, due to its structure, is not only able to absorb relatively large amounts of active ingredient, but that can also ensure a differentiated release of active ingredients. The corresponding implant should preferably be able to be produced with relatively few work steps and, if possible, be accessible to the implant surface without complex coating processes.

This object is achieved by an implant comprising a plurality of openings on at least one surface, the openings causing a receiving volume of> 0.1 pL / cm ² , preferably> 1 pL / cm ² , particularly preferably> 5 pL / cm ² and where the receiving volume is 1 to 95% by volume, preferably 20 to 40% by volume, filled with a matrix and the matrix is loaded with at least one active ingredient.

Ways to produce an implant according to the invention are given below.

The wording that the “openings require a receiving volume” means, in connection with the present invention, that the respective openings make the said receiving volume accessible, for example for filling processes. This receiving volume is defined by the depressions in the surface.

An active ingredient within the meaning of the present invention is a substance which is intended for use in or on the human or animal body and is intended as a means with properties for healing or alleviating or preventing human or animal diseases or pathological complaints or which is in or on the human or applied to the animal's body or administered to a human or animal can either to restore, correct or influence the physiological functions through a pharmacological, immunological or metabolic action. An active ingredient in the context of the present invention is in particular a substance which, after the implantation of the implant, brings about a (targeted and intended) physiological effect, preferably for better tolerance of the implant in the body.

For the definition of the intake volume, reference is made to the explanations below.

For the purposes of the present invention, a matrix is at least one substance in which at least one active ingredient can be dissolved and / or suspended and / or in particular an open-pored organic or inorganic network which, in the present case, fills part of the receiving volume. In particular, for the purposes of the present invention, the matrix is preferably able to chemically or physically bind active substances in the context of the present invention to its material surface (that is also to the surface of pores or channels). It is of course preferred that this bond be released again under physiological conditions, that is to say the conditions under which the respective implant is implanted in the body. The matrix is preferably not an active ingredient for the purposes of this invention, that is to say in particular not an antibiotic (preferably gentamicin, meropenem, imipenem, ceftriaxone, cefepime, vancomycin, teicoplanin, clindamycin, spiramycin, piperacillin, amoxicillin, flucymloxacillin, penicillin B, policillin G, polycillin , Levofloxacin, sulfadiazine, minocycline, rifampicin, tazobactam), no cytostatic, no immunotherapeutic (especially monoclonal antibody, fusion protein, soluble cytokine receptor, recombinant cytokine, small molecule mimetic), no cartilage, no blood cells and no cells, no cells; no cartilage tissue, no precursor cells, no bone cells (especially osteocytes, osteoblasts), no skin cells, no antimicrobial peptides or proteins (especially collagen), no bone morphogenetic proteins such as BMP1, BMP2, BMP3, BMP4, BMP5, BMP6, BMP7, BMP8A, BMP8 BMP10, BMP15, GDF10, no antivirals, no bacteriophage, no metal compounds made from gold, silver, zinc, platinum or copper (especially their nitrates, carbonates, acetates and chlorides) and no antiseptics (especially chlorhexidine gluconate, cetylpyridinium chloride, cety I pyride) iniu mch ioride, hexetidine; ammonium compounds, especially methacrylamidopropyltrimethylammonium chlorides and povidone iodine).

The person skilled in the art understands that within the meaning of the present invention there is always a matrix and an active substance physically or chemically bound to this (including dissolved, suspended), active substance and matrix being different substances. The implant according to the invention has the advantage that, on the one hand, it has a relatively high intake volume, but on the other hand, the presence of a matrix within this intake volume allows the release behavior of the active substance to be adjusted in a targeted manner. The correspondingly high receiving volume can be generated particularly well by the method according to the invention described below.

The determination of the intake volume and the matrix volume proportions is described below:

In case of doubt, the measurement of the uptake volume and the matrix volume takes place on the basis of sections of the sample.

Step 1: First, the sample is embedded, e.g. using an investment material, often a reactive casting resin, so that the wells and the filled matrix can be prepared without damage.

Step 2: In order to exclude symmetry-related artifacts when determining the uptake volume and the matrix volume on the substrate surface, p (n) sections of the sample are made, the sections being at an angle of 1807 p (n) to one another. Here p (n) is a prime number from the sequence of prime numbers with n> 4. With 7 cuts, the cuts would be at an angle of ~ 25.7 ° to each other. The cut surfaces are polished for better microscopic evaluation. Each cut at a certain angle must preferably have at least 20 openings. If necessary, several cuts can be made on a substrate at the same angle for this.

The graphic conditions for the recording volume definition and for further definitions are explained with reference to FIG. 1 shows a schematic drawing of the surface structure with a matrix of an implant according to the invention. The reference symbols have the following meaning:

According to FIG. 1 it can be seen that, if there is an opening at the point to be examined, a circle with a radius of 3 mm is graphically inserted over this opening so that this circle is exactly twice (once on each side of the opening. tion) touches the implant according to the invention (contact points A1).

The secant (Sei) running through these two points of contact then represents the plane of contact for the respective opening and thus the limitation of the receiving volume to the outside for the determination of the receiving volume. The connection of the individual contact points A1 along the secants Sei lying between the adjacent contact points A1 results in the enveloping E1, which thus defines the entire contact plane and the delimitation of the receiving volume.

In FIG. 1 it can also be seen that a matrix M1 is present within the receiving volume. In addition, V1 represents the depth of the respective structure; this is the vertical line below the envelope of the respective depression structure that has the longest stretch.

Step 3: The evaluation of the sections provides the sum of the area (in pm ² ) of the depressions below the contact plane, along the envelope egg. Furthermore, the sum of the area of the matrix below the contact planes along the envelope is determined on the cuts. If microscopic images do not provide sufficient contrast, EDX (EDX: energy dispersive X-ray spectroscopy) images can be used, for example. If the cuts are made obliquely into the substrate, that is to say that the cutting plane does not lie in the plane parallel to the normal to the surface of the plane of contact, must the cutting planes are viewed in such a way that they provide a projection onto the plane that is parallel to the surface normal of the plane of contact.

Step 4: From the quotient of the area of the depressions Av divided by the length of the envelope L, converting the units results in the equivalent numerical value of the receiving volume per area, which is equivalent to the mean depression <l> per area or per length.

Absorption volume / area [m ³ / m ² ] = Av / L [m ² / m] = <l> [= [m]

From the quotient of the area of the matrix AM divided by the length of the envelope L, converting the units results in the equivalent numerical value of the matrix volume per area.

Matrix volume / area [m ³ / m ² ] = AM / L [m ² / m]

The smallest and the largest measured value are discarded. The mean value of the filling volumes and the mean value of the matrix volumes are determined from the remaining five measured values. The matrix volume fraction results from the ratio of the matrix volume to the recording volume. The filling volume results from the subtraction of the matrix volume from the receiving volume.

Then the measurement is repeated from step 1 with the next higher prime number p (n + 1) from the prime number sequence, for example 11 sections at an angle of 180 ° divided p (n + 1) or by 11. If the deviation of the determined filling volume per area (in L / cm ² ) or the matrix filling proportion (in%) with p (n) and p (n + 1) sections, e.g. 7 sections and 11 sections, is greater than 15% apart, the measurement is repeated with a greater number of cuts. If the measurement deviation of the mean values from the n + 1 and n + 2 sections is below 15%, these measurement results are used to determine the well volumes per area and the matrix volume parts. According to the invention, it is preferred that the implant according to the invention has a multiplicity of openings in the area of the surface, these openings causing a depth of> 5 μm, preferably> 50 μm and particularly preferably> 100 μm. How the depth (under the openings) is measured can be seen from the description given above. This depth ensures that a large receiving volume is available, which also means that there is sufficient space for the matrix and also for a matrix-free space, the filling volume.

For the purposes of the present invention, it is preferred that the uptake volume is 1 to 95% by volume, preferably 15 to 60% by volume, and particularly preferably 20 to 40% by volume, filled with the matrix.

To determine the matrix-filled portion of the receiving volume, reference is also made to the description above, while reference is made to the description below for the possibility of introducing the matrix into the implant according to the invention. In the case of an implant according to the invention, it is preferred that the matrix comprises or consists of a material selected from the group consisting of hydrogel; Oleogel; Emulsion gel; Thermogel; Alginate; (Poly) sugar; Polylactite; Hyaluronic acid; Heparin; Protein especially collagen; Titanium dioxide; Zinc oxide; Silver oxide; Fat especially palmitate; Silicon dioxide; Plasma polymer comprising silicon and / or carbon; Peptide; Nucleic acid; Lipid; Lignin; Silicone; Bone substitute material; in particular human bones, bone material obtained from animal or vegetable material, synthetic bone materials such as PMMA, bioactive glass; Calcium carbonate; Calcium sulfate; Tricalcium phosphate; Tryglyceride; Hydroxyapatite; Glass ceramic; Chitosan; Strength; Polyurethane; Mucin; Chitin; Zinc oxide); Tin titanium oxide and zirconium oxide and mixtures thereof. Also preferred according to the invention is an implant in which the active ingredient loading the matrix is selected from the group consisting of antibiotics (preferably gentamicin, meropenem, imipenem, ceftriaxone, cefepime, vancomycin, teicoplanin, clindamycin, spiramycin, piperacillin, amoxicillin, flucloxacillin, G , Polymyxin B, ciprofloxacin, levofloxacin, sulfadiazine, minocycline, rifampicin, tazobactam; cytostatic; immunotherapeutic, in particular monoclonal antibodies, fusion protein, soluble cytokine receptor, recombinant cytokine, small molecule cells, tissue precursors and cartilage cells; , Bone cell, in particular osteocyte, osteoblast; skin cell; antimicrobial peptide, protein, in particular collagen; bone morphogenetic protein such as BMP1, BMP2, BMP3, BMP4, BMP5, BMP6, BMP7, BMP8A, BMP8B, BMP10, BMP15, GDF10 from antiviral agent; Bakteri Gold , Silver, zinc, platinum or K copper especially their nitrates; Carbonate; Acetate; Chloride; and antiseptic, especially chlorhexi- dingluconate, cetylpyridinium chloride, cetyl pyridinium chloride, hexetidine; Ammonium compounds, especially methacrylamidopropyltrimethylammonium chlorides and povidone iodine.

It is particularly preferred that the active ingredient is selected from the group consisting of bone morphogenetic protein, blood product, cell (tissue and in particular cartilage cell, precursor cell, bone cell and phage.

The person skilled in the art will adapt the selection of the matrix to the particular application. So an example - depending on the active ingredient to be used with which the matrix is to be loaded - in the event that a slow release of the active ingredient with which the matrix is loaded is desired, use a matrix that has a relatively firm connection of the active substance itself is guaranteed, in particular under the conditions that exist in the intended use of the implant.

Of course, there is also the possibility of using a matrix with suitable solubility so that the release of the active ingredient is actually determined by the dissolution process of the matrix.

An implant according to the invention is preferred in the present invention, the implant comprising a second active ingredient in the depressions.

In this context, it is particularly advantageous that there are actually two compartments within the receiving volume, namely on the one hand the matrix and on the other hand the unfilled receiving volume (filling volume) which is available for receiving, for example, the second active ingredient. Accordingly, it is preferred according to the invention that the second active ingredient is not bound to the matrix, that is to say that the matrix is not loaded with this second active ingredient.

This configuration makes it possible to set up an interaction between two active ingredients. For example, it is preferred according to the invention that the second active substance, under the condition of the implanted state of the implant, has a higher release rate than the active substance bound to the matrix. For example, it is possible to use those active ingredients as the second active ingredient in which they are to develop their effects immediately after implantation, for example anti-inflammatory active ingredients, while the active ingredients bound to the matrix (the active ingredients with which the Matrix is loaded) a later release should develop, for example to promote the ingrowth process. With a suitable configuration of the matrix, it is even possible that active substances which would hinder each other in their respective effectiveness are released one after the other in such a way that precisely this undesirable effect does not occur. In this context, it is preferred that the second active ingredient is selected from the group consisting of antibiotics (preferably gentamicin, meropenem, imipe nem, ceftriaxone, cefepime, vancomycin, teicoplanin, clindamycin, spiramycin, piperacillin, amoxicillin, flucloxacillin, penicillin G, polymyxin B, ciprofloxacin, levofloxacin, sulfadiazine, minocycline, rifampicin, tazobactam; cytostatic; immunotherapeutic, in particular monoclonal antibody, fusion protein, soluble cytokine receptor, recombinant cytokine; blood products; blood products; blood products; Cartilage tissue, precursor cells, bone cells, especially osteocytes, osteoblasts; skin cells; antimicrobial peptide, protein, especially collagen; bone morphogenetic protein such as BMP1, BMP2, BMP3, BMP4, BMP5, BMP6, BMP7, BMP8A, BMP8B, BMP10, BMP15; Virikum; Bacteriophage; Metal compounds made from gold, silver, zinc, platinum or copper, in particular their Nitrates; Carbonate; Acetate; Chloride; and antiseptic, in particular chlorhexidine gluconate, cetylpyridinium chloride, cetylpyridinium chloride, hexetidine; Ammonium compounds, in particular methacrylamidopropyltrimethylammonium chlorides and povidone iodine. It is particularly preferred that the second active ingredient is selected from the group of antibiotics, antiseptics, metal compounds, cytostatics; Immunotherapeutics. In addition or as an alternative, the second active ingredient is selected from the group consisting of phage, virus, fungus and cell.

An implant according to the invention is preferred, the surface with a large number of openings consisting of a material selected from the group consisting of titanium or titanium alloys, titanium-nickel alloys, stainless steel, magnesium, steel, magnesium or magnesium alloys, polymers, in particular PTFE, PET, PMMA, PE, PEEK, PEKK, PEAK, Teflon, fiber composite materials and bone material and preferably the material is the same as the basic material of the implant or from which the basic material of the implant was created.

In this context, the basic material of the implant is the material of which the implant is mainly made. It is therefore preferred that the zone of the implant which comprises the receiving volume consists directly of the base material of the implant or at least was produced from this base material in a suitable process. A preferred base material is metal or the aforementioned metal alloys, in particular titanium, titanium alloys, stainless steel, magnesium or magnesium alloys. With a suitable method (see below) it is possible to create the zone with the receiving volume from the base material of the implant. This can of course lead to changes in the base material, such as changes in grain sizes and crystallinity.

In principle, however, it is also possible to generate the receiving volume, the base material being a polymer, for example by choosing a suitable method so that the upper layer of the polymer behaves like a foam.

According to the invention, an implant according to the invention is preferred in this context, wherein at least part of the receiving volume represents a channel or a part of the channel which is completely or partially open to the surface, the cross section of the channel having a local maximum width between the channel bottom and the contact plane, on the perpendicular section to the surface, measured parallel to the plane of contact and perpendicular to the longitudinal axis of the duct.

Such channels can not only provide a large absorption volume, they can also be designed in such a way that the opening of these channels is located at certain points on the implant, with a local release maximum also being able to be generated within the implant surface.

The generation of such channels is described in detail in the German patent application with the official file number 102018133553.9, the description parts of this application, provided they concern the generation of corresponding channels, becoming part of the present application by reference.

Preferred implants according to the invention comprise a concentration of openings in the range of 4 to 10 ⁶ openings per cm ² , preferably 100 to 10 ⁵ openings per cm ² and particularly preferably 1000 to 10 ⁴ openings per cm ² on the at least one surface. Part of the invention is a method for producing an implant according to the invention, comprising the steps of a.) Providing a basic implant body, b.) Generating the openings and the receiving volume, as defined above for the implants according to the invention, on at least one surface of the basic implant body, c .) Filling the receiving volume with a matrix, as defined above for the implants according to the invention, and d.) Loading the matrix with an active ingredient.

The method according to the invention thus includes in a step b.) The generation of the receiving volume, which is preferably carried out by substrate reshaping, particularly preferably by substrate reshaping by means of a laser.

In step c.), Part of the receiving volume is filled with matrix material which, for example, has small pores and / or a different physical and / or chemical bonding behavior than the rest of the receiving volume surface, in particular with respect to the active ingredient to be loaded in step d.) .

According to the invention, it may be preferred before step c.) Or after step c.) To treat the surface of the implant, in particular in the area of the receiving volume, preferably with a plasma-based treatment, in particular a plasma polymer coating, for example by incorporating silver and / or tungsten in the corresponding coatings to achieve a synergetic effect on antibacterial surfaces.

It is preferred according to the invention that the base body of the implant according to the invention or the base material of the implant according to the invention is a metallic material. In a preferred method according to the invention, in step b.), The metallic material is treated with continuous (CW), quasi-continuous (QCW) or laser radiation pulsed in the nanosecond range, which leads to melting of the substrate material leads. By repeatedly and directly successive irradiation of the same treatment area (spot area) with a large number of laser pulses with a high pulse repetition frequency (kHz range), the melted material zone is displaced to the edge area of the laser interaction zone by the convection currents formed therein and by gas phase expansion, so that Craters or pores arise. These primary pores form the receiving volume and, on the one hand, have the function of receiving matrix materials; on the other hand, if they are not completely filled with matrix material, these primary pores offer a filling volume that can accommodate further active ingredients (second active ingredient). These active ingredients are protected from dripping or shearing off by the primary pores.

The rasterization of the implant surface with the laser beam (e.g. using suitable scanning optics) can be used to produce surfaces with a regular structure. The shape, size and density of the structures created depends primarily on the fluence (energy density), the pulse repetition frequency, the number of pulses per treatment site and the pulse overlap. Depending on the choice of parameters, the resulting areas can consist of separated and therefore non-connected pores with overhangs at the pore opening as well as more complex-shaped structures. The pulse overlap of the laser treatment can be selected in the preferred direction in such a way that the individual treatment areas strongly overlap. The result is a series of cavities along the scanning direction, which are connected to one another under the surface and largely closed by the laser-induced overhangs. These cavities have openings in which media can be taken up at regular intervals.

In the case of metals or metal alloys in particular, the laser-induced temperature input causes not only pore formation but also a change in the microstructure in the material surrounding the structures. The microstructure is homogenized, which leads to increased corrosion stability (e.g. with titanium or steel). In addition, the brief thermal input followed by rapid solidification leads to an adjustable increase in mechanical strength of the material. Comparable effects are not to be expected in the case of ultrashort pulse lasers due to the lower thermal input, which clearly emphasizes the preferred product according to the invention from the prior art. Compared to the generation of structures using ultrashort pulse lasers, the preferred method described also has the advantage of being implemented using a more cost-effective laser Systems. Since very high powers are required for the evaporation, the creation of deep pores in the pm range with an ultrashort pulse laser also requires a great deal of time.

The preferred laser method can in principle be used on all metallic materials, as long as they form a melt phase under laser irradiation. The emitted wavelength of the laser source used is not restricted. However, this is preferably a wavelength and pulse duration which lead to a thermal interaction on the material. They are particularly preferably lasers in the near (fiber or Nd: YAG laser) or medium IR range (CO2 laser) with pulse durations greater than or equal to the ns range (> 1 ns). The fluence hitting the surface must be sufficiently high to generate a melt front.

The receiving volumes produced in step b.) Can be filled with substructures (matrix). The matrix defines a volume below the original volume.

FIG. 2 shows, by way of example, the schematic structure of the described recording volumes and matrix on the substrate surface, the structures according to the invention not being restricted to these geometries.

FIG. 2 schematically shows the surface structure of an implant according to the invention. The reference symbols denote

1 intake volume 3 matrix

5 the structure of the substrate material changed by introducing the receiving volume

7 substrate material

In addition to the storage and release capacity of the matrix, the matrix materials can be equipped with functions, e.g. by using tricalcium phosphate (TCP) as the matrix material. TCP is a bone-like mineral that is attached to bone-forming cells can adhere and proliferate. Since such a natural bone structure is formed in the receiving volume, there is a stable form fit between the bone and the implant for a firm integration of permanent implants.

Furthermore, the properties of the exposed surface of the openings can be designed differently from those of the matrix material. The different material properties of the matrix and the material forming the receiving volume can be decisive for this; alternatively, local coatings can also be used. For example, layers containing silver can be deposited on the surfaces. The surface properties can differ in terms of their topography or chemical composition, for example.

Examples of preferred matrix materials:

- Gel formers: agar / carbohydrates / mucins / unmodified and modified starch and cellulose, in particular methyl cellulose / sucrose / polylactite / PMMA / tricalcium phosphate powder or suspended particles, which are then sintered to form open foams or produce one with a binder.

- Mixtures of a matrix-forming filler (e.g. metal powder) and thermally or chemically degradable auxiliaries to form open pores. Here, after the matrix particles have sintered, the auxiliary substance is released again, so that open cavities result (e.g., open-pored metal, polymer or ceramic foams). - Electrochemical approaches for layer generation with pore formation, e.g. MicroArc Oxidation (MAO) [3], anodization process e.g. chromic acid anodization on titanium.

- Gas phase deposition of TTIP foams

- Wet chemical approaches:

+ Sol gel process e.g. poly (e-caprolactam) and hydroxyapatite coatings

+ Tricalcium phosphate (TCP) in a calcination reaction (NH4) 2 (HP04) and Ca (NQ3) * 24 H20))] within the pores. In general, it is thus possible to design the implant according to the invention in such a way that a controllable and longer-lasting release of the active substances stored in the receiving volume can be ensured. For this purpose, with a suitable design of the manufacturing process, increased mechanical resistance of the surfaces can also be achieved, in particular when the metal surfaces are treated with laser.

The matrix used can be used to control the rate of release of an active ingredient. In a preferred variant according to the invention of the implant according to the invention, however, it is also possible to design the matrix in such a way that active substances are bound to it, which are later released as other active substances (here the second active substances). The temporal control of the active ingredient release is possible in the context of this invention both through the selection of the suitable substrate materials for generating the volume, the shape and shape of the volume-forming pores as well as through the appropriate selection of matrix materials the view of the active ingredients to be used will be taken.

In addition, it is possible to further control the release behavior through the distribution of the openings as well as through the opening geometries produced and, if necessary, specially produced surface properties. In a preferred method according to the invention, it is possible to produce the receiving volume from the base material of the implant in a one-step process. Because the matrix material is arranged within the receiving volume, it is protected from being washed out or from mechanical stress such as shearing off.

The invention is explained in more detail below using examples.

Examples

Example 1 (L2):

Generation of the recording volume Substrate: titanium alloy Ti6AI4V Laser parameters L2: Nd: YAG laser; Wavelength = 1064 nm; Pulse duration = 199 ns; Focus diameter (1 / e ² ) = 107 gm; Average power = 100 W; Pulse repetition rate = 200 kHz; Repetition rate pulses per area = 20; Grid spacing in x-direction = 0.106 mm; Grid spacing in y-direction = 0.053 mm; Fluence = 5 J / cm ²

Laser used: CL100 (company CleanLaser) with 2D scanner (Stamp 10 series) and f-theta lens with a focal length of f = 330 mm. In this laser treatment, the sample rasterization was carried out in such a way that only 20 pulses were applied to a point before the laser spot was placed at the next, neighboring point.

Morphology L2:

- Surface with pores (receiving volume) along the laser scanning direction with an average pore opening diameter of 100 gm; - Cross-section of the sample, perpendicular to the laser direction with vase-like structures and overhangs or pores.

- Connected cavernous pore openings along the y-scan direction

- Structural changes due to laser-induced remelting and rapid solidification at a depth of approx. 300 gm, including unaffected bulk material, absorption capacity L2: water = 3.0 ± 0.3 gL / cm ²

Hardness measurement L2: Hardness measurements and measurements of the modulus of elasticity show that the generated edge zone with pores shows no change in hardness or modulus of elasticity.

Activation effect L2: The laser-treated surfaces are hydrophilic after the laser treatment (step I). The uptake volume of 3.0 pL / cm was confirmed with the aid of the determination method described above by means of grinding. For the metallographic investigation, the sample was embedded in a transparent epoxy resin matrix (Epofix from Struers) so that there is sufficient microscopic image contrast to the substrate material. This was followed by seven metallographic grinding of the sample, parallel to the surface normal (polishing bench: Rotopol 4), preparation: ground with SiC paper and then polished out ([diamond, silicon oxide]). The seven cuts were made at an angle of 0 °; 26 °; 51 °; 77 °; 103 °; 128.5 ° and 154 ° around the plumb points of the surface normal. Each section was analyzed with a digital microscope (manufacturer Key e nee) at a magnification of 300x.

The microscopic images were evaluated with the image processing software ImageJ. For this purpose, a circle with a 3 mm radius was first inserted into the microscopic image above the depressions. Wherever the circle has two points of contact with the substrate surface, points of contact were inserted into the images. The adjacent points of contact were connected to form the envelope and the length determined with ImageJ was noted. Sufficient microscopic images were analyzed under each cut angle that a total of at least 20 wells were examined. The total area of the depressions was determined using ImageJ and divided by the respective length of the envelope so that the average depression length or, by conversion, the average volume under the various angles results.

To validate the results, a further 11 sections were produced and analyzed, the sections being in angular segments of 0 °, 16 °, 33 °, 49 °, 65 °, 82 °, 98 °, 115 °, 131 °, 147 °, and 164 ° were generated around the surface normal. To determine the mean recording volume, the largest and smallest measured values were deleted and the mean value of the remaining 5 or 9 micrographs was determined.

Table 1: Acquisition volume based on the sections in 25.7 ° steps or 16.4 ° steps around the surface normal

The measurements on the basis of the seven sections resulted in an absorption volume of 3.18 gL / cm ² , or on the basis of the eleven sections of 3.09 gL / cm ² . The error between the two measurements is 3%, less than 15%, so that the filling volume of the sample is 3.1 gL / cm.

Example 2 (L17): Influence of the focus diameter:

Substrate: titanium alloy Ti6AI4V

Laser parameters L17: Nd: YAG laser; Wavelength = 1064 nm; Pulse duration = 199 ns; Focus diameter (1 / e ² ) = 52 gm; Average power = 30 W; Pulse repetition rate = 200 kHz; Repetition rate pulses per area = 15; Grid spacing in x-direction = 0.052 mm; Grid spacing y-direction = 0.026 mm; Fluence = 7 J / cm ² .

Laser used: CL100 (company CleanLaser) with 2D scanner (Stamp 10 series) and f-theta lens with a focal length of f = 330 mm.

In this laser treatment, the sample rasterization was carried out in such a way that only 15 pulses were applied to a point before the laser spot was placed at the next, neighboring point. Example 3 (L3.1-3): Influence of the energy density / fluence on the pore size

Substrate: steel 316L

Laser parameters: Nd: YAG laser; Wavelength = 1064 nm; Focus diameter (1 / e ² ) = 107 gm; Average power = 100 W; Repetition rate pulses per area = 50; Grid spacing in x direction = 0.106 mm; Grid spacing in y-direction = 0.053 mm

In this laser treatment, the sample rasterization was carried out in such a way that only 20 or 26 pulses were applied to a point before the laser spot was placed at the next, neighboring point.

Table 2 shows the greater the fluence or the energy entered, the greater the intake volume.

Table 2: Influence of the fluence on the intake volume

Example 4: Matrix made of tricalcium phosphate (TCP)

Substrate: Ti6Al4V In the substrate treated according to Example 1, a TCP matrix was introduced into the wells by applying a suspension of TCP nanoparticles (<100 nm; TCP: tricalcium phosphate) in ethanol followed by a drying step. The TCP nanoparticles (American Elements) were dispersed with 20% by weight in ethanol. The dispersion was first mixed with a magnetic stirrer for 10 minutes. This suspension was then placed in an ultrasonic tank for 10 min to break up agglomerates. The samples from Example 1 were filled in the suspension within 3 minutes of the application of ultrasound using an immersion process for 30 seconds. The samples were then dried at 50 ° C. for 30 minutes in order to evaporate the ethanol. Loose particles near the surface were cleaned off by laser (CL100 with Stamp 10 optics and f-theta lens with 330 mm focal length; pulse repetition frequency 200 kHz; average power 30 W; 200 ns; meandering with 50% pulse overlap; Gaussian profile with 3 J / cm ² ) from removed from the surface. The mass increase of the samples was 0.3 mg / cm ²

(Fine balance)

The samples were then fixed in the investment material as in Example 1 and prepared in seven sections, each rotated by 25.7 ° around the surface normal (angle of the individual sections: 0 °; 26 °; 51 °; 77 °; 103 °; 128, 5 ° and 154 °). The evaluation of the areas of the TCP matrix in the depressions in the microscope in relation to the envelope resulted in a filling volume of 0.08 pL / cm ² .

According to the determination according to Example 1, the matrix accounted for 3% of the absorption volume.

Example 5: Determination of the recess volume and the matrix volume of the surface Production of the surface recesses:

2 cm by 2 cm stainless steel (316L) flat substrates were used as the substrate starting material. Surface depressions were created with a laser. The following laser system with the parameters shown in the table was used for this: Laser: 100W Nd: YAG laser (type CL100 from CleanLaser, Herzogenrath, Germany with stamp optics and f (330) and f (160) f-theta lens

Determination of the recess volume of the surface:

Preparation: About 100 μl of water were pipetted onto the laser-treated samples. The resulting miniscus on the surface was then removed with a lint-free cloth. To do this, a 4-fold Kimwipe cloth (Kimberly Clark 7552, Kimtech Science Precision Cloths) is pressed onto the surface for one second. The increase in mass of the samples, based on the treated and wetted area, was then determined with a precision balance (difference between the mass before and after filling). Accordingly, the surface has an absorption capacity of 4.7 ± 0.6 mg / cm ² (mean value and standard deviation from five individual measurements). The density of the water (calculated with 1g / cm ³ ) results in a pore volume of PV = 4.7 pl / cm ² .

This was verified with the volume measurement using the grinding technique as described in Example 1.

Matrix filling The surface depressions were filled with the matrix tricalcium phosphate (TCP) in a dipping process. A dispersion of 5 g of tricalcium phosphate (American Elements, Prod. Code. CA-PAT-01-NP.100N, nanopowder d <100 nm, typically d = 20 ~ 40 nm, density = 3.14 g / cm ³ ) made with 25 ml of ethanol. The steel sheets with depressions were stored in this solution for 5 minutes. The samples were then dried in an oven at 50 ° C. for 30 minutes. The subsequent weighing of the filled samples resulted in a matrix uptake of 3.1 ± 0.25 mg / cm ² or a matrix volume of MV = 1.0 ± 0.1 mI / cm ² (mean values and standard deviations from five individual measurements). This results in a filling volume of the depressions in the steel surfaces with the matrix of tricalcium phosphate of 21% by volume.

The above value was also verified with the volume measurement using the grinding technique as described in Example 1. Example 6: Double active ingredient filling and dispensing

Sample preparation:

2 cm by 2 cm Ti6Al4V flat substrates were used as the substrate starting material. Surface depressions (receiving volumes) were created with a laser. The following laser system was used for this with the parameters shown in the table:

Laser: 100W Nd: YAG laser (type CL100 from CleanLaser, Herzogenrath, Germany with stamp optics and f (330) and f (160) f-theta lens

Determination of the uptake volume of the surface: Preparation: About 100 μl of water were pipetted onto the laser-treated samples. The resulting miniscus on the surface was then removed with a lint-free cloth. To do this, a 4-fold Kimwipe cloth (Kimberly Clark 7552, Kimtech Science Precision Cloths) is pressed onto the surface for one second. The increase in mass of the samples, based on the treated and wetted area, was then determined with a precision balance. Accordingly, the surface has an absorption capacity of 12 ± 2 mg / cm ² (mean value and standard deviation from five individual measurements). over the density of the water (calculated with 1 g / cm ³ ) results in a pore volume of PV = 12 mI / cm ² .

This was verified with the volume measurement using the grinding technique as described in Example 1. The surface depressions of the titanium substrates were first filled with 30 ml of a solution of sucrose, water and methylene blue (49.96% by weight water, 49.96% by weight sucrose, 0.08% by weight methylene blue) using a pipette. The samples were then dried (80 ° C. for 60 min. In a convection oven) and the increase in mass was determined using a fine balance. The subsequent weighing of the filled samples resulted in a sucrose matrix uptake of 4.6 mg / cm ² , or a matrix volume of MV = 2.9 ml / cm ² . This results in a filling of the steel surfaces with depressions with a matrix of sugar of 24 vol .-%. This value was also verified with the volume measurement using the cutting technique as described in Example 1. This matrix contains 7 pg / cm ^{2 of} the active ingredient substitute methylene blue. An unfilled polylactide (PLA) matrix was applied to the sucrose matrix in order to delay the later release of the active substance substitute methylene blue. To this end, 50 ml of a solution of PLA and dichloromethane (10% by weight PLA in 90% by weight dichloromethane) were pipetted onto the samples. The samples were then dried (80 ° C. for 60 min. In a convection oven) and the increase in mass was determined using a fine balance. The subsequent weighing of the filled samples gave an area-related PLA matrix uptake of 1.6 mg / cm ² , or a matrix volume of MV = 1 mI / cm ² . This corresponds to a proportion of the intake volume of 8.3% by volume. This value was also verified with the volume measurement using the cutting technique as described in Example 1.

The active ingredient substitute methyl orange in a suspension of ethanol 98.8% by weight and 0.2% by weight methyl orange was applied to the char matrix. For this purpose, 20 ml of this solution were pipetted onto the samples. The samples were then dried (80 ° C. for 60 minutes in a convection oven).

Measurement of the release of the active ingredients

The release of the active substance was verified by means of time-resolved UV-VIS spectroscopy. For this purpose, the 316L steel samples loaded in the steps were placed in a cuvette with 8 ml of isotonic saline solution (9 g / l). The absorption measurements of the light, at The characteristic 400 nm for methyl orange and 520 nm for methylene blue show in Figure 1 that the sample first releases methyl orange and with a time delay methylene blue into the saline solution.

The results are shown in FIG. 3: Time-resolved UV-VIS spectroscopy for measuring the light absorption of methylene blue and methyl orange in 8 ml of isotonic saline, released from the surface depressions of a 316L steel plate with a sucrose matrix with methylene blue, a time lag layer made of PLA and methyl orange .

Claims

Patent claims:

1. An implant, comprising a plurality of openings on at least one surface, the openings causing a receiving volume of> 0.1 pL / cm ² , preferably> 1 pL / cm ² , particularly preferably> 5 pL / cm ² , and wherein the receiving volume is 1 - 95% by volume, preferably 20 - 40% by volume filled with a matrix and the matrix is loaded with an active ingredient.

2. The implant according to claim 1, wherein the openings require a depth of> 5 pm, preferably> 50 pm, particularly preferably> 100 pm deep.

3. The implant according to claim 1 or 2, wherein the matrix comprises or preferably consists of a material selected from the group consisting of hydrogel; Oleogel;

Emulsion gel; Thermogel; Alginate; (Poly) sugar; Polylactite; Hyaluronic acid; Heparin; Protein especially collagen; Titanium dioxide; Zinc oxide; Silver oxide; Fat especially palmitate; Silicon dioxide; Plasma polymer comprising silicon and / or carbon; Peptide; Nucleic acid; Lipid; Lignin; Silicone; Bone substitute material; in particular human bones, bone material obtained from animal or vegetable material, synthetic bone materials such as PMMA, bioactive glass; Calcium carbonate; Calcium sulfate; Tricalcium phosphate; Tryglyceride; Hydroxyapatite; Glass ceramic; Chitosan; Strength; Polyurethane; Mucin; Chitin; Zinc oxide); Tin titanium oxide and zirconium oxide and mixtures thereof.

4. Implant according to one of the preceding claims, wherein the active ingredient loading the matrix is selected from the group consisting of antibiotics (preferably

Gentamicin, Meropenem, Imipenem, Ceftriaxone, Cefepime, Vancomycin, Teicoplanin, Clindamycin, Spiramycin, Piperacillin, Amoxicillin, Flucloxacillin, Penicillin G, Polymyxin B, Ciprofloxacin, Tazobycin, Razifloxacin, Sulfocadlin; Cytostatic agent; Immunotherapeutic in particular monoclonal antibody, fusion protein, soluble cytokine receptor, recombinant cytokine, small molecule mimetic; Blood: blood products; Cell; Tissue and in particular cartilage cells; Cartilage tissue, precursor cells, bone cells, in particular osteocytes, osteoblasts; Skin cell; antimicrobial peptide, protein in particular collagen; bone morphogenetic protein such as BMP1, BMP2, BMP3, BMP4, BMP5, BMP6, BMP7, BMP8A, BMP8B, BMP10, BMP15, GDF10; Antiviral; Bacteriophage; Metal compounds made from gold, silver, zinc, platinum or copper, in particular their nitrates; Carbonate; Acetate; Chloride; and antiseptics, in particular chlorhexidine gluconate, cetylpyridinium chloride, cetylpyridinium chloride, hexetidine; Ammonium compounds, especially methacrylamidopropyltrimethylammonium chlorides and povidone iodine.

5. Implant according to one of the preceding claims, wherein the implant comprises a second active substance in the depressions.

6. The implant according to claim 5, wherein the second active substance has a higher release rate than the active substance bound to the matrix under conditions of the implanted state.

7. Implant according to claim 5 or 6, wherein the second active ingredient is selected from the group consisting of antibiotic (preferably gentamicin, meropenem, imipenem, ceftriaxone, cefepime, vancomycin, teicoplanin, clindamycin, spiramycin, piperacillin, amoxicillin, flucloxacillin, penicillin, Polymyxin B, ciprofloxacin, levofloxacin, sulphadiacin, minocycline, rifampicin, tazobactam; cytostatic; immunotherapeutic, in particular monoclonal antibodies, fusion protein, soluble cytokine receptor, recombinant cytokine, blood products, cartilage and especially cartilage; Precursor cell, bone cell in particular osteocyte, osteoblast; skin cell; antimicrobial peptide, protein in particular collagen; bone morphogenetic protein such as BMP1, BMP2, BMP3, BMP4, BMP5, BMP6, BMP7, BMP8A, BMP8B, BMP10, BMP15, GDF; Metal compound made of gold, silver, zinc, platinum or copper, in particular their nitrate e; Carbonate; Acetate; Chloride; and antiseptics, in particular chlorhexidine gluconate, cetylpyridinium chloride, cetyl pyridinium chloride, hexetidine; Ammonium compounds, in particular methacrylamidopropy-trimethylammonium chlorides and povidone-iodine.

8. Implant according to one of the preceding claims, wherein at least the surface with the plurality of openings consists of a material selected from the group consisting of titanium or titanium alloys, titanium-nickel alloys, stainless steel, magnesium, steel, magnesium or magnesium alloys, polymers in particular PTFE, PET, PMMA, PE, PEEK, PEKK, PEAK, Teflon, fiber composite materials and bone material and preferably the material is the same as the base material of the implant or from which the base material of the implant was created.

9. Implant according to one of the preceding claims, wherein at least part of the receiving volume represents a channel or part of a channel which is completely or partially open to the surface, the cross-section of the channel having a local maximum width between the channel bottom and the plane of contact , on the perpendicular section to the surface, measured parallel to the plane of contact and perpendicular to the longitudinal axis of the canal.

10. A method for producing an implant according to one of claims 1 to 9, comprising the steps: a) providing an implant base body, b) generating the openings and the receiving volume, as defined in one of claims 1 to 9, on at least one surface of the implant base body , c) filling the receiving volume with a matrix as defined in one of claims 1 to 9 and d) loading the matrix with an active ingredient.