Medical glass element

Abstract

A material that is less populated by biofilms than known materials and is well tolerated by the body is provided. The material is an element introducible into or attachable on a human or animal body and includes a glass and/or glass ceramic and/or ceramic material at least in some areas thereof, which inhibits the formation of biofilms and/or on which human or animal cells grow if the element is introduced into the human or animal body or attached thereto, wherein the glass and/or glass ceramic material comprises at least: SiO.sub.2 in a range from 60 to 75 wt % and ZnO in a range from 1 to 7 wt %.

Claims

1. A structural article, consisting of a unitary, monolithic material capable of inhibiting the formation of biofilms thereon when the structural article is in contact with a human or animal body, the material comprising a glass and/or glass ceramic and/or ceramic that comprises SiO.sub.2 in a range from 60 to 75 wt %, R.sub.2O in a range from 5 to 20 wt %, RO in a range from 0 to 10 wt %, Al.sub.2O.sub.3 in a range from 1 to 6 wt %, B.sub.2O.sub.3 in a range from 0 to 10 wt %, TiO.sub.2 in a range from 0 to 8 wt %, ZnO in a range from 1 to 7 wt %, and FeO in a range from 0 to 5 wt %, wherein R.sub.2O is an oxide or a combination of oxides selected from the group consisting of Li.sub.2O, Na.sub.2O, and K.sub.2O, and wherein RO is an oxide or a combination of oxides selected from the group consisting of MgO, CaO, BaO, SrO, and any combinations thereof.

2. The structural article as claimed in claim 1, wherein the glass and/or glass ceramic and/or ceramic material comprises: SiO.sub.2 in a range from 60 to 70 wt %, R.sub.2O in a range from 5 to 20 wt %, RO in a range from 0 to 10 wt %, Al.sub.2O.sub.3 in a range from 1 to 5 wt %, B.sub.2O.sub.3 in a range from 0 to 10 wt %, TiO.sub.2 in a range from 0 to 8 wt %, ZnO in a range from 1 to 7 wt %, FeO in a range from 0 to 5 wt %, and Na.sub.2O in a range from 2 to 10 wt %, and/or K.sub.2O in a range from 3.5 to 10 wt %.

3. The structural article as claimed in claim 1, wherein the glass and/or glass ceramic and/or ceramic material comprises: a content of Ag of less than 0.3 wt %; and/or a content of P.sub.2O.sub.5 of less than 0.5 wt %; and/or a content of F of less than 1 wt %.

4. The structural article as claimed in claim 1, wherein the structural article is configured to be introduced into the human or animal body.

5. The structural article as claimed in claim 1, wherein the structural article is configured to be implanted into the human or animal body.

6. The structural article as claimed in claim 1, wherein the structural article is configured to be attached to the human or animal body.

7. The structural article as claimed in claim 1, wherein the structural article is selected from the group consisting of an implant, a casing feedthrough of an implant, a vascular support, a stent, a catheter, an artificial heart valve, a casing for a transponder, a casing for a defibrillator, a casing for a pacemaker, a lab-on-chip, and a contact lens.

8. The structural article of a material as claimed in claim 1, wherein the material comprises SiO.sub.2 in a range from 62 to 66 wt %, Al.sub.2O.sub.3 in a range from 3.8 to 4.5 wt %, B.sub.2O.sub.3 in a range from 0 to 10 wt %, TiO.sub.2 in a range from 3.5 to 4.5 wt %, ZnO in a range from 5 to 7 wt %, FeO in a range from 0.001 to 0.005 wt %, Na.sub.2O in a range from 5.9 to 6.5 wt %, K.sub.2O in a range from 8.3 to 9.1 wt %, and SeO.sub.2 in a range from 0 to 0.04 wt %.

9. A structural article consisting of a substrate capable of inhibiting the formation of biofilms thereon when introduced into or attached onto a human or animal body, wherein the substrate includes a material of a glass and/or glass ceramic and/or ceramic of: SiO.sub.2 in a range from 60 to 75 wt %, R.sub.2O in a range from 5 to 20 wt %, RO in a range from 0 to 10 wt %, Al.sub.2O.sub.3 in a range from 1 to 6 wt %, B.sub.2O.sub.3 in a range from 0 to 10 wt %, TiO.sub.2 in a range from 0 to 8 wt %, ZnO in a range from 1 to 7 wt %, and FeO in a range from 0 to 5 wt %, wherein R.sub.2O is an oxide or a combination of oxides selected from the group consisting of Li.sub.2O, Na.sub.2O, and K.sub.2O, and wherein RO is an oxide or a combination of oxides selected from the group consisting of MgO, CaO, BaO, SrO, and any combinations thereof.

10. The structural article as claimed in claim 9, wherein the glass and/or glass ceramic and/or ceramic material comprises: SiO.sub.2 in a range from 60 to 70 wt %, R.sub.2O in a range from 5 to 20 wt %, RO in a range from 0 to 10 wt %, Al.sub.2O.sub.3 in a range from 1 to 5 wt %, B.sub.2O.sub.3 in a range from 0 to 10 wt %, TiO.sub.2 in a range from 0 to 8 wt %, ZnO in a range from 1 to 7 wt %, FeO in a range from 0 to 5 wt %, and Na.sub.2O in a range from 2 to 10 wt %, and/or K.sub.2O in a range from 3.5 to 10 wt %.

11. The structural article as claimed in claim 9, wherein the glass and/or glass ceramic and/or ceramic material comprises: a content of Ag of less than 0.3 wt %; and/or a content of P.sub.2O.sub.5 of less than 0.5 wt %; and/or a content of F of less than 1 wt %.

12. The structural article as claimed in claim 9, wherein the structural article is configured to be introduced into the human or animal body.

13. The structural article as claimed in claim 9, wherein the structural article is configured to be implanted into the human or animal body.

14. The structural article as claimed in claim 9, wherein the structural article is configured to be attached to the human or animal body.

15. The structural article as claimed in claim 9, wherein the structural article is selected from the group consisting of an implant, a casing feedthrough of an implant, a vascular support, a stent, a catheter, an artificial heart valve, a casing for a transponder, a casing for a defibrillator, a casing for a pacemaker, a lab-on-chip, and a contact lens.

16. The structural article of a material as claimed in claim 9, wherein the material comprises SiO.sub.2 in a range from 62 to 66 wt %, Al.sub.2O.sub.3 in a range from 3.8 to 4.5 wt %, B.sub.2O.sub.3 in a range from 0 to 10 wt %, TiO.sub.2 in a range from 3.5 to 4.5 wt %, ZnO in a range from 5 to 7 wt %, FeO in a range from 0.001 to 0.005 wt %, Na.sub.2O in a range from 5.9 to 6.5 wt %, K.sub.2O in a range from 8.3 to 9.1 wt %, and SeO.sub.2 in a range from 0 to 0.04 wt %.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

(2) The invention will now be explained in more detail by way of exemplary embodiments and with reference to the accompanying drawings. Identical and similar components are designated with the same reference numerals, and features of the various exemplary embodiments can be combined and/or substituted by each other.

(3) FIG. 1 shows an analysis and visualization of biofilm growth after culturing for 24 hours: initial data analysis of biofilm-covered surface, cumulatively for all bacteria;

(4) FIG. 2 shows an analysis and visualization of biofilm growth after culturing for 24 hours: quantitative analysis of biofilm-covered surface for each of the bacterial species;

(5) FIG. 3 shows an analysis and visualization of biofilm growth after culturing for 24 hours: representative images of biofilms on soda-lime glass;

(6) FIG. 4 shows an analysis and visualization of biofilm growth after culturing for 24 hours: representative images of biofilms on glass according to a first embodiment of the invention;

(7) FIG. 5 shows cytotoxicity and hemocompatibility of soda-lime glass and several borosilicate glasses: representative images of cultured muscle cells, Caco2 cells, and L929 mouse cells;

(8) FIG. 6 shows cytotoxicity and hemocompatibility of soda-lime glass and several borosilicate glasses: data relating to hemolysis;

(9) FIG. 7 shows cytotoxicity and hemocompatibility of soda-lime glass and several borosilicate glasses: data relating to erythrocyte aggregation;

(10) FIG. 8 shows cytotoxicity and hemocompatibility of soda-lime glass and several borosilicate glasses: representative images of cultured cells of MSSA, Enterococcus faecalis, Enterococcus faecium, Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa, Proteus mirabilis, Staphylococcus epidermis;

(11) FIGS. 9a, 9b, and 9c schematically illustrate an implantable casing for an electronic component according to a first embodiment of the invention; and

(12) FIG. 10 schematically illustrates a vascular support according to another embodiment of the invention.

DETAILED DESCRITPION

(13) In order to investigate the inhibition of biofilm growth and the growth of human and animal cells, experiments were performed with different glasses. Glasses BF1 and BF2 were used as embodiments of the invention. Glasses VG1, VG2, and VG3 were examined as comparative examples.

(14) Table 1 below gives an overview of the chemical composition of the investigated glasses and glass ceramics:

(15) TABLE-US-00001 Content (wt %) VG1 VG2 VG3 BF1 BF2 SiO.sub.2 72.48 81.19 61.59 63.03 63.06 Al.sub.2O.sub.3 1.21 2.41 16.96 4.11 4.11 Na.sub.2O 14.36 3.52 12.32 6.08 6.08 K.sub.2O 1.21 0.08 4.14 8.51 8.51 MgO 4.32 0.00 3.94 0.00 0.00 CaO 6.43 0.00 0.00 0.00 0.00 ZnO 0.00 0.00 0.00 5.83 5.83 B.sub.2O.sub.3 0.00 12.76 0.00 8.22 8.22 CeO.sub.2 0.00 0.00 0.30 0.00 0.00 TiO.sub.2 0.00 0.00 0.00 3.98 4.11 SnO.sub.2 0.00 0.00 0.40 0.00 0.00 Sb.sub.2O.sub.3 0.00 0.00 0.00 0.20 0.00 F.sub.2 0.00 0.00 0.30 0.00 0.000 FeO 0.01 0.04 0.05 0.05 0.05 SeO.sub.2 0.00 0.00 0.00 0.00 0.03 Total 100.00 100.00 100.00 100.00 100.00

(16) The glasses were tested in the form of sheets. Initially, the sheets were ultrasonically cleaned in 1% Deconex 12 PA (Borer advanced cleaning solutions) at 40 C. for 15 min. The reagent was first removed with warm tap water and then by washing with deionized water. Thereafter, the sheets were treated using ultrasound in deionized water at 40 C. for 5 min. Finally, the sheets were dried in a nitrogen stream.

(17) For the tests of biofilm formation, eight typical representatives of nosocomial infections were examined, namely MSSA: Staphylococcus aureus, methicillin-sensitive (ATCC 29213), Staphylococcus epidermis (Pp 62a), Enterococcus faecalis (ATCC 29212), Enterococcus faecium (SMZ 20477), Escherichia coli (ATCC 25922), Klebsiella pneumonia (ATCC 700603), Pseudomonas aeruginosa (PA01), and Proteus Mirabilis (VBK 4479).

(18) The bacterial seed stocks were stored at 80 C. in 10 vol % glycerol solution. Prior to culturing in liquid medium, a strand of frozen bacteria was plated on lysogeny broth (LB) agar (1.5%) sheets and incubated overnight at 37 C. A single colony of each of the strains pathogenic for humans was cultured overnight in Mueller-Hinton (MH) medium at 37 C.

(19) For biofilm formation, the cultures were freshly seeded in MH medium at a dilution of 1:1000 and were filled into 82 sections of silicone structures (SCHOTT Nexterion) attached to the glass sheets. Biofilms were grown at 37 C. over a period of 24 hours without shaking.

(20) The biofilms were stained using the LIVE/DEAD BacLight Bacterial Viability Kit (Life Technologies). After staining, the bacterial supernatant was carefully removed, and the biofilms were carefully washed once with 300 L (microliters) of a 0.9% NaCl solution. Then, they were embedded in Fluoromount-G (SouthernBiotech, BIOZOL) and covered with Nexterion glass cover sheets (SCHOTT Nexterion). Visualization of the biofilms was performed as described above.

(21) FIGS. 1 to 4 show results of the analysis and visualization of biofilm growth after culturing for 24 hours. The symbol p represents the p-value or significance value which is an indicator for the evaluation of statistical tests. In biological sciences, a threshold of 5% has been established (maximum error probability or significance level =0.05). That means: If the probability for a result to be coincidental is less than 5%, it is considered to be significant (p<0.05).

(22) The statistical analysis of the biofilm-covered surface areas (cumulative for all species) is given in Table 2 below, wherein N is the number of experiments, and SEM is standard error of mean.

(23) TABLE-US-00002 Biofilm surface area Biofilm Degree of biofilm (%) thickness homogeneity Glass type Mean SEM (mm) (% incomplete) VG1 (N = 24) 69.33 7.041 10 to 30 <10 VG2 (N = 27) 21.03 1.500 10 to 30 <20 VG3 (N = 25) 14.32 1.875 10 to 30 <50 BF1 (N = 27) 0.76 0.294 4 to 10 >95 BF2 (N = 25) 0.07 0.026 4 to 10 >95

(24) All investigated human-pathogenic strains grew well on the surfaces of the glass corresponding to VG1 and on the sheets with the composition of VG2 and VG3. After 24 hours, most of the bacteria lived, which can be verified by green staining using SYTO9. The sporadic dead cells (stained red by propidium iodide) correspond to the usual decrease in biofilms.

(25) On glasses BF1 and BF2 according to the invention, all investigated human-pathogenic germs showed reduced biofilm formation. Biofilm thickness is greatly reduced and is in a range between 4 m and 10 m (microns). In addition, the biofilms on the glasses of the invention exhibit morphological modifications with diffuse and porous structures. The surface areas actually covered by biofilms, namely 0.760.294% and 0.070.026% are greatly reduced in comparison to the other investigated glasses. Furthermore, the existing biofilms on the glasses of the invention exhibit greatly increased porosity of more than 95% in comparison to the other investigated glasses. Like the well grown biofilms on VG1, VG2, and VG3, the diminished biofilms only show a small number of dead cells.

(26) These results surprisingly indicate that the chemical composition of the inventive materials BF1 and BF2 prevents the first step for adhesion of bacteria. So far, the investigated glasses according to the invention were used as resistant covers for touch panels of navigation devices integrated in automobiles, or as substrates for capacitive sensors and filters for camera modules in mobile phones, and as casing for CCD image sensors. Therefore, a person skilled in the field of microbiology never came into contact with these glasses.

(27) FIGS. 5 to 8 illustrate results of in vitro determined cytotoxicity and hemocompatibility of soda-lime glass and different borosilicate glasses.

(28) In order to evaluate modifications in cell morphology and growth performance, muscle cells, Caco2 cells, and L929 mouse fibroblasts were cultured on the different glasses for 48 hours. Compared with control cells in cell culture flasks, no changes in cell morphology and growth performance were found for all glasses. As can be seen from the images of FIG. 5, no apoptotic cells and abnormalities can be found in the cell environment. None of the examined glass compositions showed any signs of cytotoxicity.

(29) For investigating hemolysis, erythrocytes were incubated on the glass surfaces for two hours. As proved by the results plotted in FIG. 6, none of the glasses exhibits proportions of hemolysis of more than 0.57%, regardless of the glass composition. According to the ASTM F756-00 standard, a hemoglobin release between 0 and 2% is considered non-hemolytic. This indicates that there is no detectable disorder of the membranes of the red blood cells.

(30) Additionally it was investigated to what extent the types of material are capable of causing aggregation of erythrocytes. Aggregation of erythrocytes is an undesirable phenomenon which leads to side effects on the circulation and even lethal toxicity. The aggregation of erythrocytes was visualized microscopically after two hours of incubation on the glass surfaces. Treatment with 25 kDa bPEI at 30 mg/mL as a positive control resulted in the formation of aggregates (level 3 according to the classification discussed above). However, as shown in FIG. 7, no aggregation of red blood cells was found for any of the investigated materials. Moreover, all glass compositions exhibited very good hemocompatibility.

(31) Among the germs used, S. epidermis basically showed low tendency to form biofilms on the glasses. By contrast, K. pneumoniae and MSSA showed an elevated tendency to adhesion and growth on the glass surfaces, as is illustrated by the images of FIG. 8. However, even for these germs biofilm formation is significantly reduced on the glasses of the invention.

(32) Thus, glasses and/or glass ceramics and/or ceramics with the composition according to the invention are particularly suitable for the development of highly efficient anti-biofilm surfaces or coatings. Compared to the comparative examples VG1 to VG3, the glass and/or glass ceramic and/or ceramic material of the invention exhibits reduced biofilm adherence, increased biofilm porosity, and reduced biofilm thickness, and furthermore is excellently cytocompatible and hemocompatible without toxicity to eukaryotic cells.

(33) With these surprising properties, diverse applications of the invention are possible in the field of medicine.

(34) FIGS. 9a-9c and 10 illustrate exemplary applications for the glass or glass ceramic material of the invention.

(35) FIGS. 9a-9c illustrates a casing 1 for electronic components 2. Transponder casings, also known as transponders tubes, are easily manufactured as sections of tubing. One end is then sealed by fuse sealing, for example. Such a casing for a transponder is illustrated in FIG. 9A. An electronic component known as transponder is then introduced into the tube through the still open end shown on the right side in the figure, see FIG. 9B. The transponder may e.g. comprise an RFID chip or a sensor. The still open end of the tube may then be closed by heat application, for example using a laser and/or infrared radiation, so that the casing will then advantageously be hermetically sealed, as shown in FIG. 9C. In a preferred embodiment of the invention the casing is autoclavable.

(36) The proportion of FeO in the glass and/or glass ceramic and/or ceramic material may promote the sealing of the tube in particular when a laser and/or infrared radiation is employed, in particular because it increases absorption of the material in the infrared spectral range.

(37) Typical dimensions for such transponder casings are in a range of up to 10 mm, preferably in a range of up to 5 mm, more preferably in a range between 1 mm and 4 mm for the outer diameter, and in a range of up to 100 mm, preferably in a range of up to 70 mm, more preferably in a range between 5 mm and 50 mm in length. The wall thickness is in particular in a range of up to 2 mm, preferably in a range of up to 1.5 mm, more preferably in a range between 0.03 mm and 1.1 mm.

(38) It is likewise possible for the element in the form of a tube section, for example, to be equipped with means permeable for an active substance, such as a membrane, on at least one end thereof, and to have an active substance deposited in the interior thereof. In this way, an implant for administering active substances can easily be produced.

(39) It is also possible to integrate electronic components in such an implant for administering active substances, and the electronic component may in particular control the conditions of and/or trigger active substance release, in particular the timing and/or amount of active substance release. This electronic component may in particular as well be designed so as to be capable of communicating, via electrical conductors, e.g. wires and/or contacts, but also by wireless communication, with electronic devices outside the body which may in particular transmit control and/or sensor signals to the electronic component within the implant. In this way the described implant may be part of a more complex diagnostic and/or treatment apparatus.

(40) It is similarly possible for substances, in particular liquids from the human or animal body to enter into the interior of the implant through the permeable means in order to be then analyzed there by the one or more electronic components. Data obtained from the analysis may be transmitted to electronic devices outside the human or animal body.

(41) FIG. 10 illustrates a stent 3 as a further possible application of the glass or glass ceramic material according to the invention. Stent 3 is inserted in a hollow organ 4, for example a blood vessel. Stent 3 is made of a metal mesh, for example of titanium. The enlarged detail A on the right side of the figure shows a portion of a metal filament 5 of the metal mesh. According to the invention, metal filaments 5 have a coating 6, at least in areas thereof, which is made of the glass and/or glass ceramic material in accordance with a composition as described above. In this manner, susceptibility of the stent 3 for microbial colonization is significantly reduced as compared to known materials. Moreover, a stent coated in this manner is very well tolerated by the human or animal body.

(42) It will be apparent to those skilled in the art that the invention is not limited to the examples described above, but rather may be varied in many ways. In particular it is possible for the features of the individual illustrated examples to be combined or substituted for each other.