Silica sol material for the production of biodegradable and / or resorbable silica gel materials, its production and use

Abstract

Silica sol material is available by a) a hydrolysis-condensation reaction of tetraethoxysilane is carried out under acid catalysis at an initial pH of 0 to ≤ 7, optionally in the presence of a water-soluble solvent, wherein for the acid catalysis, tetraethoxysilane and nitric acid water are used in a molar ratio in the range of 1:1.7 to 1:1.9, preferably in the range of 1:1.7 to 1:1.8, and the hydrolysis-condensation reaction is carried out for at least 16 h, preferably 18 h and between 20 °C and 60 °C, particularly preferably at room temperature (20 °C to 25 °C); and b) by subsequent evaporation with gentle mixing of the reaction system, a single-phase solution with a viscosity in the range of 0.5 Pa s to 2 Pa s (at a shear rate of 10 s -1 at 4 °C) is generated, c) this solution is subsequently cooled to a temperature of -20 °C to 10 °C, and d) is subjected to kinetically controlled ripening at a temperature of -20 °C to 10 °C, whereby a homogeneous sol is formed and the ripening is continued until the viscosity of the sol is between 30 Pa s and 100 Pa s (at a shear rate of 10 s -1 at 4 °C) and a loss factor of 2 to 5 (at 4 °C, 10 1 / s, 1% deformation).

Description

[0001] The invention relates to a novel silica sol material for producing biodegradable and / or resorbable silica gel materials with improved properties, as well as a process for its production and its use. The invention also relates to biodegradable and / or bioresorbable silica gel fiber materials.

[0002] There are numerous efforts to develop biodegradable and / or bioresorbable materials for various applications in human medicine and medical technology. These areas also face ever-increasing demands, particularly regarding the biocompatibility, biological efficacy, and toxicological properties of the materials. DE 600 35 672 T2 discloses a method for adjusting the biodegradability of silica fibers, comprising spinning the fibers from a silica sol, wherein the viscosity of the sol from which the fiber is spun is selected.

[0003] Resorbable silica gels are known in the art. DE 196 09 551 C1 describes biodegradable, bioresorbable fiber structures. These fibers can be obtained in a sol-gel process by drawing threads from a spinning dope and optionally drying them. The spinning dope contains one or more partially or fully hydrolytically condensed silicon compounds derived from monomers of the general formula SiX4 by hydrolytic condensation. These fibers have the disadvantage that, if degraded immediately after the spinning process, they do not yet exhibit optimal results in cytotoxicity tests and must sometimes be classified as cytotoxic. Such toxicity is generally undesirable, especially for use in human medicine or medical technology, for example, in the field of wound healing.The process for producing the fibers according to DE 196 09 551 C1 also has the disadvantage that the resulting mixture is already a multiphase mixture after removal of the solvent in the hydrolysis-condensation step and must be subjected to filtration to remove the resulting solid. Furthermore, a large proportion of the spinnable sol is lost due to the formation of the solid phase and the mandatory filtration step. According to the process of DE 196 09 551 C1, the formation of a significant proportion of a solid phase, in particular gel formation, cannot be reliably suppressed even during maturation. This further reduces the proportion of spinnable sol mass.

[0004] Independently, it has been demonstrated that the fibers and nonwovens according to the invention exhibit improved wound healing properties. Furthermore, the fibers and nonwovens according to the invention are particularly suitable for use as cell support structures.

[0005] The object of the present invention is to provide a novel silica sol material for the production of biodegradable and / or bioresorbable silica gel materials. Furthermore, the object of the present invention is to provide biodegradable and / or bioresorbable silica gel materials that exhibit improved cytotoxicity and / or wound healing properties. A further object can be seen in providing improved cell support structures, for example, for the in vitro production of skin implants, cartilage, and bone.

[0006] The object is achieved by a silica sol material according to claim 1. According to this, a silica sol material can be obtained by a) a hydrolysis-condensation reaction of tetraethoxysilane is carried out under acid catalysis at an initial pH of 0 to ≤ 7, optionally in the presence of a water-soluble solvent, wherein for the acid catalysis, tetraethoxysilane and nitric acid water are used in a molar ratio in the range of 1:1.7 to 1:1.9, preferably in the range of 1:1.7 to 1:1.8, and the hydrolysis-condensation reaction is carried out for at least 16 h, preferably 18 h and between 20 °C and 60 °C, particularly preferably at room temperature (20 °C to 25 °C); and b) by subsequent evaporation with gentle mixing of the reaction system, a single-phase solution with a viscosity in the range of 0.5 Pa s to 2 Pa s (at a shear rate of 10 s -1 at 4 °C) is generated, c) this solution is subsequently cooled to a temperature of -20 °C to 10 °C, and d) is subjected to kinetically controlled ripening at a temperature of -20 °C to 10 °C, whereby a homogeneous sol is formed and the ripening is continued until the viscosity of the sol is between 30 Pa s and 100 Pa s (at a shear rate of 10 s -1 at 4 °C) and a loss factor of 2 to 5 (at 4 °C, 10 1 / s, 1% deformation).

[0007] According to the invention, tetraethoxysilane (TEOS) is used as the Si compound in the hydrolysis-condensation reaction according to the invention. Ethanol or a water / ethanol mixture can preferably be used as the water-soluble solvent. The tetraethoxysilane can be used in a ratio of ≥ 1 to ethanol.

[0008] The initial pH value of 0 to ≤ 7, preferably from 2 to 5, is adjusted with nitric acid water. However, other acidic mixtures and / or solutions that can locally generate NO or NO2 would also be suitable for carrying out the present invention. These can be, for example, acidic mixtures and / or solutions that enzymatically (by means of a nitroxide synthase, NOS) generate nitric oxide (NO) in a physiological environment with molecular oxygen, which in turn is quickly converted into NO2 by the body, or they can also be organic nitrates or nitrate esters (so-called NO donors), e.g. ethyl nitrate, which form NO with the help of an organic nitrate reductase. Thiol groups (cysteine) are required for this enzymatic release of NO.

[0009] In addition to diluted nitric acid, an aqueous or alcoholic (particularly preferred: an aqueous diluted ethanolic) solution of a physiologically acceptable acid (e.g. citric, succinic, tartaric, acetic or ascorbic acid) and at least one essential (e.g. L-arginine, particularly preferred; L-valine, L-leucine, L-isoleucine, L-phenylalanine, L-thyroxine, L-methionine, L-lycine or L-tryptophan) or non-essential amino acid (e.g. L-glutamine, L-glutamic acid, L-asparagine, L-aspartic acid, L-cysteine, L-glycine, L-alanine, L-proline, L-histidine, L-tyrosine) would also be suitable as a substrate for NOS, to adjust the pH to the desired value in the weakly to moderately acidic range. to set.

[0010] The hydrolysis-condensation reaction is carried out with tetraethoxysilane and nitric acid water in a molar ratio between 1:1.7 and 1:1.9, preferably in a ratio between 1:1.7 and 1:1.8. The nitric acid water can be used as 0.01 N HNO3.

[0011] The hydrolysis-condensation is carried out over a period of at least 16 hours, preferably at least 18 hours, at a temperature of 20°C - 60°C, more preferably at about 20°C to about 50°C and, for example - when using the materials according to the invention for wound treatment - at room temperature (about 20°C to about 25°C) or at about 37°C.

[0012] In a preferred embodiment of the present invention, the hydrolysis can be carried out over a period of at least 16 hours, preferably at least 18 hours up to 4 weeks. The hydrolysis time is preferably from 24 hours to 18 days, particularly preferably from 3 to 8 days. It has surprisingly been found that with an extended hydrolysis-condensation time compared to the previously customary times of a few hours at room temperature, a homogeneous single-phase solution can be obtained after removal of the solvent in step b), which no longer requires filtration before maturation in step d).

[0013] The first hydrolysis-condensation reaction is preferably carried out batchwise in a stirred vessel or a single-neck round-bottom flask with a stir bar. Tetraethoxysilane and the solvent (e.g., ethanol) are preferably initially charged. The acid is then rapidly added, preferably in the form of 0.01 N HNO3 (e.g., 0.01 mol HNO3 per mol TEOS). Due to the acid strength in the reaction mixture, the first hydrolysis-condensation reaction proceeds rapidly, and the contents of the vessel heat up by approximately 40 °C before the temperature begins to decrease during the reaction time (i.e., in step a)) (due to natural cooling to ambient temperature or the heating medium temperature).

[0014] The removal of the water-soluble solvent (e.g. ethanol, water) in step b) is carried out in a preferred embodiment of the invention in a closed apparatus in which mixing is possible (preferably a rotary evaporator or stirred tank) with simultaneous removal of the solvent (water, ethanol) by evaporation at a pressure of 1 to 1013 mbar, preferably at a pressure of < 600 mbar, optionally with continuous supply of a chemically inert carrier gas to reduce the partial pressure of the evaporating components from 1 - 8 m 3 / h (preferably at 2.5 to 4.5 m 3 / h), a reaction temperature of 30 °C to 90 °C, preferably 60 °C - 75 °C, more preferably 60 °C - 70 °C and with gentle mixing of the reaction system for up to 80 min -1 (preferably at 20 min -1 up to 60 minutes -1 ) up to a viscosity of the mixture of 0.5 Pa s to 2 Pa s at a shear rate of 10 s -1at 4 °C, preferably approx. 1 Pa s (measurement at 4 °C, shear rate 10 s -1 ), carried out.

[0015] According to the invention, "entraining gas stream" refers to a gas stream that is added to the gas volume above the liquid phase of the reaction system. To maintain the isobaric conditions in the reaction vessel, a gaseous volume stream must be removed, consisting of both the "entraining gas" and the component(s) to be evaporated. The resulting partial pressure reduction, i.e., the reduction in the proportion of the component(s) to be evaporated or the component mixture in the gas space, increases the driving force for evaporation of the solvent at the liquid surface.

[0016] In a particularly preferred embodiment, the "entraining gas stream" is distributed by means of a gas distributor suitably arranged in the gas space of the apparatus in such a way that sufficient entraining gas exchange is ensured just above the liquid surface, but without direct convection flow onto the liquid surface. In extreme cases, this can lead to local gelling, which is undesirable. Gas distributors by means of which this embodiment can be implemented are known to those skilled in the art.

[0017] As the reaction / polymerization progresses (indicated by the increase in viscosity), the phase equilibrium shifts, so that the corresponding equilibrium pressure of the solvent in the vapor phase becomes increasingly lower. When the equilibrium pressure drops to the total pressure in the gas phase, evaporation ceases.

[0018] To further evaporate solvent, the pressure must therefore be reduced, the carrier gas flow must be variably adjusted and / or the temperature must be increased.

[0019] In a preferred embodiment of the present invention, at least one of the process parameters pressure, carrier gas flow and / or temperature is adjusted in a time-variable manner.

[0020] In a preferred embodiment of the invention, the evaporation in step b) takes place at a constant temperature and a pressure which varies over time.

[0021] In a preferred embodiment of the invention, nitrogen and / or air is used as the chemically inert carrier gas stream to reduce the partial pressure.

[0022] In a preferred embodiment of the invention, the water-soluble solvent is removed by means of a combination of vacuum and entraining gas flow. In this embodiment of the invention, the total pressure and entraining gas flow can be adjusted independently of one another, either constantly or over time. In this embodiment of the invention, ideally, at least one of the process parameters—pressure, entraining gas flow, and / or temperature—is adjusted over time. This makes it possible, for example, to integrally achieve a specific reaction time at a desired degree of evaporation and / or to adapt the evaporation rate to the reaction kinetics.

[0023] In a preferred embodiment of the invention, the evaporation in step b) is carried out at a constant temperature and a pressure which is variable over time, the pressure being reduced to < 600 mbar, preferably < 500 mbar, particularly preferably < 100 mbar, starting from atmospheric pressure or slightly reduced pressure until the end of the second hydrolysis-condensation reaction.

[0024] In the combined mode (vacuum with carrier gas flow), a constant or variable negative pressure of < 600 mbar is preferred.

[0025] Temperatures above 60 °C are particularly preferred in order to promote a reductive conversion of HNO3 to NO, given the otherwise significantly increasing concentration of HNO3 in the residual solvent. This highly volatile gas (normal boiling point approximately -150 °C) is oxidized upon escape from the liquid phase upon contact with air to form low-boiling NO2 (bp approximately 21 °C), which is removed from the system with the exhaust air or gas stream. In this way, the acid concentration in the material according to the invention is limited or reduced. Alternatively, the acid strength can also be reduced in one of the subsequent steps, e.g., by venting the solid body, e.g., as a fiber fleece.

[0026] However, if the organic acid / arginine system is used instead of nitric acid, the pH value can be increased or the acid strength reduced, if desired, e.g., using Tris solutions (if the acid, e.g., acetic acid, cannot be expelled) shortly before application by rinsing in an aqueous Tris solution.

[0027] Surprisingly, in comparison to DE 196 09 551 C1, it was discovered that by gently mixing the reaction system at 20 min -1 up to 80 minutes -1, the formation of a concentration gradient across the height of the batch in the reaction vessel during reactive evaporation (step b)) can be prevented. This, together with the extended hydrolysis-condensation reaction time of at least 16 hours, contributes to the fact that at least 70%, preferably at least 80%, and most preferably at least 90% of the entire reaction batch can be spun in the process according to the invention.

[0028] Step b) is carried out until a single-phase solution with a viscosity in the range of 0.5 Pa s to 2 Pa s at a shear rate of 10 s -1 at 4 °C, preferably approx. 1 Pa s (measurement at 4 °C, shear rate 10 s -1 ), is generated.

[0029] According to the invention, the reaction progress in step b) is monitored via the viscosity.

[0030] The homogeneous and single-phase solution resulting from the hydrolysis-condensation reaction in step b) is subsequently cooled (step c)) and advantageously subjected to a kinetically controlled maturation quantitatively and optionally without filtration.

[0031] According to the invention, ripening (step d)) is carried out at a temperature of -20°C to 10°C, preferably at 2°C to 4°C (e.g., in a refrigerator). Ripening is preferably carried out at 4°C. Due to the low temperature, further condensation can occur in a kinetically controlled manner during the ripening period, starting from tetraethoxysilane. Oligomeric and / or polymeric siloxanes and / or silanols can be formed in this mixture. The oligomers and / or polymers can also aggregate via hydrogen bonds. After ripening, according to the invention, a pseudoplastic, homogeneous, single-phase sol mass can be obtained. Advantageously, the competing formation of a three-dimensional polymeric gel network can therefore be largely suppressed. A homogeneous sol mass can therefore be obtained that has no solid second phase, in particular largely no gel phase.

[0032] The maturation is continued until the sol viscosity reaches 30 Pa s to 100 Pa s (at a shear rate of 10 s -1 at 4 °C) and a loss factor of 2 to 5 (at 4 °C, 10 1 / s, 1% deformation). The loss factor is the quotient of the viscous to elastic component of the dynamic viscosity.

[0033] The maturation time can be from 3 days to 4 weeks. According to the invention, the sol obtained in step d) has a viscosity between 30 Pa s and 100 Pa s (shear rate 10 s -1 at 4 °C) with a loss factor (at 4 °C, 10 1 / s, 1% deformation) of 2 to 5, preferably 2.5 to 3.5.

[0034] If the fiber or nonwoven according to the invention is to be used for wound healing, the sol obtained in step d) preferably has a viscosity of 35 Pa s to 75 Pa s (shear rate 10 s -1 at 4 °C) and more preferably from 35 Pa s to 45 Pa s (shear rate 10 s -1at 4 °C) preferably with a loss factor (at 4 °C, 10 1 / s, 1% deformation) of 2.5 to 3.5.

[0035] A loss factor that is too high means the material is too elastic, which, for example, prevents the formation of a stable thread during spinning (gelling, thread breakage). If the loss factor is too low, the material is so fluid that stable thread formation is impossible (droplets).

[0036] The conditions for the maturation time can vary if the silica sol material according to the invention is to be subsequently processed into a powder instead of into a spinnable fiber. In this case, the dynamic viscosity at the end of step d) is preferably about 60 Pa s (shear rate 10 s -1 at 4 °C).

[0037] In the case of processing the silica sol material into a monolith, the dynamic viscosity at the end of d) is preferably greater than or equal to 70 Pa s (shear rate 10 s-1 at 4 °C. If the silica sol material is to be used to coat bodies or surfaces, the dynamic viscosity, depending on the desired layer thickness, is less than or equal to 10 Pa s (shear rate 10 s -1 at 4 °C).

[0038] Preferably, the resulting sol mass can be used at least approximately quantitatively in further production steps and / or processes for biodegradable and / or resorbable silica gel materials. The silica sol material obtained in step d) is preferably spinnable. According to the invention, a spinning process can be provided in a further step e).

[0039] Such a spinning process step can be carried out under usual conditions, as described for example in DE 196 09 551 C1 and DE 10 2004 063 599 A1.

[0040] The silica sol material is blown out, for example, via a pressure vessel through a nozzle plate with individual nozzles (pressure in the vessel 1-100 bar, preferably 20 to 30 bar).

[0041] The spinning shaft is typically 1-5 m long, preferably 2 m. The climate in the spinning shaft is controlled in terms of temperature and humidity. Temperatures between 20 °C and 30 °C and a dew point of -5 °C to 10 °C are preferred, or a humidity of 20 to 40% relative humidity, preferably 20 to 25% relative humidity, and particularly preferably approximately 20% relative humidity.

[0042] After falling through the spinning shaft, the fibers retain their shape and are deposited on a traversing table. The mesh size of the resulting fiber web is adjusted, among other things, by the traversing speed. This is a few cm / s. A biaxial movement thus creates a tightly woven fiber web (nonwoven) in which, based on TEOS as the Si-containing starting compound, generally still contains more than 25 to 33% of the ethoxy groups.

[0043] Especially when using the materials according to the invention for wound treatment, the basis weight of the fiber material is preferably at least 90 g / m 2 and particularly preferably at least 150 g / m 2 The thickness of the wound dressing (consisting of the spunbonded nonwoven) is preferably at least 0.8 mm and more preferably at least 1.5 mm. The fiber diameter is preferably at least about 45 µm.

[0044] The silica gel fiber materials and products resulting from the process according to the invention, for example threads, fibers, nonwovens and / or fabrics, have excellent biological degradability and biological resorption capacity.

[0045] A further advantage of the invention is that silica gel fiber materials produced according to the invention exhibit significantly improved values ​​in cytotoxicity tests in the presence of L929 mouse fibroblasts compared to fibers obtained by the process of DE 196 09 551 C1 (see Example 1 and Comparative Example). Products produced from the silica gel material according to the invention are therefore characterized by particularly good biocompatibility. The threads, fibers, or nonwovens according to the invention can therefore be advantageously used as biodegradable and / or bioresorbable materials and products in human medicine or medical technology.

[0046] Independently of this, it has been experimentally demonstrated that the fibers and nonwovens according to the invention have improved wound healing properties. The materials according to the invention can therefore be used advantageously in the field of wound treatment and wound healing. Threads can be used, for example, as surgical suture material or as reinforcing fibers. Nonwovens according to the invention can be used particularly advantageously in the treatment of superficial wounds.

[0047] The biodegradable and bioresorbable fibers and nonwovens according to the invention can be produced by a controlled hydrolysis-condensation reaction of tetraethoxysilane and nitric acid water by the following steps: a) a hydrolysis-condensation reaction of tetraethoxysilane is acid-catalyzed at an initial pH of 0 to ≤ 7, optionally in the presence of a water-soluble solvent, wherein for the acid catalysis, tetraethoxysilane and nitric acid water are used in a molar ratio in the range of 1:1.7 to 1:1.9, preferably in the range of 1:1.7 to 1:1.8, and the hydrolysis-condensation reaction is carried out for at least 16 h, preferably 18 h and between 20 °C and 60 °C, particularly preferably at room temperature (20 °C to 25 °C); and b) Generation of a single-phase solution with a viscosity in the range of 0.5 Pa s to 2 Pa s (at a shear rate of 10 s -1 at 4 °C) by subsequent evaporation with gentle mixing of the reaction system, c) cooling this solution subsequently to a temperature of -20 °C to 10 °C, and d) subjecting this solution to a kinetically controlled ripening at a temperature of -20 °C to 10 °C, whereby a homogeneous sol is formed and the ripening is continued until the viscosity of the sol is between 30 Pa s and 100 Pa s (at a shear rate of 10 s -1 at 4 °C) and a loss factor of 2 to 5 (at 4 °C, 10 1 / s, 1% deformation), and e) spinning the sol obtained in d) in a spinning process.

[0048] Since TEOS is used as the Si compound in the hydrolysis-condensation reaction in step a), a homogeneous solution is obtained after evaporation in step b) with sufficient hydrolysis time. During the maturation period at low temperature, a kinetically controlled reaction takes place in step c). The mixture is then dissolved in step d) as a homogeneous single-phase mass and is thus obtained as a spinnable silica sol material.

[0049] The fibers or nonwovens produced according to the invention can be advantageously used as bioresorbable and / or bioactive materials in human medicine, medical technology, filter technology, biotechnology, or as insulation materials. In particular, the materials produced according to the invention can be advantageously used in the field of wound treatment and wound healing. Fibers can be used, for example, as surgical suture material or as reinforcing fibers. Nonwovens can be used particularly advantageously in the treatment of superficial wounds, in the filtration of body fluids (e.g., blood), or in bioreactors as a culture aid.

[0050] A further embodiment of the invention may be a drug delivery system and / or a pharmaceutical formulation, a micropowder and / or a nanopowder.

[0051] Such powder forms can be obtained by adding a desired active ingredient, for example one or more pharmaceuticals, to the silica sol material according to the invention (the active ingredient can optionally also be covalently bound by a further hydrolysis-condensation reaction) and creating a homogeneous mixture. Particularly when temperature-sensitive active ingredients are added, the mixture of sol and active ingredient(s) is subjected to gentle drying, e.g., spray-drying or freeze-drying. If the active ingredient is not temperature-sensitive or is not added at all, drying can also be effected at (significantly) elevated temperatures. This preferably results in a bioresorbable and / or bioactive silica matrix forming around the active ingredient. This matrix is ​​particularly suitable for encapsulating liquid active ingredients.Liquids can be enclosed in the matrix for long-term stability and released again in a controlled manner. Encapsulation enables the mechanical and chemical stabilization of the active ingredients, improved handling of such liquid active ingredients and pharmaceuticals, and helps prevent uncontrolled evaporation of the active ingredients. Of course, other substances and / or excipients adapted to the respective application can be present in the final formulation (powder). The particles of a micropowder according to the invention preferably have a size (average diameter) of 0.01 µm to 100 µm, in particular 0.1 µm to 20 µm. The nanopowder particles generally have a size (average diameter) of ≤ 100 nm.

[0052] In a further embodiment, a mixture of at least one active ingredient with the silica sol material according to the invention can be poured into a mold. After drying, a monolith can be obtained in this way. Such monoliths can be used in the form of solid implants as a drug delivery system, for example subcutaneously. They can be used, for example, as a depot for contraceptives and release the active ingredient over a longer period of time. Such implants according to the invention have good biological compatibility. The monoliths can preferably have a diameter of ≥ 0.5 mm. Alternatively, the monoliths can also be comminuted and ground into powder.

[0053] In another embodiment, the silica sol material can be coated using conventional coating methods, for example by dipping the body to be coated into the silica sol material, by pouring it on, or by spin-coating or spraying the silica sol material. The silica sol material is preferably coated onto coated tablets or capsules. For this purpose, pressed powdered pharmaceutical mixtures are provided with a bioresorbable and / or bioactive coating consisting of the silica sol material according to the invention. This makes it possible to control and / or regulate the release of (further) active ingredients (e.g., via the layer thickness and / or the layer sequence) within the formulation. Such a coating can also be applied to body part implants, thereby improving the (biological) compatibility of the implants, e.g., mitigating or preventing rejection reactions.

[0054] Highly viscous sols, especially hydrogels, can be supplemented or replaced by the silica gel material according to the invention. These high-viscosity sols and hydrogels are used in medicine and cosmetics as active ingredients or drug carriers. Hydrogels are generally widely used in the treatment of large wounds (wound treatment and wound healing).

[0055] Advantageously, the addition of the silica sol material can improve biocompatibility and thus wound healing. The hydrogels according to the invention can therefore be advantageously used as bioresorbable and / or bioactive products in medicine, particularly human medicine or medical technology.

[0056] A fiber matrix made from a fiber according to the invention serves in a method for in vitro cell proliferation as a cell support substance and / or guiding structure for the extracellular matrix formed by the cells, or provides the cells with the opportunity to find a spatial arrangement that allows the cells to proliferate and / or achieve their genetically determined differentiation. The advantages of the method are exemplified in Example 3.

[0057] Cells that can be used include, for example, undifferentiated pluripotent stem cells or genetically modified or native differentiated cells of various types and degrees of differentiation.

[0058] The cells applied to the fiber matrix adhere to the matrix or proliferate primarily two-dimensionally on this matrix to form an extracellular matrix or messenger substances (hormones). The fiber matrix preferably forms a surface element, in particular in the form of a fleece or woven fabric made of fibers according to the invention. This fiber matrix is ​​preferably porous, so that the introduced / applied cells penetrate it, assume a three-dimensional distribution and can trigger spatial tissue and organ growth or release messenger substances according to their differentiation, which is genetically determined or induced by added differentiation factors. Alternatively, the matrix is ​​designed as a dense fiber network that is impenetrable by the introduced / applied cells, with the possibility of two-dimensional cell distribution and the simultaneous possibility of three-dimensional tissue and organ growth in the sense of a "composite graft."

[0059] The in vitro propagation method is preferably used for the in vitro production of cell complexes, tissues and / or organs.

[0060] Using the process described above, a cell network, tissue, and / or organs can be produced. Such a cell network, tissue, and / or organs are suitable, for example, as an in vitro model for drug-tissue-organ interactions. A variety of methods are used to produce tissue outside the human body; these are summarized under the broad term "tissue engineering." Depending on the type of tissue, cells are isolated from their existing tissue network and induced to proliferate. The cells are then either applied to flat materials of varying consistencies or introduced into porous or gel-like materials, thereby inducing tissue maturation and, if necessary, stimulating it with differentiation factors. Tissue maturation can occur outside or inside the body.The fiber matrix according to the invention has the advantage that it is biodegradable and / or bioresorbable, but - as Example 3 shows - nevertheless virtually retains its two- or three-dimensional shape during in vitro propagation over a certain period of time. In a cell composite, tissues, and / or organs with a fiber matrix made of polysilicic acid, produced from the fibers according to the invention, the biodegradable and / or bioresorbable fiber matrix is ​​at least 60%, preferably at least 70%, and particularly preferably at least 80% identical to the original two- or three-dimensional shape of the fiber matrix after a period of 4 weeks following initial in vitro cell colonization.For example, in such an embodiment, the fiber matrix according to the invention preferably degrades and / or resorbs only after the cell composite, tissue and / or organ has been applied to / into an animal or human body.

[0061] Depending on the cell type, the cells must either be released from their matrix by enzymatic digestion or mechanical separation, or stimulated to grow under physiological conditions by placing them on or in a nutrient medium. The aforementioned fiber matrix acts as a guide structure for cell growth or as a guide structure for the accumulation of extracellular matrix and tissue components. The fiber material can be used in various configurations. The expert knows which configuration to choose based on the (cell) tissue to be produced. The possible configurations are the following: 1) as a surface element, as a dense fiber network which allows penetration that exceeds the dimensions of the applied cells, but only to a limited extent (the average size of the holes / fiber or network spaces is by no means larger, preferably even smaller than the average size of the cells to be cultivated; thus, the cells can "grow into the fibers", but only in such a way that they adhere well to the fiber substrate), with essentially the sole, or at least the primary, possibility of two-dimensional cell distribution and planar cell, tissue and organ growth; 2) as a three-dimensional spatial element, as a porous fiber network penetrable by cells (the average size of the holes / fiber or network spaces is by no means smaller, preferably even larger than the average size of the cells to be cultivated) with the possibility of three-dimensional cell distribution and spatial cell, tissue, and organ growth; 3) as a combination of 1) and 2) in the sense of a "composite graft" or organ by combining cells, tissues or organs and surface covering tissue (e.g., organ capsule). 3) This variant is considered for tissue structures composed of multiple cell types. For example, blood vessels consist of endothelium and connective tissue. The endothelium, with its flat structure, serves as the lining of a blood vessel, while the connective tissue acts as the vessel's supporting substance and forms the three-dimensional hollow structure. By combining 1) the endothelium as a flat element for the growth of endothelium and 2) the connective tissue as a three-dimensional spatial element for the growth of connective tissue, a vessel can ultimately be reconstructed.

[0062] Below are listed some tissue or cell types that are particularly suitable for propagation / production using one of the three variants and are therefore preferred.

[0063] For application 1) preferably the following tissues: epithelium, endothelium, urothelium, mucosa, dura, connective tissue; and preferably the following cells: pluripotent stem cells, chondrocytes (cartilage; chondrocyte proliferation requires a two-dimensional medium, whereas chondrocyte differentiation and cartilage matrix formation require a three-dimensional medium. With regard to cartilage, this only refers to cells when they dedifferentiate and proliferate. Differentiation follows in application 2)), osteocytes (bone; either two- or three-dimensional, the same applies here as for chondrocytes), nerve cells (nerves), hair cells (inner ear hearing organ) or their precursor cells at any stage of differentiation (e.g. pluripotent stem cells).

[0064] For application 2), the following cells: the cells described for application 1) after their areal proliferation, organ-specific cells (e.g., hepatocytes, nephrocytes, cardiomyocytes, pancreocytes), CNS cells with / without endocrine function, e.g., retina, neurocytes, pineal gland, dopaminergic cells, vascular cells (e.g., angiocytes), cells with endocrine or exocrine function (e.g., islet cells, adrenal cells, salivary gland cells, epithelial cells, thyrocytes), cells of the immune system (e.g., macrophages, B cells, T cells, or their precursor cells at any stage of differentiation, such as pluripotent stem cells). The cells of the immune system are cultured three-dimensionally because, after penetrating the blood-tissue barrier, they encounter a three-dimensional scaffold (depending on the tissue type) in the tissue and exert their effect there in three dimensions.

[0065] For application 3) the following cells / tissues / organs: trachea, bronchi, vessels, lymphatic tissue, urethra, ureter, kidney, bladder, adrenal gland, liver, spleen, heart, vessels, thyroid, tonsils, salivary glands, brain, muscle (smooth, striated), intervertebral discs, meniscus, heart, lungs, gall bladder, esophagus, intestine, eye.

[0066] Examples 1 to 3 of EP 1 262 542 A2 describe exemplary possible applications with fibers known from DE 196 09 551 C1. A further possible application of the material used in the invention is the colonization of the material with cells that have an endocrine or exocrine function and release active substances (e.g. hormones, interleukins, inflammatory mediators, enzymes) that exert an effect inside or outside the organism. This means that the material used according to the invention, when colonized with cells with an endocrine or exocrine function, can also be used outside the body to produce the aforementioned active substances, which are then made available to the body as medicaments using known methods. An effect exerted outside the body can serve to influence tissue or cells with the released substance.

[0067] Another use of the matrix is ​​as a bioresorbable bio-implant as a guide for the body's own wound healing beneath or at the level of the skin, mucous membranes, or within the body during operations on organs and tissues. For this purpose, the material is introduced, if possible, by a physician as a surface element or three-dimensional spatial element into the wound or organs / tissue, either directly or together with wound-healing substances or medications, for example during an operation. The properties of the bioresorbable, inorganic material in the form of fibers used according to the invention result in only a slight change in the tissue environment for the cells to be cultured; in particular, no acidic environment is created, thus preventing any negative influence on tissue and organ differentiation. Furthermore, the material undergoes complete degradation, regardless of the pH value of the tissue.Due to the simultaneous development of tissue and organs, vital tissue is always present, with the potential for penetration by anti-infective drugs in the event of unwanted colonization by pathogens (infection). Furthermore, the fiber matrix can be infused with active ingredients from various substance groups, with the potential to positively influence tissue and organ differentiation by exerting an active and passive effect at the site of application, as well as by exerting an effect at a distant site. These include, in particular, anti-infective agents, but also agents that support and modulate wound healing, the inflammatory response, and tissue differentiation, such as growth factors (IGF, TGF, FGF, etc.), glucocorticoids and interleukins, as well as chemotherapeutic agents and immunosuppressants.

[0068] The bioresorbable, inorganic fibers used enable the cells to adhere, allowing them to proliferate along the fibers and also allowing them to form a tissue or organ matrix. Simultaneously with the proliferation of cells or the formation of a tissue or organ matrix, the fiber structure degrades. Ideally, the tissue, organ, or cell structure is correlated with the degradation rate of the fiber material by varying the condensation of the fibers. The less advanced the condensation process (i.e., the elimination of water and thus polycondensation) is, the better the material can be degraded. The highest OH content and thus the most rapidly degradable fiber is obtained from freshly spun fibers that are subsequently immersed in ethanol. The condensation process is also influenced by the spinning parameters, i.e.,Stripping rate, atmosphere, spinning temperature, etc. Fibers produced in this way are biodegradable and bioresorbable and dissolve within an adjustable period of time, preferably from 2 to 10 weeks, with the degradation rate correlating with the number of silanol groups in the fiber. Another aspect concerns the use of the cells, organs, and tissues, after they have been treated with drugs and / or active ingredients, as in vitro models for drug-tissue-organ interactions. This allows animal experiments to be minimized or avoided.

[0069] In a method for producing a skin implant, in which skin cells are applied to the surface of a nutrient solution and allowed to grow, a surface element made of a fiber according to the invention is placed on the nutrient solution.

[0070] A skin implant consists of skin cells and a surface element with fibers according to the invention. A surface element (preferably planar) enables the extensive and thus rapid growth of skin cells, possibly with the use of infiltrated medications.

[0071] The invention will be explained in more detail with the following examples, without being limited thereto.

[0072] All stated viscosities were measured using Physica viscometers (type MCR300 and MCR301) at a shear rate of 10 s -1 measured at 4 °C. ExamplesExample 1 (not according to the invention)Silica sol material and bioresorbable and biodegradable silica gel material

[0073] As starting materials for the hydrolysis-condensation, 4 mol of TEOS (tetraethoxysiloxane) in ethanol were placed in a reaction vessel, and 7 mol of water in the form of a 0.01 N HNO3 solution were added and mixed with stirring. The mixture was stirred for 8 days at room temperature. The solution from the hydrolysis-condensation reaction was subsequently converted into a nearly water- and ethanol-free solution by evaporation and condensation in a beaker at 70 °C. This solution was single-phase, contained no solids, and had a viscosity of 1 Pa s (shear rate of 10 s). -1 at 4 °C). The solution was cooled to 4 °C and subjected to maturation at this temperature. After a maturation period of 18 days, a homogeneous single-phase sol mass with a viscosity of 43 Pa s (shear rate 10 s -1at 4 °C). The sol mass had no discernible solid phase. The homogeneous sol mass could be spun into fibers. It is also referred to as spinning dope.

[0074] The fibers were produced in a conventional spinning system. The spinning dope was filled into a pressure cylinder cooled to -15 °C and pressurized to 20 bar. The resulting force forced the sol through nozzles, forming threads. Depending on the nozzle diameter, the threads had a diameter of 5 to 100 µm.

[0075] The flowable, honey-like threads fell under their own weight into a spinning shaft located beneath the pressure cylinder, where they reacted to form a largely solid shape, forming dimensionally stable threads. The threads were still reactive on their surfaces, allowing them to bond together at the contact surfaces upon impact with a charging table (if provided). Adjustable stroke cycles of the charging table created further cross-links between the fibers, forming a nonwoven.

[0076] Advantageously, the threads obtained according to the invention were drier than fibers obtained under comparable spinning conditions and manufactured according to the process of DE 196 09 551 C1. As a result, less cross-linked and therefore more flexible nonwovens were obtained in the subsequent production of nonwovens according to the invention.

[0077] The nonwoven fabric produced according to the invention was subjected to a cytotoxicological test according to ISO 10993-5 (1999) and EN 30993-5 (1994). After extraction of the nonwoven material with DMEM ("Dulbecco's Modified Eagle's Medium"), the extract was sterile filtered and mixed with FCS (fetal calf serum; 10% FCS in the extract). This FCS-mixed extract was applied under sterile conditions to fibroblasts of the mouse cell line L929 and stored for 48 h at 37°C and a CO2 partial pressure of 5%.

[0078] Triton X 100 was used as a toxic control substance, and the cell culture medium was used as a non-toxic control substance. The cells were fixed and stained with methylene blue to determine the cell count. After acid extraction of the methylene blue, the dye content was measured photometrically, and the absorbance was compared with a standard curve to determine the cell count based on the dye absorbance. The measurement of the cell count compared to the control showed that the silica gel material according to the invention did not exhibit any cytotoxic properties. Measurements of the protein content (after alkaline lysis and protein content determination using the Bradford method) and the release of lactate dehydrogenase (LDH; photometric method) confirmed the results. Comparison example

[0079] Under the same conditions, toxicity measurements were conducted with a nonwoven material produced analogously to the example in DE 196 09 551 C1 with a hydrolysis-condensation time of 1.5 hours. Only 50% of the total reaction mixture could be spun. The resulting fiber material was found to be cytotoxic in the cytotoxicity test. Example 2 (according to the invention)

[0080] In another study, five different nonwoven fabrics according to the invention (KG211, KG226, AEH06KGF553, AEH06KGF563 and AEHKGF565) were compared with a resorbable control wound therapeutic (Promogran®) in a wound healing study on guinea pigs lasting over 3 months.

[0081] Differences in the nonwoven fabrics according to the invention result from the different manufacturing parameters listed in Table 1 below. Parameter / Description KG211 KG226 AEH06KGF553 AEH06KGF563 AEHKGF565 maturation Devices ripening vessel 500 ml PP cup 500 ml PP cup 500 ml PP cup 500 ml PP cup 500 ml PP cup Storage during ripening Refrigerator Refrigerator Refrigerator Refrigerator Refrigerator process Termination criterion / goal of the process step dynamic viscosity 39.2 loss factor 3.12 dynamic viscosity 41.2 loss factor 2.69 dynamic viscosity 45 loss factor 2.6 dynamic viscosity 73 loss factor 4.7 dynamic viscosity 44 loss factor 3.6 Ripening temperature 4 °C 4 °C 4 °C 4 °C 4°C Type of storage of the ripening cup resting, upright resting, upright resting, upright resting, upright resting, upright Duration of maturation 28 d 39 d 11d 10 d 19 d (Temporary) storage Devices storage vessel 500 ml PP cup 500 ml PP cup 500 ml PP cup 500 ml PP cup 500 ml PP cup Place of storage freezer freezer freezer freezer freezer Storage temperature - 80 °C - 80 °C - 80 °C - 80 °C - 80 °C Type of storage of the ripening cup resting, upright resting, upright resting, upright resting, upright resting, upright Spinning nozzle plate 7 nozzles, D = 150 µm 7 nozzles, D = 150 µm 7 nozzles, D = 150 µm 7 nozzles, D = 150 µm 7 nozzles, D = 150 µm Spinning tower approx. 2 m approx. 2 m approx. 2 m approx. 2 m approx. 2 m Charging table single-axle single-axle two-axle two-axle two-axle Thawing a frozen sample in the refrigerator 01 : 30 : 00 h 01 : 45 : 00 h 01 : 40 : 00 h 01: 30 : 00 h 02 : 00 : 00 h Tempering the spinning container Waiting time after 03 : 30 : 00 h 03 : 00 : 00 h 03 : 30 : 00 h 02 : 10 : 00 h 03 : 00 : 00 h Filling the spinning container Pressure in the spinning container 20 bar 20 bar 30 bar 20 bar 20 bar Temperature in the spinning tower 21°C 22 °C 23 °C 23 °C 22 °C Humidity in the spinning tower 20 % rF 33 % rF 34 % rF 20 % rF 22 % rF Spinning time for a fleece 6 minutes 5 minutes 6 minutes 12 minutes 6 minutes Movement pattern charging table Stroke length: 28 cm Stroke cycles: 16 / min Stroke length: 28 cm Stroke cycles: 16 / min Stroke length: 28 cm Stroke cycles: 16 / min Stroke length: 28 cm Stroke cycles: 16 / min Stroke length: 28 cm Stroke cycles: 16 / min Cutting Devices Cutting 5 × 5 cm 5 × 5 cm 5 × 5 cm 5 × 5 cm 5 × 5 cm Product analytics Basis weight 185 g / m 2 165 g / m 2 ca. 200 g / m 2 90 g / m 2 15 g / m 2 Thickness of the wound dressing 1.8 mm 2.1 mm 1.3 mm 0.8 mm 1.4 mm Fiber diameter 44 µm 56 µm 61 µm 45 µm 50 µm Behavior during the bending test very flexible, easy to split into individual layers very flexible, easy to split into individual layers Partial fracture, fracture of the outermost layers No inherent stability, extremely soft and flexible very flexible, no breakage, soft, sometimes splitting into individual layers Free ethanol content 0,61 w% 0,79 w% 0,87 w% 0,31 w% 0,67 w% Ethoxy group content 31,3 w% 32,1 w% 27 w% 32,8 w% 33,2 w%

[0082] For the study, dermo-epidermal wounds were surgically created in 36 guinea pigs. In each animal, the dermis and epidermis were cut on both sides of the spine in an approximate area of ​​6.25 cm 2 (2.5 x 2.5 cm) were removed. The wounds were created using a scalpel. The panniculus carnosus was not damaged. The wound dressings according to the invention and Promogran® were applied to the respective wounds. The materials were covered with a non-adhesive wound dressing (URGOTUL®) and a semipermeable adhesive polyurethane film (TEGADERM® or OPSITEE). A cohesive bandage (gauze and ELASTOPLAST®) protected the wound dressings over the wound. Each nonwoven fabric and the control material were tested on 5 animals, corresponding to 10 wounds (n = 10). Wound healing was evaluated at various time intervals using macroscopic, morphometric, and histological examinations.

[0083] No local intolerance was observed with any of the wound dressings tested. Morphometric studies showed that wounds treated with Promogran® achieved 50% wound closure somewhat earlier than those treated with the nonwovens. However, the time to achieve complete (100%) or near-complete (75%, 95%) wound closure was somewhat delayed for Promogran® compared to most nonwovens. 100% healing was achieved on average after approximately 23 days for KG211 and KG226, after approximately 24 days for AEH06KGF553, AEH06KGF563, and AEH06KGF565, and after an average of 26 days for Promogran®.

[0084] Histological examinations of KG211 animals 28 days after wound creation showed very good wound healing (see Fig.1a). Only the local tissue reaction was not yet fully stabilized, as isolated macrophages were still observed. Regardless, the granulation tissue was unremarkable, showed a normal thickness, and was covered by a newly formed, closed epithelial layer.

[0085] Histological examinations of the Promogran® animals 28 days after wound creation showed a strongly vacuolated granulation tissue permeated by polymorphonuclear cells (see Fig. 1b). In contrast to KG211, the granulation tissue was not covered by an epithelial layer.

[0086] The wound dressings according to the invention therefore show shortened wound healing while simultaneously generating a better granulation layer and minimizing inflammatory processes compared to Promogran® in the first 4 weeks of wound healing. Example 3 (not according to the invention)

[0087] The non-inventive fiber matrix KG119, made of biodegradable and / or bioresorbable fibers as cell support substance, as well as collagen and polyglycolic acid (PGA), was sterilized with gamma rays and placed in a complete medium in an incubator for one hour. The fiber matrix KG119 is a nonwoven fabric as a flat element. It was manufactured according to the process parameters shown in Table 2. The blank was punched out in a circular shape (see Fig. 3):

[0088] Before cell seeding, the medium was renewed. Human dermal fibroblast cells were then added. Cell culture was performed in 24-well Falcon 351147 plastic plates.

[0089] The medium was changed daily. The cell seeding medium was Gibco Dulbecco's Modified Eagle's Medium 42430-250 supplemented with 10% fetal calf serum (FCS) and 100 units / ml penicillin, 0.25 µg / ml amphotericin B, and 0.1 mg / ml streptomycin as antibiotics. During cell growth, 50 µg / ml ascorbic acid was added to the medium after the initial medium change. As the cell count increased, it became necessary to supplement the medium with a sodium bicarbonate buffer solution (7.5% Sigma). Cell standards (control cells without cell support) were cultured in standard tissue culture dishes and glass-bottom Iwaki plates.

[0090] The "alamarBlue®" assay was performed using Serotec reagents. These were diluted to 10% with HBSS (phenol-free) buffer, adjusted to 37°C, and filter-sterilized. The cell supports containing the cells were washed in PBS and then removed from their original plates and placed in tissue culture dishes and glass-bottom Iwaki plates.

[0091] The metabolic activity measured with the “alamarBlue®” assay is a function of the cell number and the metabolic activity of the individual cells. Fig. Figure 2 compares the activity (shown as a fluorescence measurement) of dermal fibroblasts on the different matrices collagen, PGA and the fiber matrix KG119 as well as cells without scaffold (control culture, Ctrl) at a culture duration of one week (Wk 1), 2 weeks (Wk 2) and 4 weeks (Wk 4).

[0092] The primary adhesion of cells to KG119 is strong and comparable to that of collagen. KG119 and collagen outperform PGA in terms of cell adhesion (data not shown). The longer the cells grow on the matrices, the more clearly the superiority of the KG119 fibrous matrix becomes apparent. Fig. Figure 2 shows that KG119 outperforms other cell support structures in terms of cell metabolic activity. This high metabolic activity is maintained throughout the entire measurement period (4 weeks). In contrast, collagen, PGA, and cells without cell support structures cannot maintain metabolic activity over this period. Only KG119 exhibits high cell adhesion and cell proliferation while maintaining metabolic activity throughout the entire period.

[0093] Fig.Figure 3 shows the collagen, PGA, and KG119 cell scaffolds before cultivation with human dermal fibroblast cells and after 4 weeks of culture. Collagen and PGA cell scaffolds contract and degrade into a dense tissue ball. Only KG119 retains its original shape. Within KG119, a dense dermal tissue mass has formed, and the fibers are firmly attached to the tissue.

Claims

[1] Silica sol material is available by a) a hydrolysis-condensation reaction of tetraethoxysilane is carried out under acid catalysis at an initial pH of 0 to ≤ 7, optionally in the presence of a water-soluble solvent, wherein for the acid catalysis, tetraethoxysilane and nitric acid water are used in a molar ratio in the range of 1:1.7 to 1:1.9, preferably in the range of 1:1.7 to 1:1.8, and the hydrolysis-condensation reaction is carried out for at least 16 h, preferably 18 h and between 20 °C and 60 °C, particularly preferably at room temperature (20 °C to 25 °C); and b) by subsequent evaporation with gentle mixing of the reaction system, a single-phase solution with a viscosity in the range of 0.5 Pa s to 2 Pa s (at a shear rate of 10 s -1 at 4 °C) is generated, c) this solution is subsequently cooled to a temperature of -20 °C to 10 °C, and d) is subjected to kinetically controlled ripening at a temperature of -20 °C to 10 °C, whereby a homogeneous sol is formed and the ripening is continued until the viscosity of the sol is between 30 Pa s and 100 Pa s (at a shear rate of 10 s -1 at 4 °C) and a loss factor of 2 to 5 (at 4 °C, 10 1 / s, 1% deformation). [2] Material according to claim 1, characterized by that the hydrolysis-condensation reaction in step a) is carried out at 20 °C to 50 °C over a period of at least 16 hours up to 4 weeks, preferably 18 hours to 4 weeks, particularly preferably 24 hours to 18 days, most particularly preferably between 3 and 8 days. [3] Material according to claim 1 or 2, characterized by that step b) takes place in a closed apparatus at a reaction temperature of about 30 °C to about 90 °C. [4] Material according to one of the preceding claims, characterized bythat the solution in step c) is cooled to 2 °C to 4 °C, preferably to 4 °C. [5] Material according to one of the preceding claims, characterized by that the maturation in step d) takes place at a temperature of 2 °C to 4 °C, preferably at 4 °C. [6] Use of a material according to any one of claims 1 to 5 as a material for the production of biodegradable and / or bioresorbable silica gel materials. [7] Use of a material according to one of claims 1 to 5 as spinning material for the production of biodegradable and / or bioresorbable fibers and nonwovens in human medicine and / or medical technology, in particular for wound treatment and / or wound healing. [8] Use of a material according to any one of claims 1 to 5 as a material for the production of a bioresorbable and / or bioactive powder and / or monolith and / or for the production of a bioresorbable and / or bioactive coating. [9] Biodegradable and / or bioresorbable fiber material, characterized by that a silica sol material according to one of claims 1 to 5 is subsequently spun in a spinning process. [10] Biodegradable and / or bioresorbable fiber material according to claim 9, characterized by that the fiber material comprises fibers, continuous filaments, nonwovens and / or fabrics. [11] Process for the preparation of a silica sol material which can be spun to at least 70% of the total reaction mixture, by a) a hydrolysis-condensation reaction of tetraethoxysilane is acid-catalyzed at an initial pH of 0 to ≤ 7, optionally in the presence of a water-soluble solvent, wherein for the acid catalysis, tetraethoxysilane and nitric acid water are used in a molar ratio in the range of 1:1.7 to 1:1.9, preferably in the range of 1:1.7 to 1:1.8, and the hydrolysis-condensation reaction is carried out for at least 16 h, preferably 18 h and between 20 °C and 60 °C, particularly preferably at room temperature (20 °C to 25 °C); and b) Generation of a single-phase solution with a viscosity in the range of 0.5 Pa s to 2 Pa s (at a shear rate of 10 s -1 at 4 °C) by subsequent evaporation with gentle mixing of the reaction system, c) cooling this solution subsequently to a temperature of -20 °C to 10 °C, and d) subjecting this solution to a kinetically controlled ripening at a temperature of -20 °C to 10 °C, whereby a homogeneous sol is formed and the ripening is continued until the viscosity of the sol is between 30 Pa s and 100 Pa s (at a shear rate of 10 s -1 at 4 °C) and a loss factor of 2 to 5 (at 4 °C, 10 1 / s, 1% deformation).

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