DE102004041368A1 - Sprayable, aqueous polyvinyl alcohol gel, useful e.g. in biomedicine, orthopedics and plastic surgery, comprises two polymers of different molecular weights and forms gel in situ after injection - Google Patents

Abstract

Sprayable polyvinyl alcohol (PVA) gel (A) that: forms a solution at 0-100[deg]C containing essentially only PVA and water; and comprises two PVAs, PVA1 and PVA2, with degrees of polymerization (DP) over 1000 and 50-1000, respectively, and both with degree of hydrolysis over 98mole%.

Description

The The present invention relates to polyvinyl alcohol gels, in particular Hydrogels for the use in the organism are suitable and at the place of application (in situ) from a viscous liquid by means of partial crystallization and network formation are formed.

polyvinyl alcohol (PVA), the bsw. obtained by hydrolysis of polyvinyl acetate can, is almost completely biological degradable and at elevated temperature good water-soluble. Hydrogels based on PVA can made with the consistency of biological tissue and cartilage be and have in the living organism outstanding stability and biocompatibility, which on the one hand in the high water content of these gels and on the other hand in the macromolecule self-founded is similar to that of the organism owing to the numerous hydroxyl groups Water, pointedly, "as polymerized Long-chain water is perceived. "Therefore, PVA gels (PVAG) for applications predestined in the living organism, especially PVAG, those without chemical cross-linking, without radiation crosslinking and without Aid be prepared by problematic chemicals.

at The previous process for the preparation of such PVAG is described in a first step at elevated Temperatures of bsw. 120 ° C a solution of PVA, which are cooled to room temperature and poured into a mold can. In the following, various methods of gel formation are used, being the PVA solution Frozen at least once and then thawed again (freeze / thaw). Typically, the solvent is water, show the PVA solutions a concentration Cp of PVA in the range of 5 - 15% and they are with cooling rates of about 0.1 ° C / min cooled to temperatures of about -15 to -30 ° C, about 1 - 24h at leave this temperature and then at about 0.1 ° C / min again thawed. After such a cycle the PVAGs are opaque and very soft. You can already at touch damaged the strength sm of a PVAG with Cp = 15% bsw. is lying in Range of 0.04MPa and modulus E in the range of 0.01MPa. By Repetition of the freeze / thaw treatment will be the mechanical one Properties continuously improved, after 10 cycles bsw. lies the strength sm in the range of 1MPa and the modulus of elasticity in the range of 0.1MPa. After another Cycles only slightly improve the mechanical properties. Such PVAG are often described in the prior art, bsw. from F. Yokoyama et al in Colloid & Polymer Science (1986), 264, pages 595-601.

A modified method is in US 4734097 starting from an aqueous PVA solution, for example in Example 3 with Cp = 8%, only one freeze / thaw cycle is used and the PVA-water mixture in the frozen state by applying a vacuum for 10 hours to a concentration Cp of 42% is dehydrated. After thawing, a whitish opaque gel was then obtained with a strength sm of 0.5MPa, which was proposed for use as artificial tissue in the human body. PVAGs produced by this process have been patented for a variety of applications, bsw. for artificial organs and membranes in EP 0107055 (artificial organs or membrands for medical use), as dermal gels in EP 0095892 (wound-covering materials), for use as a cooling medium in EP 0070986 (Gel for use as cooling-medium), as insulation gel for low temperatures in JP 57190072 , as a phantom for NMR diagnosis in GB 2209401 (phantoms for NMR diagnosis), or as golf ball filling in GB 2182571 (golf ball cores).

Another modified method is in US 6231605 described, starting from an aqueous PVA solution, for example, in Example 1 with Cp = 15% first three freeze / thaw cycles were applied at -20 ° C, after which the resulting gel was placed in water and thus swelled. The gel was transparent in this state but so weak that it could not maintain its shape outside of water. Then the swollen gel was subjected to a freeze / thaw treatment twice and then resulted in an opaque elastic gel with an E-modulus of about 0.4 MPa. Such gels have also been proposed as a tissue replacement in the human body. for heart valves, vessels, tendons, cartilage, meniscus urethra.

In another modified method in US 4663358 The PVA solution is prepared by means of mixtures of water and organic solvents, in particular DMSO (dimethyl sulfoxide), and then frozen at -20 ° C. Subsequently, the resulting gel is stored in water to largely extract the DMSO, dried in the atmosphere, and then dried under vacuum to extract the residue of DMSO. After swelling of the samples in water, PVAG were obtained which showed a transparency of up to 99% and had strengths of up to 5.6 MPa. Such transparent PVAGs have been proposed for biomedical and food industry applications.

As mentioned, the methods mentioned for the production of biocompatible PVAG have the common feature that a pourable solution is used and at least one freeze / thaw cycle is used. For in situ gelation, where the PVAG is located within the organism at the site of Ver is formed, the known methods are obviously not suitable. For such applications it is necessary that the PVAG be formed at temperatures around 37 ° C.

Short description the invention

The Invention describes a PVA and water-containing mixture which in the area of body temperature, especially in the living organism (in situ) by partial crystallization forming a network. The mixture is sufficiently low-viscosity, so they are minimally invasive, bsw. through a cannula to the place of use can be brought where the gelation starts quickly, bsw. in the Range of minutes. The viscosity of the mixture, the gelation kinetics and the final properties can do this varied widely and adapted to specific requirements become. Such in situ gelling PVA mixtures are substitutes of biological tissues and cartilage, bsw. can do that defective discs are repaired

Type of used PVA

While so far for PVAG with high strengths and moduli of elasticity, preferably fully hydrolyzed PVA with highest Polymerization degrees DP of up to about 18,000 were used in this Invention at least partially applied a contrary approach.

On the one hand becomes a first preferably fully hydrolyzed PVA1 with high DP used, on the other hand, in combination with such PVA1 also a preferably fully hydrolyzed PVA2 with medium and in particular low DP in the range of about 1000 - 50 used. It is immediately clear that the viscosity of the solution is reduced by the mixture of PVA1 and PVA2 will and higher Concentrations Cp processed by solution method can be. Mowiol 3-98 with DP = 360 bsw. indicates at Cp = 20% and at RT one viscosity of only 100 mPas and only at Cp of about 60% at RT limiting viscosity of 10'000mPas. At 100 ° C Cp can even be up to about 70%.

At first you would expect that by the proportion of PVA2 the mechanical properties of the resulting PVAG can be reduced, the benefit of higher solution concentration thus at least partially canceled. Surprisingly however, an adverse effect was noted. Will be at the same In the event of a constant Cp, a proportion of PVA1 replaced by PVA2 results PVAG with higher E moduli, with the supposed disadvantage turns out to be an advantage and to obvious advantage of the higher solution concentration Cp is added. This tendency remains up to high degrees of substitution of PVA1 valid by PVA2. Solid elastic gels with high elasticity can bsw. also with PVA1 : PVA2 = 5: 95 while using PVA2 alone brittle Gels with low elasticity result. The effect of PVA2 can be explained by the fact that short-chain PVA very good, i. fast, complete and especially at temperatures> 0 ° C. can crystallize, whereby the crystalline portion of the PVAG is increased. The better crystallizability from PVA2 opposite PVA1 is at least partially due to the different crystallizations Entropy conditionally. Next finds a heterocrystallization of PVA1 and PVA2 instead, i. the crystallites, which are the points of attachment of the gel constituting the gel have both PVA1 as well as PVA2 macromolecules on, with the shorter-chain PVA2 macromolecules the crystallization of segments of PVA1 macromolecules into heterocrystallites induce. Overall, higher network densities are thus achieved. i.e. more closely meshed networks and thus higher moduli of elasticity of the resulting PVAG.

By the use of PVA3, which long chain branching with a DP these long chains of> 50 is a further improvement of the mechanical properties of PVAG possible, especially when PVA3 is used in combination with PVA2 and / or PVA1 becomes. By the different side chains by heterocrystallization are incorporated into different crystallites, resulting in additional tie points of the network, these join points then covalent nature.

While previously pourable concentrations Cp in the range of 5 to a maximum of 30% (depending on the DP of the PVA) were common, now the range of 30 to about 90% has become accessible, with lower concentrations Cp than 30% are possible with this method , which is the case especially with very high DP. By using a proportion of PVA2 that contributes only little to the viscosity, the viscosity can be kept low even at high concentrations Cp. With the increase in Cp, PVA-water blends show a very different behavior with respect to gel formation compared to low-concentration solution gelation. While in the freeze / thaw process freezing of the PVA requires the removal of water (formation of frozen ice phases in addition to very high Cp or low water content phases), thereby inducing crystallization, Cp is high from the start in the new process and the use of freeze / thaw cycles is no longer mandatory. The gel or network formation by crystallization is possible even at higher temperatures. Bsw. is at Cp at 40% gelation at room temperature as effective as when using freeze / thaw cycles. The higher the Cp and the PVA2 content is set, the higher the temperature, the gel formation begins, so even temperatures> RT can be used. In the simplest case, a PVA-water mixture can be easily stored after shaping, eg at body temperature, whereby the gelation takes place on a time scale of minutes to days. The strength of the obtained PVAG increases steadily with Cp, whereby values of bsw. 25MPa and moduli of 30MPa can be adjusted and also complete transparency can be obtained. When PVA prepared in this way is immersed in water, swelling takes place, as a result of which Cp and the mechanical properties decrease. The degree of swelling is essentially determined by the set network density and can also be defined by its parameters, in particular minimized.

Full Description of the invention

PVA1, PVA2, PVA3

to Selection of suitable PVA types will be three groups of parameters distinguished the parameters which the regularity of the PVA such as degrees of hydrolysis DH, content G of 1,2-glycol, tacticity, and proportion at short chain branches, the parameters of the molecular weight distribution such as DPn, DPw, as well as the parameters of the topology of macromolecules such as degree of branching of long chains and length this long or side chains.

With regard to the first group of parameters, the same requirements are imposed on PVA1, PVA2 and PVA3, which allow the best possible crystallizability of the PVA and high stability of the crystallites. Thus, deviations from the ideal structure [-CH ₂ -CHOH-] _n should be kept proportionately as low as possible.

Of the Degree of hydrolysis DH in mol% is> 95, preferably> 98, more preferably> 99, most preferably> 99.8.

Of the Content G of 1,2-glycol in mol% is <3, preferably <1, more preferably <0.5, most preferably <0.2.

The number of short chain branches per monomer unit is <10 ^-2 , preferably <10 ^-3 , more preferably <10 ^-4 , most preferably <10 ^-6 .

Further disorders the regularity Like carbonyl groups in the chain are also undesirable, with usual However PVA is negligible, typically <0.02mo1%.

Regarding the tacticity an atactic conformation is preferred over an isotactic one, most preferred is a syndiotactic conformation, bez. one preferably high proportion of syndiotactic diads. The tacticity of PVA is determined by the nature of the monomers, whereby the precursor polymer, from which then the PVA is obtained, polymerized, and by the reaction conditions in this polymerization, with decreasing Temperature during the polymerization increases the syndiotactic fraction.

If the precursor polymer is polymerized from vinyl acetate derivatives of the type CH ₂ = CHOCOR, wherein R bsw. H, CH ₃ , C ₃ H ₇ , C ₄ H ₉ , CCIH ₂ , CCI ₃ , CF ₃ C ₄ H ₅ F ₄ , C ₆ H ₇ F ₆ , or C ₆ H ₅ may be, the proportion increases syndiotactic diads with the volume of the group R to (while the 1,2-glycol content advantageously decreases), and the tacticity obtained in the precursor polymer is retained in the subsequent hydrolysis to the PVA. Preference is therefore given to monomers for the polymerization of the precursor polymer, such as vinyl acetate, vinyl chloroacetate, vinyldichloroacetate, vinyl bromoacetate, in particular vinyl trifluoroacetate.

Becomes the precursor Polymer of aliphatic vinyl esters produced, are also high levels of Syndiotatkischen Diaden get while the resulting PVA also has very low 1,2-glycol contents exhibit. Examples are vinyl format, vinyl propionate, vinyl butyrate, Pivalate. By means of vinyl pivalate can also very high molecular weights be achieved.

fully hydrolyzed PVA obtained from polyvinyl acetate are also at high crystallization levels at 100 ° C soluble in water, while Fully hydrolyzed PVA, whose precursor polymer of vinyl acetate derivatives with voluminous Group R (e.g., vinyl trifluoroacetate) or aliphatic vinyl acid esters (e.g., vinyl frit, vinyl pivalate) as a result of low 1,2-glycol content and high syndiotactic content Diads even at 100 ° C in insoluble Shape can be obtained. From this, the importance of these parameters for the crystallizability and the stability the crystallites clearly. Such PVA are therefore for the present Invention particularly suitable.

With regard to the molecular weight distribution, different requirements are placed on PVA1, PVA2 and PVA3. For previous PVAG-based PVAGs, the literature typically gives a value of 1000 to 1500 as a lower limit for the average degree of polymerization DP, the type of average (DPn, DPw, DPv) usually being unspecified. The polydispersity P = DPw / DPn of PVA obtained by saponification from polyvinyl acetate is in the range of about 2 - 2.5, with which a conversion of these averages and an interpretation are possible. At DP around 500 friable and brittle PVAG are obtained according to previous methods. This is understandable because the macromolecules are not long enough to form effective connections between crystallites. Thus, the crystallites can easily slip off each other, and hardly any strength is obtained. As the DP decreases, this friable consistency continues to increase. A prerequisite for effective compounds is that at least two segments of a macromolecule be incorporated into at least two crystallites. As the DP increases, the number of crystallites involved in different segments of a PVA macromolecule increases, and mechanically more stable and increasingly elastic networks are obtained, which is why PVAGs as high as possible are advantageous in previous PVAGs. The fact that deep DP only contains friable and brittle PVAG may have been a reason why deep DP was not considered for PVAG.

For PVA1 and PVA3 will be for the present invention uses PVA with DP> 1000, preferably> 2000, more preferably> 3000, most preferably> 5000. The upper limit is due to the state of the art for the production of most molecular PVA given, where currently PVA with DP up to about 18,000 can be produced.

For PVA2 be PVA with comparatively low DP used, on the one hand to the viscosity the solutions and to reduce melting, on the other hand, high crystallization rates and degrees of crystallinity, as well as maintain high network densities. PVA2 is for the present Invention with DP in the range of about 50 - 1000, preferably before 60 - 500, still more preferably 70-300, most preferably 75-200 used. The lower limit is due to the stability of the PVA2 formed crystallites (where by heterocrystallization Segments of PVA1 and PVA3 are installed). The slat thickness of this Crystallite is directly proportional to DP and DP at low DP stability across from Temperature and solvent (Water) increases with the lamella thickness. At high DP takes the Lamella thickness usually again, because then the macromolecules no longer crystallize in the fully extended conformation, but preferably a refolding takes place and deeper lamella thicknesses result. Thus, through the choice of suitable DP of PVA2 also has a positive effect on the stability the crystallites are obtained, which in particular for in vivo Applications of PVAG is significant. The optimum DP range in this regard lies at about 75 - 200.

Concerning polydispersity P = DPw / DPn of the three PVA types, especially in PVA2, P <5 is still preferred more preferably <3, most preferably <2.

Regarding the Topology are common PVA predominantly linear, long-chain branching occurs at usual PVA if any, then rarely on. Almost complete or complete linearity is preferred for short-chain PVA2, this condition being practical always fulfilled is while long chain PVA1 need not necessarily be as linear as possible Proportion of long chain branches may even be advantageous in PVA1 be, if the length of this Side chains one DP> 50 having. For PVA3, however, there is a significant proportion of long-chain branches for its functionality the decisive characteristic feature, wherein for the degrees of polymerization DP these long or side chains apply the same requirements as for the DP of PVA2. Thus, it is possible that the different side chains of a macromolecule PVA3 can be incorporated into different crystallites (together with PVA1 and / or PVA2), creating an additional Crosslinking of these crystallites results, so get higher network densities become. PVA3 PVA's are currently not commercially available. However, PVA obtained from polyvinyl benzoate is known to be effective at suitable reaction conditions in the polymerization of vinyl benzoate Langkettenverzweigungen can be obtained. A another possibility The preparation of PVA3 can be achieved by grafting PVA of type PVA2 on PVA type PVA1, the number and length of the Side chains can be adjusted.

mixtures

Of the Proportion of PVA2 based on PVA in% by weight is in the range 10-99, preferably 20-96, most preferably 30-94. A high proportion of PVA2 is especially useful for setting high moduli of elasticity advantageous, with surprisingly still very high strains to be obtained.

Of the Percentage of PAV3 based on PVA in% by weight is in the range 1-80, preferably 2 - 60, on most preferred 3 - 50.

Of the Proportion of PVA based on PVA and swelling agent in% by weight in the range 5 - 90, preferably 7-95, most preferably 10-80.

processing and gelation

For the production of PVAG according to the invention, the components PVA1, PVA2 and optionally PVA3 are converted into an aqueous solution. The components can be dissolved separately or together and for the preparation of the solution, the known standard methods can be used. It is important to have a thorough mixing of the components, for which various mixing methods can be used. The property of gelability under in situ conditions (around 37 ° C, im Body), the kinetics of gelation and the final properties of the gel are adjusted by the type of components used, their ratio and the water content.

swelling

When Swelling agents are here swelling agents in the strict sense, as also solvents designated. The most important swelling agent is water and water in most cases used as sole swelling agent or in mixtures with others Swelling agents, however, besides those in the prior art Described solution and solution Swelling agents and mixtures thereof in question as bsw. DMSO, dimethylformamide, Acetamide or polyols such as bsw. Glycerine, erythritol, xylitol, sorbitol, mannitol, Galactitol, tagatose, lactitol, maltitol, maltulose, isomalt, methylene glycol, Ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol, Butanediol, pentanediol, hexanetriol. The swelling agent can also have a salt content (physiological saline solution).

Other polymers

Next PVA allows the PVAG to modify the properties and for specific Applications contain other polymers, bsw. synthetic polymers like bsw. Polycarbonates, polyacrylates and polymethacrylates, polyethylene glycols, Polyethylene oxides, polyvinylpyrrolidones, polycaprolactones or polymers natural Origin like bsw. Hydrocolloids and polysaccharides, in particular Strength and strength Derivatives.

additives

When Additives are simple fillers and functional fillers or active ingredients.

applications

There the inventive PVAG obtained with a wide range of mechanical properties can be a whole range of biomedical in situ applications are possible where tissue and cartilage in the body wholly or partially can be replaced, bsw. in the field of orthopedics. Examples are replacement and repair of disc, tendons, ligaments, joint Surfaces, Meniscus or soft tissues, nerve sheath, urethra, heart valves etc. Typically, the gellable viscous PVA mixture is added the place of the mission where the network building starts. Such in situ gelling PVA mixtures can also be used as a substitute for silicone be used, bsw. For cosmetic measures.

analyzes

The Mechanical properties were measured using an Instron Tensile Tester carried out, the samples were punched out of pressed films of 0.5mm thickness and had a sample length of 13mm and a width of 2mm. The stretching speed was 10cm / min. The measured values obtained are averages of at least 5 individual tensile tests. For control was after the Tensile test of the water content of the examined samples.

example 1

components: PVA 1: Mowiol 66-100, nearly 100% hydrolyzed, DPw = 4500 PVA2: Mowiol 3-98, 98% hydrolyzed, DPw = 360

10 g PVA1 was dissolved with 100 ml H ₂ O in the flask while stirring with a magnetic stirrer at 100 ° C. for 30 min. From this homogeneous solution, 35g was transferred to a Brabender Kneader. The temperature of the kneader was 90 ° C, and the speed was set to 180upm. To the solution in the kneading chamber was added 30 g of PVA2 in the form of granules. After a mixing time of 4 minutes, a homogeneous mixture was obtained. The water content of this mixture was 49% (water based on PVA and water) and the proportion of PVA1 based on PVA1 and PVA2 was 9.6%. Of the mixture 5ml was drawn into a syringe, which had previously been heated at 40 ° C. After 3 minutes, the PVA solution was discharged through an injection needle of 5 cm in length and 0.5 mm inner diameter into a Petri dish heated to 40 ° C. The viscosity was low enough that the solution could be discharged through the injection needle with little pressure. After about 3 minutes, a noticeable gelation could be detected.

Further Features, advantages and applications of the invention result from the following description of the figures, wherein:

1 : shows a PVA mixture according to the invention when exiting an injection needle;

2 : shows the time course of curing the PVAG according to the invention.

1 shows the in situ gelable PVA mixture at the exit from an injection needle of 5cm length and an inner diameter of 0.5mm. After about 3 minutes, a significant gel formation could be detected.

2 shows the cure of in situ PVAG at 40 ° C. After 1 h already 62% of the modulus of elasticity was after 2 bez. Received 5 days or 71% of the strength after 2 bez. 5 days.

The discharge of the PVA solution through the injection needle is in 1 shown. In 2 the curing process is represented as a function of time on the basis of modulus of elasticity and strength. The elongation at break varied only slightly with the hardening time and was around 300%.

This PVAG is suitable For the restoration of defective discs. It is at still intact annulus a gel strength in compression of 1-2MPa needed the gel volume is at max. about 5ml, and the temperature of the injected PVA solution should be below about 56 ° C, gelation at 37 ° C drain, and the viscosity the PVA solution should be deep enough that it can be injected through a cannula of about 2mm. Rapid gelation is required to allow the injected mixture through the puncture channel can no longer escape. Not anymore intact annulus (e.g., in the presence of a hernia) is the required Gel strength at 4-6MPa while the other conditions remain the same except for the diameter the cannula, which can be up to 6mm tall.

Example 2

The same components and the same procedure as in Example 1, but the solution of PVA1 with 7g PVA1 and 100ml H ₂ O was prepared and was added in the kneader 25g PVA2. After a mixing time of 3 minutes, a homogeneous mixture was obtained. The water content of this mixture was 54.5% (water based on PVA and water), and the proportion of PVA1 based on PVA1 and PVA2 was 8.4% Of the mixture 5ml was drawn into a syringe, which had previously been tempered at 40 ° C. was. After 3 minutes, the PVA solution was discharged through an injection needle of 5 cm in length and 0.5 mm inner diameter into a Petri dish heated to 40 ° C. The viscosity was significantly lower than in Example 1 and was about 1500mPas. After about 10 minutes, a slight gel formation could be detected. After one day, the modulus of elasticity was around 4 MPa, the strength at around 1.5 MPa and the elongation at break at around 200%.

The Examples 1 and 2 show that the kinetics of gel formation and the Final properties very sensitive to water content and proportion depend on PVA2. There is nevertheless a wide range of possibilities of different Formulations that can gel in situ. By bsw. instead of Mowiol 66-100 a nearly fully hydrolyzed type with reduced Molecular weight as Mowiol 28-99 is used, the proportion increased to PVA1 be without the viscosity increases too much. As a result, PVAGs with higher elongation at break can be obtained become. Instead of Mowiol 3-98, a fully hydrolyzed type of comparable Molecular weight used, the same water content is the Gel formation kinetics are accelerated and will receive higher moduli and strengths, or Alternatively, the water content can be increased, in which case the viscosity decreases comparable results regarding Kinetics and mechanical properties are obtained. The specified Examples are therefore not intended to be limiting.

Claims (11)

Polyvinyl alcohol gel, characterized in that the gel is formed in situ by partial crystallization. Polyvinyl alcohol gel according to claim 1, characterized that the gel of a polyvinyl alcohol and water Mixture is obtained, wherein the viscosity of the mixture in mPas at 40 ° C <100,000, preferably <50,000, most preferably <10,000. Polyvinyl alcohol gel according to one of the preceding Claims, characterized in that the gel formation is in situ in the range of Minutes after dumping the polyvinyl alcohol mixture. Polyvinyl alcohol gel according to one of the preceding Claims, characterized in that the gel comprises at least two polyvinyl alcohols of the types PVA1, PVA2 and PVA3, as well as a swelling agent, wherein the degrees of polymerization DP of PVA1 and PVA3 are> 1000 and the Degree of polymerization DP of PVA2 is in the range 50-1000 and PVA1 and PVA2 are predominantly linear while PVA3 has a proportion of Langkettenverzweigungen. Polyvinyl alcohol gel, characterized in that its modulus E and / or its strength sm in MPa> 0.1, more preferably> 0.5, in particular> 1, most preferably> 5, and optionally the stress-strain curve at an interval within the range from 0 - 300% Stretching a negative curvature having. Polyvinyl alcohol gel, according to one of the preceding claims, characterized in that a) the degree of hydrolysis of PVA1, PVA2 and PVA3 in mol%> 95, preferably> 98, more preferably> 99, most preferably>99.8; and b) the content of PVA1, PVA2 and PVA3 to 1,2-glycol is in mol% <3, preferably <1, more preferably <0.5, most preferably <0.2; and c) the number of short chain branches of PVA1, PVA2 and PVA3 per monomer unit is <10 ^-2 , preferably <10 ^-3 , more preferably <10 ^-4 , most preferably <10 ^-6 ; and d) PVA1, PVA2 and PVA3 preferably have an atactic conformation, most preferably a predominantly syndiotactic conformation. Polyvinyl alcohol gel, according to one of the preceding Claims, characterized in that a) PVA1 and PVA3 a degree of polymerization DP> 1000, preferably> 2000, more preferably> 3000, most preferably> 5000; and b) PVA2 has a degree of polymerization DP in the range of 50-1000, preferably 60-500, more preferably 70-300, most preferably 75-200 having. Polyvinyl alcohol gel, according to one of the preceding Claims, characterized in that a) the proportion of PVA2 related on PVA in% by weight in the range 10-99, preferably 20-96, most preferably 30-94 lies; and b) the proportion of PAV3 based on PVA in% by weight in the range 1 - 80, preferably 2 - 60, most preferably 3 - 50 lies; and c) the share of total PVA relative to total PVA and swelling agent in% by weight in the range 5-90, preferably 7-95, on most preferred is 10-80. Polyvinyl alcohol gel, according to one of the preceding Claims, characterized in that a) whose modulus E in MPa> 0.1, preferably> 1, more preferably> 5, in particular> 10, most preferably> 15 and optionally the stress-strain curve at an interval within the range from 0 - 300% Stretching a negative curvature having; and or b) whose strength sm in MPa> 1, preferably> 3, more preferably> 5, in particular> 10, most preferably> 15, and optionally its elongation at break eb in%> 50, preferably> 100, even more preferably> 150, most preferably> 200 is. Polyvinyl alcohol gel, according to one of the preceding Claims, characterized in that its degree of swelling Q in water in the range 1.01 - 3, preferably 1.03 - 2, most preferably 1.05 - 1.5 lies. Use of a polyvinyl alcohol gel after a of the preceding claims as in situ PVAG in the field of biomedicine or in the area of Tissue and scaffold engineering and in orthopedics, bsw. as artificial Organs and membranes, heart valves, vessels, urethra, tendons, joint resurfacing, Cartilage, Meniscus or Intervertebral Discs (Total Disc Replacement, Nucleoplasty, Facet Replacement, Segment Replacement, Vertebroplasty, Kyphoplasty, Lordoplasty) as a replacement or repair of tissue or in the field cosmetic or plastic surgery bsw. as an alternative to Silicone implants.