in endoprosthesis practice by way of purposeful injections to remedy preferably those defects in humans which are due to traumatic, congenital or age distorsions of the shape and dimensions or due to loss of form stability of some organs consisting of soft tissues. e.g.: plastic surgery for correcting the form and dimensions of the face and other parts of the body and, specifically, mammoplasty (preferably in the case of mammary aplasia or hypomastia), male sexology (in the cases of feeble erection) for improving potency through injecting an elastic medium into spongy vascular tissue of the penis.

Demands for an improvement in bodily shape and functioning as mentioned above and other similar cases have become widespread and are frequently reasoned by the mere patient's desire.

That is why biocompatible materials for the above mentioned applications should satisfy some hardly consistent requirements. Among the most important requirements are:
 

	long-term (preferably life-long) retaining of the shape and dimensions of an organ, where an endoprosthesis has been placed, irrespective of the age when the patient was operated;
	minimal trauma occurance and the shortest possible introduction of a biocompatible material, especially in large-dosage (up to 1000 ml) applications.

That is why to meet the above application requirements it is practical to use gelling biocompatible materials.

Actually, minimal trauma occurance and the shortest possible introduction of a biocompatible material, absence of carcinogenicity and minimal allergic reactions being the fact, are achieved by using a water solution of bovine collagen which, being a highly refined and partially depolymerized product, turns into an elastic and mechanically stable hydrogel at a temperature below 37 deg. C. following injection into the organ that has been treated as to shape and dimensions (see (Ford Ch., Martin D. M., Warner Th, F. Injectable collagen in laryngeal rehabilitation//LARYNGOSCOPE, 1984, 94, pp.513-518).

Being protein, collagen, however, would completely be resorbed in the patient's body in a considerably short period of time (less than half a year).

It is, therefore, suitable for use in endoprosthetic practice primarily in the cases when a complete substitution of an endoprosthesis for connective tissues is acceptable or when a patient, according to medical indications, needs a precisely temporary endoprosthesis.

It should be also noted that due to its resorption ability and to intra-tissue and inter-tissue migration, and whereas it is susceptible of an enzyme attack, the bovine collagen solution is practically unsuitable for application as a material for long-term endoprostheses.

Considering the above, the gelling biocompatible materials based on synthetic polymers are more preferable.

Thus, the biocompatible gelling material in the form of hydrophilic esters of polyglycols and of metacrylic acid is known to be applied in endoprosthetic practice (Kresa L., Rems T.. Wichterle O. Hydrogel implant in vocal cord//Otolaryngol. Head Neck Surg.—1988, V. 98, No 3. pp. 242-245).

A required dose of such dry material is implanted via a section in the region of cosmetic or functional treatment and then the operative wound is satured. Thereafter, the material swells by absorbing water from adjacent tissues, to thereby provide for a local increase in the volume of the corrected organ.

This biocompatible material is characterized by a high biochemical stability. In application, however, a durable therapeutic effect is achieved at the expense of traumatic surgical interventions associated with edemas and aseptic inflammations.

Therefore, the most promising for endoprosthetic practice and other applications are commercially available injectable liquid biocompatible gelling materials.

The biocompatible gelling material as a solution containing water-insoluble polymers, among them non-cross-linked acrylonitrile polymers or their copolymers, polyvinylacetate, a linear or low-branched polymer or copolymer of 2-hydroxyethyl-acrylate and methyl-acrylate, poly-n-vinyliminocarbonile and dimethylsulfoxide or other polar readily miscible with water organic solvents, may be exemplified (Stoy V., Chvapil M., U.S. Pat. No. 4,631,188; 1986). In obtaining copolymers, use may be made of additional monomers, such as acrylamide (including N-substituted), acrylhydrazide (including N-substituted), acrylic acid and acrylates, glutarimide and vinyl sulfone; and the polar readily miscible with water solvents such as glycerol and its mono- or diacetates, methanol, ethanol, propanol and izopropanol, dimethylformamide, glycols and other suitable solvents.

This material is highly efficient in the treatment of minor cosmetic or functional defects, specifically lips and other parts of a face.

However, in correcting the mammary fonn and dimensions with endoprostheses, up to 1 liter of the material can be required. In such cases, an amount of an organic solvent, injected together with the gelling polymer, sustantially exceeds the physiologically permissible minimum to result in erythema and, in some cases, an allergic shock. Also, due to a linear structure of the gelling polymer applied, endoprostheses are observed to have a low form-stability, the greater in volume, the lower in quality.

That is why, the most preferable are commercially available hydrogels that contain no allergens.

Among them, the most closely bearing on the invention is a biocompatible hydrogel containing 3.0% by weight of a polymer based on acrylamide produced by the use of a free-radical polymerization initiator (specifically, ammonium persulfate) in a dispersion medium such as bidistilled pyrogen-free water (USSR Inventor's certificate 1,697,756).

This hydrogel is in fact completely biocompatible with the man's tissues and liquids in all the above aspects and, therefore, can be applied in considerable (up to 1 liter) amounts, causing no expressed negative biochemical and biological aftereffects. In the region of injection, it forms a structure readily permeable not only by water, ions, oxygen but by low-molecular metabolites as well. The hydrogel implants, are invaded at a considerably high rate (by the 5-6th month) with a young fibrous tissue of a recipient.

This hydrogel, however, has low viscosity and, therefore, low elasticity and high mobility. Water contained in the hydrogel is loosely bound with the macromolecules of polyacrylamide and is readily removed from the implants to result in manifest shrinkage thereof and a considerable decrease in cosmetic or teurapeutic effect. That is why, in the case of placing voluminous (e.g., intramammar) endoprostheses, the implants show as low resistance to external deformation loads and shrinkage as large is their initial volume.

Due to its high fluidity, this hydrogel has low efficiency.

Therefore, the invention has for its object to provide a biocompatible hydrogel which, by improving the polyacrylamide composition, would ensure elasticity, shape retention, and stability of bulky implants and offer greater therapeutic and cosmetic results in endoprosthetic applications.

The above problem has been resolved by providing a biocompatible hydrogel containing a polymer based on acrylamide produced by using an initiator of radical polymerization in pyrogen-free water as a dispersion medium, in which according to the invention said polymer is cross-linked polyacrylamide produced by using a biocompatible cross-linking agent.

Being permeable for water, ions, oxygen and low-molecular metabolites and being suitable for applications by injection, the hydrogel of the invention has a more regular and more advantageous water-binding structure to thereby provide for bulky, highly elastic and form-retaining implants (e.g., intramammary endoprostheses and supporting rods in the spongy vascular tissue of the penis tampons in lung caverns) that are invaded with a soft highly-vascularized connective tissue at an extremely slow rate (months to years). Due to structural, biochemical, anatomical and physiological advantages, as described above, there is a substantional cosmetic and/or therapeutic effect as well as an encrease in durability of such effects in endoprosthetic applications.

According to the first further caracterizing feature of the invention the biocompatible hydrogel contains cross-linked polyacrylamide produced by using methylene-bis-acrylamide, as a cross-linking agent, and a mixture of ammonium persulphate and tetramethylenediamine as an initiator of polymerization. Methylene-bis-acrylamide is ananalogous to the base monomer (acrylamide) both by its composition and biocompatibility, while use of the above-mentioned mixture of polymerization initiators is favorable in the fairly regular cross-linking of polyacrylamide chain macromolecules to provide an elastic space network suitable for injecting the hydrogel.

According to a further aspect of the invention the biocompatible hydrogel contains from 3.5 to 9.0% by weight of said cross-linked polyacrylamide. This range of concentration is providing the maximum therapeutic or cosmetic effect in the injection endoprosthetic practice or tamponing. Concentrations below 3.5% make the hydrogel unstable only to be applied as a base for medicinal ointments or electroconducting immersion media for cardio- or encephalography, while concentrations above 6.0% decrease fluidity of the hydrogel practically to zero and is practicable, in manufacturing relatively firm, form-retaining, precast endoprostheses that require a surgical procedure to have access to the region of placing such an endoprosthesis.

The invention is hereafter disclosed by:
 

	a description of the initial reagents, method of preparing the novel biocompatible hydrogel, examples of carrying out the method, and the results of laboratory tests on said hydrogel;
	examples of the formulations of the biocompatible hydrogel;
	a description of the methods and the results of chemical, biochemical and medical studies of the novel biocompatible hydrogel;
	a description of the ways of correcting cosmetic and functional defects of a human body by means of purposeful injections with the novel biocompatible hydrogel, and
	information on its practical applications.

To prepare the novel biocompatible hydrogel use was made of the reagents as shown in Table 1.

Apart from bidistilled water, reagents commercially avaliable under the tradename REANAL (Hungary) were used in the experiments, namely: acrylamide and methylene-bis-acrylamide in the form of white crystals, tetramethylethylenediamine as a white oily liquid and ammonium persulfate in the form of colorless crystals.

Conventionally, the novel biocompatible gel is prepared by the following method:

Under aseptic laboratory conditions, calculated amounts of acrylamide and diluted water solutions of the cross-linking agent (methyl-bis-acrylamide) and initiators of polymerization (ammonuim persulfate and TMED), are introduced into a sterile glass vessel. These reagents are thoroughly stirred, then diluted with water (alternatively with the physiological solution, alternatively other diluted water solution of a physiologically neutral salt, e.g, sodium acetate); the mixture is then filtrated and the filtrate is allowed to stand until the hydrogel of cross-linked polyacrylamide (hereinafter CL PAA) is obtained.

The prepared CL PAA hydrogel is controlled for the following characteristics:
 

	appearance by sight (the hydrogel should be transparent, colorless, free of impurities);
	refraction index (to be within the range of 1.334 to 1.350);
	pH (to be within the range of 7.0-9.0);
	heavy metal contents (to be no less than 0.001% by eight), and
	sterility.

The invention will be readily understood by reading the following examples.

EXAMPLE 1

Preparation of a low-concentration biocompatible hydrogel

20.3 g of acrylamide, 8.7 ml of a 2% methyl-bis-acrylamide aqueous solution, 7.5 ml of a 1% TMED aqueous solution, and 15 ml of a 4% ammonium persulfate aqueous solution were mixed in a 1 liter capacity glass vessel. Water was then added to obtain a total volume of 580 ml, the mixture was filtered through a glass filter and the filtrate was allowed to stand for at least 20 minutes until 3.5% CL PAA hydrogel was formed.

EXAMPLE 2

Preparation of a high-concentration biocompatible hydrogel

34.2 g of acrylamide, 60 ml of a 1% methyl-bis-acrylamide aqueous solution, 6 ml of a 1% TMED aqueous solution, and 25 ml of a 0.48% ammonium persulfate aqueous solution were mixed in a 1 liter capacity glass vessel. Water was then added to obtain a total volume of 380 ml, the mixture was filtered through a glass filter and the filtrate was allowed to stand for at least 20 minutes until 9% CL PAA hydrogel was formed.

EXAMPLE 3

Preparation of a medium-concentration biocompatible hydrogel

24 g of acrylamide, 50 ml of a 1% methyl-bis-acrylamide aqueous solution, 25 ml of a 1% TMED aqueous solution, and 50 ml of a 1.3% ammonium persulfate aqueous solution were mixed in a 1 liter capacity glass vessel. Water was then added to obtain a total volume of 350 ml, the mixture was filtered through a glass filter and the filtrate was allowed to stand for at least 20 minutes until 5% CL PAA hydrogel was formed.

EXAMPLE 4

Preparation of a low-concentration electroconductive biocompatible hydrogel

The CL PAA hydrogel was prepared as in Example 1, except the physiological solution was used instead of water.
 

Claim 1 of 18 Claims

1. Biocompatible hydrogel for placing endoprostheses by injection, containing cross-linked polyacrylamide produced by radical polymerization and pyrogen-free water, said cross-linked polyacrylamide constituting from 3.5 to 6.0% by weight based on the total weight of the hydrogel.

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