DE10026620A1 - Biocompatible material for cell and tissue implantation, useful e.g. for drug release or cosmetic tissue augmentation, consisting of spherical particles having (semi-)permeable or porous outer shell and internal cavity - Google Patents

Abstract

A biocompatible material (I) for cell and tissue implantation comprising non-resorbable, irregular or round, spherical particles or microspheres having a semi-permeable, permeable or porous outer shell and at least one internal cavity, is new. Alternatively, the outer shell may be compact, non-porous and non-permeable. The cavity may be absent if the particles or microspheres are porous; or the material may be resorbable.

Description

Particles for technical use or for use as medical Until now, implants were predominantly compact, irregularly shaped particles or round microspheres of low porosity, but without an internal cavity or wells.

These compact particles or microspheres tend to sediment in low viscosity solutions and even high viscosity solutions, either because of the Lack of porosity or because there is no internal cavity or due to one specific gravity of more than 1.0.

The product invention of the particles or microspheres - both names are usually used in the following description in the same sense - which ones by the porosity of the body or the shell and / or at least one inner Are marked, allows the use of aqueous solutions or non-aqueous solutions as a depot or transport vehicle with or without significant reduced concentration of viscous components, such as polymeric polysaccharides or Proteins with little or no sedimentation or migration.

The product invention, equipped with functional chemical groups on the Surface and the inner porous structure or on the inner cavity special cross-linked and non-cross-linked matrix-forming properties either in the Depot liquid or the transport liquid or at the place of use.

Some examples of the benefits include improved connective tissue formation, Improved migration of connective tissue cells into the implant or improved over life rates of connective tissue cells.

The pores and internal cavities of the particles and microspheres can be covered with a active connections. This does not expand the field of application active implants to active implants. Such implants can do more than one Contain active substance with radioactive or non-radioactive properties. For example the first active ingredient could be in the transport liquid, the second active ingredient in the porous Envelope, the third active ingredient can be placed in one or more internal cavities.

Another example of the multifactorial application is the Equip the surface of the particles with reactive points, especially with  Tumor cells and tissues react and accumulate specifically. After The antitumor agent is released or the antitumor effect becomes initiated.

Examples of active or reactive material that are outside or inside the Invented particles can be loaded are: cells, stem cells, immunoreactive Cells and components or epitopes, enzymes, proteins, peptides, viruses, Virus components, microorganisms and their components, DNA, RNA, vectors, Growth factors, growth inhibitors, antiviral, antimicrobial, radioactive Components of alpha, beta or gamma radiation, sensitizer or Reagents triggered, released, or activated by various types of external or internal means, such as chemical or biological reactions, physical pressure, Sound, ultrasound, electromagnetic fields or ionizing radiation.

Such combinations result in, for example, improved medical, bio chemical or analytical effects, or the immunological reaction more clearly aligned, or tissue, organ, or cellular immune tolerance becomes improved, as in the case of organ transplants or degenerative autoimmune Diseases.

By using internal cavities, with or without recesses on the outer surface of the particles or microspheres, with or without connecting channels through the non-porous or the porous shell, the product invention stops suitable depot or a suitable means of transport and protective vehicle, for simple or complex implantable sensors, microsensors, the biochemical and can measure other parameters, semiconductor devices, CPUs, bioreactor Systems, micromachines, signal transmitters, signal transmitters, signal receivers, energy pro donating or donating institutions u. Ä., for use in human, animal or vegetable organisms, microorganisms, exiracellular and intracellularly, e.g. B. mitochondria, nucleus, ribosomes, endoplastic reticulum, for technical, medical, terrestrial, maritime, atmospheric and space Applications.

The particle invention can also be used as a two- or three-dimensional carrier and Memory used by non-holographic and holographic information whether digitized or not. In combination with suitable depot Liquid, gel or matrix, or applied vacuum, can increase the shelf life of the Information is controlled or improved.

The four size categories related to the outer dimensions of the particles of this invention are as follows: 1. less than 0.1 microns, 2. 0.1-30 microns, 3. 30-1000 microns, 4.1.0 mm-100 mm

The volume of the internal cavity of the particles can be 0.001% to 99.9% of the Total volume of the particle or microspheres.  

Typical but not exclusive examples of the type of used Materials for the invented particles are: Organic or inorganic polymers or copolymers, organic or inorganic materials, metal, purified Cytoskeletons of unicellular algae and other organisms, materials with a density of 1.0 or less or greater than 1.0.

The different types of application, depending on the particle size intended effects and uses, z. B. vary from Injection, inhalation, spraying, swallowing, drinking, surgical or non-surgical Implantation or injection, up to wearing on the outside or in body pernähe.

This invention also relates to biocompatible product compositions for (soft tissue) tissue enlargement, for human or veterinary Applications. A few examples of human and veterinary Application are: plastic / aesthetic and reconstructive surgery, (stress) Incontinence, vesico-urethral reflux, incontinence, gastroenterological reflux er diseases, glottis surgery and vocal cord paralysis, the Product application, however, is not limited to the above examples. The Product is delivered to tissue primarily by injection, in conjunction with a biocompatible transport liquid that has a positive effect on the particles transport that has infeed and storage after infeed.

The location or location of the storage for the particles can be intradermal, subdermal, subcutaneous, under the mucous membrane, which is done intramuscularly, but is not limited to the above-mentioned tissue. The shape of the particles, regardless of the Surface structure can be round, spherical or irregular; the particles contain a cavity and have a porous or non-porous shell. The particles, as such, can also have semi-permeable and / or porous characteristics.

The product material can consist of natural or synthetic material, if such a product has a cavity within the regular order has irregular shaped particle coating.

For products that have no void inside the particle, this is Patent limited to particles that are semi-permeable and / or porous channels if such particles made of biocompatible materials, such as organic Plastics, glass, metals, ceramics or natural components are.

The particle size of the product depends on its surgical or not surgical application in humans or animals, that is, different Sizes needed for plastic / aesthetic and reconstructive surgery, such as for Stress incontinence, gastroenterological reflux and other diseases. The Size distribution is given in "1 micrometer" or larger. The products can  can also be used on a non-surgical basis, such as in the case of wound / Combustion covers.

The product composition with respect to the transport, supply liquid is depending on the specific part of the body in which the product is implanted. examples for Transport liquids are water, aqueous buffers, collagen (from humans or Animal), biofermented human collagen, hyaluronic acid (from animals, from plants or fermented), polysaccharides, PVP or natural / synthetic oils; without yourself to be limited to the above examples of transport liquids.

This patent is also valid for the mentioned particles, with an empty one internal cavity that can carry specifically developed (electronic) products. Such encapsulated (electronic / mechanical) products can be used to obtain specific local tissue characteristics from humans or animals.

This patent is also valid for the mentioned particles, which have an inner Have cavity, or particles that are porous / permeable, so that it is possible include specific active or inactive components to make these active or to have non-active components have a therapeutic effect on certain tissues. Examples of such tissue interactions could be the treatment of localized tumors, vascular diseases and neurological disorders. On another example is the use of the permeability / cavity of the product as a deliverer for certain active or inactive components in the Cavity and in the inner channels of the product are encapsulated to the particles as a (neuro) transmitter bridge for paralysis symptoms of certain Nerve strands or the spine.

The material from which the particles or microspheres are made can be special Have characteristics that make them sensitive to sound, ultrasound, magnetic fields, electric fields, microwaves, infrared, visible light, UV light, or electro magnetic fields and radiation with an even smaller wavelength react or with interact with them.

The reactivity to such fields can be used as frequency or Field strength-dependent vibrations of the particles at the implantation site around the to stimulate increased production of connective tissue, the increased breakdown of adipose tissue, an improvement or change in the appearance of Wrinkles, face and body shapes, or the stimulation or the other Influencing the function, activity or growth of nerve tissue. Or you can be used to control the release, release or reaction trigger loaded active or inactive components of the particles.

The U.K. Patent Application No. 2,227,176 to Easek et al. refers to one Microimplantation method for filling deep scars, asymmetrical "orbital floors "and superficial bone defects in procedures of reconstructive surgery,  by using microparticles of approx. 20 to 3,000 microns, which with a suitable physiological vehicle and a hypodermic needle and syringe can be injected at a predetermined location, such as the base of recessed Scars, under skin regions of depressions and below the perichondrium or Periosterum for surface irregularities of bones and cartilage. Textured Microparticles, including silicone, polytetrafluoroethylene, ceramics or other inert substances can be used. In cases where hard Substances are required, biocompatible materials, such as calcium salts, including hydroxyapatite or crystalline materials, biocompatible ceramic Fabrics, biocompatible metals such as stainless steel particles or glass are used. Suitable physiological vehicles, including table salt, various types of starch, Polysaccharides and organic oils or liquids have been suggested.

The U.S. U.S. Patent No. 4,803,075 to Wallace et al. refers to an injectable Implant composition for soft tissue enlargement, which consists of an aqueous Suspension of a special biocompatible, natural or synthetic polymer and a lubricant to increase the injectability of the biomaterial suspension improve.

The U.S. U.S. Patent No. 4,837,285 to Berg et al. refers to one Composition based on collagen for expansion and restoration of soft tissues, the collagen being in the form of resorbable matrix spheres, with a medium size of approximately 50 to 350 microns, with the collagen up to 10% of the volume of the balls.

The U.S. U.S. Patent No. 4,280,954 to Yannas et al. refers to one Composition for surgical applications based on collagen is formed by contacting collagen with a mucopolysaccharide Conditions under which they form a reaction product and then that Cross-link the reaction product covalently.

The U.S. Lim Patent No. 4,352,883 discloses a method Encapsulation of a core material, in the form of living tissue or individual Cells, by forming a capsule from polysaccharide glues that are gelled can be used to form a shape-retaining mass by surrounding it changes such as pH changes, or multivalent cations such as Calcium.

Namiki, "Use of Teflon Paste in Urinary Incontinence Report by Two Cases ", Urol. Int., Vol. 39, pp. 280-282, (1984), discloses the use of a Polytetrafluoroethylene paste injection in subdermal regions to urinary incontinence to treat.

Drobeck et al., "Histological observations of soft tissue reactions Implanted Polyapartite Particles and Discs of Hydroxyapatite, "Journal of Oral  Maxillofacial Surgery, Vol 42, pp. 143-149, (1984) describes the effect short-term and long-term hydroxy-ceramic implants on soft tissues that are subcutaneous were implanted in rats and subcutaneously and subperiostal in dogs. The invention consisted of implanted hydroxyapatite in different sizes and shapes for a period of seven days to six years to determine whether migration or / and inflammation occurred.

Misiek et al., Revealed in "Soft Tissue Response to Different Shapes Hydroxyapatite Particles ", Journal of Oral Maxillofacial Surgery, Vol. 42, pp 150-160, (1984) that implanting hydroxyapatite in the form of sharp-edged particles or round particles in soft tissues of the oral cavity pockets for an inflammatory reaction at the implantation site with both particle shapes. The particles weighed 0.5 each Grams. However, the inflammation resolved more quickly at the point where round hydroxyapatite particles were implanted.

Shimizu describes in "Subcutaneous tissue responses in rats to injection Fine Particles of Synthetic Hydroxyapatite Ceramic ", Biomedical Research, Vol. 9, No. 2, pp 95-111 (1989) that subcutaneous injections and tissue distribution of fine Hydroxyapatite particles from about 0.65 to a few in diameter Micron phagocytosed by macrophages in extremely early stages. in the Large particles with a diameter of several microns were not opposed phagocytized, but they were found by numerous macrophages and multinucleated Surround giant cells. It has also been observed that the small tissue reactions essentially a non-specific foreign body reaction to hydroxyapatite particles were without any cell or tissue damage.

R. A. Appel "The Artificial Urinary Sphincter and Periurethral Injections", Obsterios and Gynecolocgy Reoort Vol. 2, No. 3, pp. 334-342 (1990), is a review article that the different types of treatment for urethral sphincter weakness writes, including the use of injectable material such as Polytetra fluoroethylene micropolymer particles, approximately 4 to 100 microns in size with unre regular forms, with glycerin and polysorbate.

Another periurethral injectable consists of highly purified cattle skin collagen, which is cross-linked with gluteraldehyde and in phosphate-buffered salt solution is distributed.

Politano et al., "Periurethral Teflon Injection in Urinary Incontinence", The Journal of Urology, Vol 111, pp. 180-183 (1974) describes the use of a polytetrahydro flourethylene paste that is injected into the urethra and perurethral tissue to give volume to this tissue to restore urine control in women male and female patients with urinary incontinence.

Malizia et al., "Migration and granulomatous response after periurethral injection tion of Polytef (Teflon) ", Journal of the American Medical Association, Vol. 251, No.  24, pp. 3277-3281, June 22-29 (1984), describes that although patients with urine Successful incontinence through periurethral injection of polytetraflourethylene paste were treated, however one study found a migration of in continental animals Has polytetrafluoroethylene particles from the investigated site.

Claes et al., "Pulmonary Migration Following Periurethral Polytetrafluoroethylene Injection for Urinary Incontinence ", The Journal of Urology, Vol. 142, pp 821-2, (September 1989), confirms Malizia's investigation through the report on a case of clinically significant migration after periurethral injection of Polytetraflourethylene paste particles in the lungs.

Ersek et al., "Bioplastique: A Newly Obtained Copolymer Microparticles ver speaks durability for soft tissue expansion ", Plastic and Recontructive Surgery, Vol. 87, No. 4, pp. 693-702, (April 1991) describes the use of a two pha copolymer of fully polymerized and vulcanized Methylmethylpolysiloxane mixed with a "plasdone" hydrogel and applied to Lip cleft, deep scars due to chickenpox and deepening due to liposuction movements, forehead wrinkles, and soft tissue filling of thin lips. It was found that the two-phase copolymer particles, neither migrated nor resorbed by the body had been structured and had particle sizes of 100-600 microns.

Lemperle et al., "PMMA Microspheres for Intradermal Implantation: Part I. Animal Research ", Annals of Plastic Surgery, Vol. 26, No. 1, pp. 57-63, (1991) describes the Use of polymethylacrylate microspheres with a particle size of 10 to 63 Microns in diameter, which are used to correct small defects in the dermis, to treat wrinkles and acne scars.

Kresa et al., "Hydron Gel Implants in Vocal Cords," Otolaryngology Head and Neck Surgery, Vol. 98, No. 3, pp. 242-245 (March 1988) describes a method for Treatment of vocal cord correction if the glottis is not closed properly is present, which consists of a molded implant made of hydrophilic gel into the voice to introduce tapes that have previously dried to a glassy, hard consistency has been.

Hirano et al., "Transcutaneous Intrafold Injection for Unilateral Vocal Cord Para lysis: Funetional Results ", Ann. Otol. Rhinol. Laryngol., Vol. 99, pp. 598-604 (1990), describes the technique of transcutaneous "intraband" silicone injection for treatment of glottis incompetence caused by unilateral vocal cord paralysis. The Silicone injection becomes more local to the patient lying on his back Anesthetic administered with the needle inserted through the cricothyroid area becomes.

Hill et al., "Autologous Fat Injection for Vocal Cord Medialization in the Canine Larynx ", Laryngoscope, Vol. 101, pp. 344-348 (April 1991) describes the use of autologous fat as an alternative to Teflon collagen as an implant material  Vocal cord medialization, regarding its use as an alternative to one of non-autologous injectable vocal cord replenishment material.

Mikaelian et al., "Lipoinjection for Unilateral Vocal Cord Paralysis", Laryngoscope, Vol. 101, pp. 4654-68 (May 1991) describes that in the commonly used Vor way of injecting Teflon paste around the vocal power with one-sided voice Improving ligament paralysis has a number of disadvantages, including respiratory difficult due to excessive injection of Teflon and an unsatisfactory speech quality. This procedure of fat injection, where fat is usually from the abdomen removed from the cover, it seems to give the treated tape a soft mass borrow while allowing him to maintain his vibratory properties. The injected fat is an endogenous material that comes back when over-injected can be recovered.

Strasnick et al., "Transcutaneous Teflon® Injection for Unilateral Vocal Cord Paralysis: An Update ", Laryngoscope, Vol. 101, pp. 785-787 (July 1991), describes the Teflon injection to restore glottal competence in para cases lysing voice disorder.

The biocompatible material contains a matrix of soft, round, white spherical, finely separated particles made of biocompatible ceramic Material, close to each other or in contact with each other, for a scaffold or lattice for autogenous, three-dimensional, randomly arranged, non-scarring soft tissue growth at the enlargement site. The enlarging material can be distributed homogeneously, e.g. B. in a biocompatible, absorbable lubricious Gel carrier, e.g. B. includes a polysaccharide. This is for better transportation of the enlargement material when injected into the tissue where the magnification esser is desired. The enlargement material is particularly suitable for urine ladder sphincter enlargement, for the treatment of incontinence, for filling of voids in soft tissues to make soft tissue vesicles for which Treatment of unilateral vocal cord paralysis, and for breast implants. It can be in or injected or implanted under the skin.

Claims (26)

1. A biocompatible material for cell and tissue implantation, characterized in that the material consists of irregular or round, spherical particles or microspheres, essentially non-absorbable, with a semi-permeable, permeable or porous outer shell and one or more internal cavities. 2. The material according to claim 1, characterized in that its Composition from natural, metallic or synthetic material can consist of or of biological origin, especially the purified Cytoskeleton of unicellular algae or organisms. 3. The material according to claim 1 and 2, characterized in that its outer shell is compact, non-porous and not permeable. 4. The material according to one of claims 1, 2 and 3, characterized in that the particles or microspheres are porous but not a cavity contain. 5. The material according to any one of claims 1, 2, 3 and 4, characterized records that the inner cavity and / or the porous portions Volume of at least 0.001% to 99.9% of the total volume turn off. 6. The material according to any one of claims 1, 2, 3, 4 and 5, characterized records that the size of the particles and microspheres is 0.01 microns Is 100 mm. 7. The material according to any one of claims 1, 2, 3, 4, 5 and 6, characterized indicates that the material is absorbable. 8. The material according to any one of claims 1, 2, 3, 4, 5, 6 and 7, characterized indicates that the density of the material is between 0.2 and 8.0. 9. The material according to any one of claims 1, 2, 3, 4, 5, 7 and 8, characterized records that the material in sizes from more than 20 microns to 10 mm is used as tissue enlarging material. 10. The material according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8 and 9, thereby characterized that the outer surface of the material or the porous Material or the inner shell surface by covalent or not covalent bonds is altered, with one or more types molecular side chains that are able to with specific tissue or Connect to cell areas or to subcellular areas or with positive and / or negative, polar or non-polar groups  specific organic or non-organic substances. 11. The material according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, thereby characterized that the outer surface of the material or the porous Material or the inner surface of the envelope by covalent or not covalent bonds with crosslinking agents is changed with the Ability to cross-link either in the depot liquid, the transport liquid or at the application site. 12. The material according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11, thereby characterized that the material in combination with a depot transport or application liquid is used. 13. The material according to one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12, characterized in that the liquid consists of water, aqueous buffer or synthetic or natural polymers in aqueous solution, or from non - aqueous liquids, collagen (human or animal origin), biofermented human or animal collagen, Hyaluronic acid (of animal, fermented or vegetable origin), Polysaccharides, PVP or natural / synthetic oils. 14. The material according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 13, characterized in that the percentage volume of the particles in the Transport / application fluid varies between more than 0.0% to 100%. With 100% particles in the end product, there is no transport liquid. 15. The material according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14, characterized in that either the transport liquid, the Outer of the particles and microspheres or the inner pores and the Cavity with one or more active or inactive components is loaded, in particular with cells, cell components, stem cells, immunoreactive cells and components, epitopes, enzymes, proteins, Peptides, viruses, virus pieces, microorganisms and their pieces, DNA, RNA, vectors, growth factors, growth inhibitors, antiviral, antimicrobial radioactive components for alpha, beta or Gamma radiation, sensitizers. 16. The material according to claim 15, characterized in that the Release or activation of the reactive components by physical forces, biochemical reactions and electromagnetic Fields or radiation is triggered. 17. The material according to claim 16, characterized in that the material depending on the application site, with externally applied forces inter acts and is set in vibration, as by sound, ultrasound, magnet fields, electric fields, microwaves, infrared or other electromagnetic  Waves to increase the production of connective tissue or influence the breakdown of adipose tissue or nerve tissue functions, including the function of the acupuncture points. 18. The material according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14, characterized in that the inner space for encapsulation or Housing simple or complex devices is used, especially sensors, microsensors around biochemical or others Measuring parameters, microsurgical devices, semiconductor devices, CPUs, Bioreactor systems, micromachines, signal transmitters, signal receivers, energy producing and energy storage systems, or one Combination of these. 19. The material according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14, characterized in that it is used as a two-dimensional or three-dimensional carrier and storage system for implanted memory cherchips, non-holographic and holographic information, digitized or not digitized. Additional use of radical scavengers in one Liquid, a gel or a matrix, or vacuum extends the shelf life for the stored information. 20. The material according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14, characterized in that it is equipped with reactive sites, that attach to tumor lines and tissues to locate them and with Antitumor substances for tumor and cancer therapy are loaded. 21. The material according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14, characterized in that it has different application methods can be used, either with or without transport liquid, especially by injection, surgical or non-surgical Implantation or natural body openings, spraying, inhalation, Swallow, drink. 22. The material according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14, characterized in that it is combined with natural or synthetic components for external use is applied as a cosmetic product or as an active ingredient for cosmetic products. 23. The material according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14, characterized in that it is not used for medical devices will, however, for cosmetic body tissue enlargements. 24. The material according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14, characterized in that it is used for diagnostic purposes becomes. 25. The material according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and  14, characterized in that it is for human medicine and veterinary medical indications is used. 26. The material according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14, characterized in that it is used as an implant for intradermal, subder male, mucosal, subcutaneous or muscular disorders is used.